https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic2017-03-21T21:28:57.675Zjasonscottsnyderjasonscottsnyder@gmail.com1941https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cokwr2017-03-21T21:28:57.675Zstauthor: Noonan, year: 2010, journal: J Neurosci, title: Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction, behaviorexamined: addiction - cocaine self administration, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: decreased drug seeking, species: rat, abstract: Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cpzh42017-03-21T21:28:57.675Zstauthor: Noonan, year: 2010, journal: J Neurosci, title: Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction, behaviorexamined: addiction - extinction of cocaine self administration, remote, neurogenesismanipulation: irradiation (post-CSA), neurogenesisassociatedwith: decreased drug seeking, species: rat, abstract: Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cre1l2017-03-21T21:28:57.675Zstauthor: Noonan, year: 2010, journal: J Neurosci, title: Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction, behaviorexamined: addiction - extinction of cocaine self administration, remote, neurogenesismanipulation: irradiation (pre-CSA), neurogenesisassociatedwith: nothing, species: rat, abstract: Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/chk2m2017-03-21T21:28:57.675Zstauthor: Noonan, year: 2010, journal: J Neurosci, title: Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction, behaviorexamined: addiction - reinstatement of cocaine self administration, remote, neurogenesismanipulation: irradiation (post-CSA), neurogenesisassociatedwith: decreased drug seeking, species: rat, abstract: Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ciyn32017-03-21T21:28:57.675Zstauthor: Noonan, year: 2010, journal: J Neurosci, title: Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction, behaviorexamined: addiction - reinstatement of cocaine self administration, remote, neurogenesismanipulation: irradiation (pre-CSA), neurogenesisassociatedwith: nothing, species: rat, abstract: Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ckd7g2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - coat state, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/clrrx2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - coat state, neurogenesismanipulation: irradiation + UCMS + AVP antag, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cyevm2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - coat state, neurogenesismanipulation: irradiation + UCMS + CRF antag, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cztg32017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - coat state, neurogenesismanipulation: irradiation + UCMS, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/d180g2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - coat state, neurogenesismanipulation: irradiation + UCMS + flx, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/d2mkx2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - coat state, neurogenesismanipulation: irradiation + UCMS + imi, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cssly2017-03-21T21:28:57.675Zstauthor: Santarelli, year: 2003, journal: Science, title: Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants., behaviorexamined: depr / anxiety - coat state (after UCMS), neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cu76f2017-03-21T21:28:57.675Zstauthor: Santarelli, year: 2003, journal: Science, title: Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants., behaviorexamined: depr / anxiety - coat state (after UCMS), neurogenesismanipulation: irradiation + flx, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cvlqs2017-03-21T21:28:57.675Zstauthor: Shors, year: 2002, journal: Hippocampus, title: Neurogenesis may relate to some but not all types of hippocampal-dependent learning., behaviorexamined: depr / anxiety - elevated plus maze, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: rat, abstract: The hippocampal formation generates new neurons throughout adulthood. Recent studies indicate that these cells possess the morphology and physiological properties of more established neurons. However, the function of adult generated neurons is still a matter of debate. We previously demonstrated that certain forms of associative learning can enhance the survival of new neurons and a reduction in neurogenesis coincides with impaired learning of the hippocampal-dependent task of trace eyeblink conditioning. Using the toxin methylazoxymethanol acetate (MAM) for proliferating cells, we tested whether reduction of neurogenesis affected learning and performance associated with different hippocampal dependent tasks: spatial navigation learning in a Morris water maze, fear responses to context and an explicit cue after training with a trace fear paradigm. We also examined exploratory behavior in an elevated plus maze. Rats were injected with MAM (7 mg/kg) or saline for 14 days, concurrent with BrdU, to label new neurons on days 10, 12, and 14. After treatment, groups of rats were tested in the various tasks. A significant reduction in new neurons in the adult hippocampus was associated with impaired performance in some tasks, but not with others. Specifically, treatment with the antimitotic agent reduced the amount of fear acquired after exposure to a trace fear conditioning paradigm but did not affect contextual fear conditioning or spatial navigation learning in the Morris water maze. Nor did MAM treatment affect exploration in the elevated plus maze. These results combined with previous ones suggest that neurogenesis may be associated with the formation of some but not all types of hippocampal-dependent memories.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cx0b92017-03-21T21:28:57.675Zstauthor: Saxe, year: 2006, journal: Proc Natl Acad Sci U S A, title: Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus., behaviorexamined: depr / anxiety - elevated plus maze, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/d9ney2017-03-21T21:28:57.675Zstauthor: Jaholkowski, year: 2009, journal: Learn Mem, title: New hippocampal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning, behaviorexamined: depr / anxiety - elevated plus maze, neurogenesismanipulation: transgenic Cyclin D2, neurogenesisassociatedwith: nothing, species: mouse, abstract: The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs known for their side effects and the results obtained vary greatly. We used a novel approach, cyclin D2 knockout mice (D2 KO mice), specifically lacking adult brain neurogenesis to verify its importance in learning and memory. D2 KO mice and their wild-type siblings were tested in several behavioral paradigms, including those in which the role of adult neurogenesis has been postulated. D2 KO mice showed no impairment in sensorimotor tests, with only sensory impairment in an olfaction-dependent task. However, D2 KO mice showed proper procedural learning as well as learning in context (including remote memory), cue, and trace fear conditioning, Morris water maze, novel object recognition test, and in a multifunctional behavioral system-IntelliCages. D2 KO mice also demonstrated correct reversal learning. Our results suggest that adult brain neurogenesis is not obligatory in learning, including the kinds of learning where the role of adult neurogenesis has previously been strongly suggested.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/db1zf2017-03-21T21:28:57.675Zstauthor: Revest, year: 2009, journal: Mol Psychiatry, title: Adult hippocampal neurogenesis is involved in anxiety-related behaviors, behaviorexamined: depr / anxiety - elevated plus maze, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: Adult hippocampal neurogenesis is a unique example of structural plasticity, the functional role of which has been a matter of intense debate. New transgenic models have recently shown that neurogenesis participates in hippocampus-mediated learning. Here, we show that transgenic animals, in which adult hippocampal neurogenesis has been specifically impaired, exhibit a striking increase in anxiety-related behaviors. Our results indicate that neurogenesis plays an important role in the regulation of affective states and could be the target of new treatments for anxiety disorders.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dcgjs2017-03-21T21:28:57.675Zstauthor: Noonan, year: 2010, journal: J Neurosci, title: Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction, behaviorexamined: depr / anxiety - extinction of sucrose self administration, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ddv492017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/d415a2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: exog. MAM + UCMS, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/d5fpr2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: exog. MAM + UCMS + flx, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/d6ua42017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: exog. MAM + UCMS + imi, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/d88ul2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: exog. MAM + UCMS + CP156526, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dkvya2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: exog. MAM + UCMS + SSR149415, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dmair2017-03-21T21:28:57.675Zstauthor: Holick, year: 2008, journal: Neuropsychopharmacology, title: Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor., behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: We previously reported that chronic, but not subchronic, treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine altered behavior in the forced swimming test (FST) in BALB/cJ mice. We now use this model to investigate mechanisms underlying the delayed onset of the behavioral response to antidepressants, specifically (1) adult hippocampal neurogenesis and (2) expression of the 5-HT1A receptor. Here, we show data validating this model of chronic antidepressant action. We found the FST to be selectively responsive to chronic administration of the SSRI fluoxetine (18 mg/kg/day) and the tricyclic antidepressant desipramine (20 mg/kg/day), but not to the antipsychotic haloperidol (1 mg/kg/day) in BALB/cJ mice. The behavioral effects of fluoxetine emerged by 12 days of treatment, and were affected neither by ablation of progenitor cells of the hippocampus nor by genetic deletion of the 5-HT1A receptor. The effect of fluoxetine in the BALB/cJ mice was also neurogenesis-independent in the novelty-induced hypophagia test. We also found that chronic fluoxetine does not induce an increase in cell proliferation or the number of young neurons as measured by BrdU and doublecortin immunolabeling, respectively, in BALB/cJ mice. These data are in contrast to our previous report using a different strain of mice (129SvEvTac). In conclusion, we find that BALB/cJ mice show a robust response to chronic SSRI treatment in the FST, which is not mediated by an increase in new neurons in the hippocampus, and does not require the 5-HT1A receptor. These findings suggest that SSRIs can produce antidepressant-like effects via distinct mechanisms in different mouse strains.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dnp342017-03-21T21:28:57.675Zstauthor: Airan, year: 2007, journal: Science, title: High-speed imaging reveals neurophysiological links to behavior in an animal model of depression., behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: The hippocampus is one of several brain areas thought to play a central role in affective behaviors, but the underlying local network dynamics are not understood. We used quantitative voltage-sensitive dye imaging to probe hippocampal dynamics with millisecond resolution in brain slices after bidirectional modulation of affective state in rat models of depression. We found that a simple measure of real-time activity-stimulus-evoked percolation of activity through the dentate gyrus relative to the hippocampal output subfield-accounted for induced changes in animal behavior independent of the underlying mechanism of action of the treatments. Our results define a circuit-level neurophysiological endophenotype for affective behavior and suggest an approach to understanding circuit-level substrates underlying psychiatric disease symptoms.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dp3nl2017-03-21T21:28:57.675Zstauthor: Revest, year: 2009, journal: Mol Psychiatry, title: Adult hippocampal neurogenesis is involved in anxiety-related behaviors, behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: nothing, species: mouse, abstract: Adult hippocampal neurogenesis is a unique example of structural plasticity, the functional role of which has been a matter of intense debate. New transgenic models have recently shown that neurogenesis participates in hippocampus-mediated learning. Here, we show that transgenic animals, in which adult hippocampal neurogenesis has been specifically impaired, exhibit a striking increase in anxiety-related behaviors. Our results indicate that neurogenesis plays an important role in the regulation of affective states and could be the target of new treatments for anxiety disorders.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/df9om2017-03-21T21:28:57.675Zstauthor: David, year: 2009, journal: Neuron, title: Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression., behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: irradiation + chronic cort, neurogenesisassociatedwith: nothing, species: mouse, abstract: Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dgo932017-03-21T21:28:57.675Zstauthor: David, year: 2009, journal: Neuron, title: Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression., behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: irradiation + chronic cort + flx, neurogenesisassociatedwith: nothing, species: mouse, abstract: Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/di2tg2017-03-21T21:28:57.675Zstauthor: Jiang, year: 2005, journal: J Clin Invest., title: Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects, behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: irradiation + HU210 (cannabinoid), neurogenesisassociatedwith: reduced depr / anxiety, species: rat, abstract: The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible correlation with behavioral change. We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 receptors to regulate neurogenesis. This hypothesis is supported by further findings that HU210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal NS/PCs likely via a sequential activation of CB1 receptors, G(i/o) proteins, and ERK signaling. Chronic, but not acute, HU210 treatment promoted neurogenesis in the hippocampal dentate gyrus of adult rats and exerted anxiolytic- and antidepressant-like effects. X-irradiation of the hippocampus blocked both the neurogenic and behavioral effects of chronic HU210 treatment, suggesting that chronic HU210 treatment produces anxiolytic- and antidepressant-like effects likely via promotion of hippocampal neurogenesis.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/djhdx2017-03-21T21:28:57.675Zstauthor: Airan, year: 2007, journal: Science, title: High-speed imaging reveals neurophysiological links to behavior in an animal model of depression., behaviorexamined: depr / anxiety - forced swim test, neurogenesismanipulation: irradiation + flx, neurogenesisassociatedwith: reduced depr / anxiety, species: rat, abstract: The hippocampus is one of several brain areas thought to play a central role in affective behaviors, but the underlying local network dynamics are not understood. We used quantitative voltage-sensitive dye imaging to probe hippocampal dynamics with millisecond resolution in brain slices after bidirectional modulation of affective state in rat models of depression. We found that a simple measure of real-time activity-stimulus-evoked percolation of activity through the dentate gyrus relative to the hippocampal output subfield-accounted for induced changes in animal behavior independent of the underlying mechanism of action of the treatments. Our results define a circuit-level neurophysiological endophenotype for affective behavior and suggest an approach to understanding circuit-level substrates underlying psychiatric disease symptoms.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dw4je2017-03-21T21:28:57.675Zstauthor: Fuss, year: 2010, journal: PLoS ONE, title: Deletion of Running-Induced Hippocampal Neurogenesis by Irradiation Prevents Development of an Anxious Phenotype in Mice, behaviorexamined: depr / anxiety - light / dark test, neurogenesismanipulation: irradiation + running, neurogenesisassociatedwith: increased depr / anxiety, species: mouse, abstract: Recent evidence postulates a role of hippocampal neurogenesis in anxiety behavior. Here we report that elevated levels of neurogenesis elicit increased anxiety in rodents. Mice performing voluntary wheel running displayed both highly elevated levels of neurogenesis and increased anxiety in three different anxiety-like paradigms: the open field, elevated O-maze, and dark-light box. Reducing neurogenesis by focalized irradiation of the hippocampus abolished this exercise-induced increase of anxiety, suggesting a direct implication of hippocampal neurogenesis in this phenotype. On the other hand, irradiated mice explored less frequently the lit compartment of the dark-light box test irrespective of wheel running, suggesting that irradiation per se induced anxiety as well. Thus, our data suggest that intermediate levels of neurogenesis are related to the lowest levels of anxiety. Moreover, using c-Fos immunocytochemistry as cellular activity marker, we observed significantly different induction patterns between runners and sedentary controls when exposed to a strong anxiogenic stimulus. Again, this effect was altered by irradiation. In contrast, the well-known induction of brain-derived neurotrophic factor (BDNF) by voluntary exercise was not disrupted by focal irradiation, indicating that hippocampal BDNF levels were not correlated with anxiety under our experimental conditions. In summary, our data demonstrate to our knowledge for the first time that increased neurogenesis has a causative implication in the induction of anxietyhttps://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dxj3v2017-03-21T21:28:57.675Zstauthor: Saxe, year: 2006, journal: Proc Natl Acad Sci U S A, title: Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus., behaviorexamined: depr / anxiety - light / dark test, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dyxo82017-03-21T21:28:57.675Zstauthor: Revest, year: 2009, journal: Mol Psychiatry, title: Adult hippocampal neurogenesis is involved in anxiety-related behaviors, behaviorexamined: depr / anxiety - light / dark test, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: Adult hippocampal neurogenesis is a unique example of structural plasticity, the functional role of which has been a matter of intense debate. New transgenic models have recently shown that neurogenesis participates in hippocampus-mediated learning. Here, we show that transgenic animals, in which adult hippocampal neurogenesis has been specifically impaired, exhibit a striking increase in anxiety-related behaviors. Our results indicate that neurogenesis plays an important role in the regulation of affective states and could be the target of new treatments for anxiety disorders.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/e0c8p2017-03-21T21:28:57.675Zstauthor: Santarelli, year: 2003, journal: Science, title: Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dqi9q2017-03-21T21:28:57.675Zstauthor: Meshi, year: 2006, journal: Nat Neurosci, title: Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Environmental enrichment increases adult hippocampal neurogenesis and alters hippocampal-dependent behavior in rodents. To investigate a causal link between these two observations, we analyzed the effect of enrichment on spatial learning and anxiety-like behavior while blocking adult hippocampal neurogenesis. We report that environmental enrichment alters behavior in mice regardless of their hippocampal neurogenic capability, providing evidence that the newborn cells do not mediate these effects of enrichment.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/drwu72017-03-21T21:28:57.675Zstauthor: Meshi, year: 2006, journal: Nat Neurosci, title: Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation + EE, neurogenesisassociatedwith: nothing, species: mouse, abstract: Environmental enrichment increases adult hippocampal neurogenesis and alters hippocampal-dependent behavior in rodents. To investigate a causal link between these two observations, we analyzed the effect of enrichment on spatial learning and anxiety-like behavior while blocking adult hippocampal neurogenesis. We report that environmental enrichment alters behavior in mice regardless of their hippocampal neurogenic capability, providing evidence that the newborn cells do not mediate these effects of enrichment.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dtbek2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/dupz12017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation + UCMS + AVP antag, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/e7d2q2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation + UCMS + CRF antag, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/e8rn72017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation + UCMS + imi, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ea67k2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation + UCMS, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ebks12017-03-21T21:28:57.675Zstauthor: Revest, year: 2009, journal: Mol Psychiatry, title: Adult hippocampal neurogenesis is involved in anxiety-related behaviors, behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: nothing, species: mouse, abstract: Adult hippocampal neurogenesis is a unique example of structural plasticity, the functional role of which has been a matter of intense debate. New transgenic models have recently shown that neurogenesis participates in hippocampus-mediated learning. Here, we show that transgenic animals, in which adult hippocampal neurogenesis has been specifically impaired, exhibit a striking increase in anxiety-related behaviors. Our results indicate that neurogenesis plays an important role in the regulation of affective states and could be the target of new treatments for anxiety disorders.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/e1qt22017-03-21T21:28:57.675Zstauthor: David, year: 2009, journal: Neuron, title: Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation + chronic cort, neurogenesisassociatedwith: nothing, species: mouse, abstract: Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/e35dj2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: reduced depr / anxiety, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/e4jxw2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: exog. MAM + UCMS, neurogenesisassociatedwith: reduced depr / anxiety, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/e5yid2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: exog. MAM + UCMS + flx, neurogenesisassociatedwith: reduced depr / anxiety, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/eilm22017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: exog. MAM + UCMS + imi, neurogenesisassociatedwith: reduced depr / anxiety, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ek06j2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: exog. MAM + UCMS + CP156526, neurogenesisassociatedwith: reduced depr / anxiety, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/eleqw2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: exog. MAM + UCMS + SSR149415, neurogenesisassociatedwith: reduced depr / anxiety, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/emtbd2017-03-21T21:28:57.675Zstauthor: Jiang, year: 2005, journal: J Clin Invest., title: Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects, behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation + HU210 (cannabinoid), neurogenesisassociatedwith: reduced depr / anxiety, species: rat, abstract: The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible correlation with behavioral change. We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 receptors to regulate neurogenesis. This hypothesis is supported by further findings that HU210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal NS/PCs likely via a sequential activation of CB1 receptors, G(i/o) proteins, and ERK signaling. Chronic, but not acute, HU210 treatment promoted neurogenesis in the hippocampal dentate gyrus of adult rats and exerted anxiolytic- and antidepressant-like effects. X-irradiation of the hippocampus blocked both the neurogenic and behavioral effects of chronic HU210 treatment, suggesting that chronic HU210 treatment produces anxiolytic- and antidepressant-like effects likely via promotion of hippocampal neurogenesis.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/eczce2017-03-21T21:28:57.675Zstauthor: Santarelli, year: 2003, journal: Science, title: Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation + flx, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/eedwv2017-03-21T21:28:57.675Zstauthor: Santarelli, year: 2003, journal: Science, title: Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation + imi, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/efsh82017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation + UCMS + flx, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/eh71p2017-03-21T21:28:57.675Zstauthor: David, year: 2009, journal: Neuron, title: Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression., behaviorexamined: depr / anxiety - novelty suppressed feeding, neurogenesismanipulation: irradiation + chronic cort + flx, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/etu5e2017-03-21T21:28:57.675Zstauthor: Holick, year: 2008, journal: Neuropsychopharmacology, title: Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor., behaviorexamined: depr / anxiety - novelty-induced hypophagia, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: We previously reported that chronic, but not subchronic, treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine altered behavior in the forced swimming test (FST) in BALB/cJ mice. We now use this model to investigate mechanisms underlying the delayed onset of the behavioral response to antidepressants, specifically (1) adult hippocampal neurogenesis and (2) expression of the 5-HT1A receptor. Here, we show data validating this model of chronic antidepressant action. We found the FST to be selectively responsive to chronic administration of the SSRI fluoxetine (18 mg/kg/day) and the tricyclic antidepressant desipramine (20 mg/kg/day), but not to the antipsychotic haloperidol (1 mg/kg/day) in BALB/cJ mice. The behavioral effects of fluoxetine emerged by 12 days of treatment, and were affected neither by ablation of progenitor cells of the hippocampus nor by genetic deletion of the 5-HT1A receptor. The effect of fluoxetine in the BALB/cJ mice was also neurogenesis-independent in the novelty-induced hypophagia test. We also found that chronic fluoxetine does not induce an increase in cell proliferation or the number of young neurons as measured by BrdU and doublecortin immunolabeling, respectively, in BALB/cJ mice. These data are in contrast to our previous report using a different strain of mice (129SvEvTac). In conclusion, we find that BALB/cJ mice show a robust response to chronic SSRI treatment in the FST, which is not mediated by an increase in new neurons in the hippocampus, and does not require the 5-HT1A receptor. These findings suggest that SSRIs can produce antidepressant-like effects via distinct mechanisms in different mouse strains.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ev8pv2017-03-21T21:28:57.675Zstauthor: Fuss, year: 2010, journal: PLoS ONE, title: Deletion of Running-Induced Hippocampal Neurogenesis by Irradiation Prevents Development of an Anxious Phenotype in Mice, behaviorexamined: depr / anxiety - O maze, neurogenesismanipulation: irradiation + running, neurogenesisassociatedwith: increased depr / anxiety, species: mouse, abstract: Recent evidence postulates a role of hippocampal neurogenesis in anxiety behavior. Here we report that elevated levels of neurogenesis elicit increased anxiety in rodents. Mice performing voluntary wheel running displayed both highly elevated levels of neurogenesis and increased anxiety in three different anxiety-like paradigms: the open field, elevated O-maze, and dark-light box. Reducing neurogenesis by focalized irradiation of the hippocampus abolished this exercise-induced increase of anxiety, suggesting a direct implication of hippocampal neurogenesis in this phenotype. On the other hand, irradiated mice explored less frequently the lit compartment of the dark-light box test irrespective of wheel running, suggesting that irradiation per se induced anxiety as well. Thus, our data suggest that intermediate levels of neurogenesis are related to the lowest levels of anxiety. Moreover, using c-Fos immunocytochemistry as cellular activity marker, we observed significantly different induction patterns between runners and sedentary controls when exposed to a strong anxiogenic stimulus. Again, this effect was altered by irradiation. In contrast, the well-known induction of brain-derived neurotrophic factor (BDNF) by voluntary exercise was not disrupted by focal irradiation, indicating that hippocampal BDNF levels were not correlated with anxiety under our experimental conditions. In summary, our data demonstrate to our knowledge for the first time that increased neurogenesis has a causative implication in the induction of anxietyhttps://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ewna82017-03-21T21:28:57.675Zstauthor: Fuss, year: 2010, journal: PLoS ONE, title: Deletion of Running-Induced Hippocampal Neurogenesis by Irradiation Prevents Development of an Anxious Phenotype in Mice, behaviorexamined: depr / anxiety - open field, neurogenesismanipulation: irradiation + running, neurogenesisassociatedwith: increased depr / anxiety, species: mouse, abstract: Recent evidence postulates a role of hippocampal neurogenesis in anxiety behavior. Here we report that elevated levels of neurogenesis elicit increased anxiety in rodents. Mice performing voluntary wheel running displayed both highly elevated levels of neurogenesis and increased anxiety in three different anxiety-like paradigms: the open field, elevated O-maze, and dark-light box. Reducing neurogenesis by focalized irradiation of the hippocampus abolished this exercise-induced increase of anxiety, suggesting a direct implication of hippocampal neurogenesis in this phenotype. On the other hand, irradiated mice explored less frequently the lit compartment of the dark-light box test irrespective of wheel running, suggesting that irradiation per se induced anxiety as well. Thus, our data suggest that intermediate levels of neurogenesis are related to the lowest levels of anxiety. Moreover, using c-Fos immunocytochemistry as cellular activity marker, we observed significantly different induction patterns between runners and sedentary controls when exposed to a strong anxiogenic stimulus. Again, this effect was altered by irradiation. In contrast, the well-known induction of brain-derived neurotrophic factor (BDNF) by voluntary exercise was not disrupted by focal irradiation, indicating that hippocampal BDNF levels were not correlated with anxiety under our experimental conditions. In summary, our data demonstrate to our knowledge for the first time that increased neurogenesis has a causative implication in the induction of anxietyhttps://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ey1up2017-03-21T21:28:57.675Zstauthor: David, year: 2009, journal: Neuron, title: Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression., behaviorexamined: depr / anxiety - open field, neurogenesismanipulation: irradiation + chronic cort, neurogenesisassociatedwith: nothing, species: mouse, abstract: Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/eo7vq2017-03-21T21:28:57.675Zstauthor: David, year: 2009, journal: Neuron, title: Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression., behaviorexamined: depr / anxiety - open field, neurogenesismanipulation: irradiation + chronic cort + flx, neurogenesisassociatedwith: nothing, species: mouse, abstract: Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/epmg72017-03-21T21:28:57.675Zstauthor: Jaholkowski, year: 2009, journal: Learn Mem, title: New hippocampal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning, behaviorexamined: depr / anxiety - open field, neurogenesismanipulation: transgenic Cyclin D2, neurogenesisassociatedwith: nothing, species: mouse, abstract: The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs known for their side effects and the results obtained vary greatly. We used a novel approach, cyclin D2 knockout mice (D2 KO mice), specifically lacking adult brain neurogenesis to verify its importance in learning and memory. D2 KO mice and their wild-type siblings were tested in several behavioral paradigms, including those in which the role of adult neurogenesis has been postulated. D2 KO mice showed no impairment in sensorimotor tests, with only sensory impairment in an olfaction-dependent task. However, D2 KO mice showed proper procedural learning as well as learning in context (including remote memory), cue, and trace fear conditioning, Morris water maze, novel object recognition test, and in a multifunctional behavioral system-IntelliCages. D2 KO mice also demonstrated correct reversal learning. Our results suggest that adult brain neurogenesis is not obligatory in learning, including the kinds of learning where the role of adult neurogenesis has previously been strongly suggested.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/er10k2017-03-21T21:28:57.675Zstauthor: Revest, year: 2009, journal: Mol Psychiatry, title: Adult hippocampal neurogenesis is involved in anxiety-related behaviors, behaviorexamined: depr / anxiety - predator avoidance, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: Adult hippocampal neurogenesis is a unique example of structural plasticity, the functional role of which has been a matter of intense debate. New transgenic models have recently shown that neurogenesis participates in hippocampus-mediated learning. Here, we show that transgenic animals, in which adult hippocampal neurogenesis has been specifically impaired, exhibit a striking increase in anxiety-related behaviors. Our results indicate that neurogenesis plays an important role in the regulation of affective states and could be the target of new treatments for anxiety disorders.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/esfl12017-03-21T21:28:57.675Zstauthor: Noonan, year: 2010, journal: J Neurosci, title: Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction, behaviorexamined: depr / anxiety - reinstatement of sucrose self administration, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/a59y22017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - splash test, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/a6oij2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - splash test, neurogenesismanipulation: irradiation + UCMS + AVP antag, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/a832w2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - splash test, neurogenesismanipulation: irradiation + UCMS + CRF antag, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/a9hnd2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - splash test, neurogenesismanipulation: irradiation + UCMS, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/9znoe2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - splash test, neurogenesismanipulation: irradiation + UCMS + flx, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/a128v2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: depr / anxiety - splash test, neurogenesismanipulation: irradiation + UCMS + imi, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/a2gt82017-03-21T21:28:57.675Zstauthor: Santarelli, year: 2003, journal: Science, title: Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants., behaviorexamined: depr / anxiety - splash test (after UCMS), neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/a3vdp2017-03-21T21:28:57.675Zstauthor: Santarelli, year: 2003, journal: Science, title: Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants., behaviorexamined: depr / anxiety - splash test (after UCMS), neurogenesismanipulation: irradiation + flx, neurogenesisassociatedwith: reduced depr / anxiety, species: mouse, abstract: Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/agihe2017-03-21T21:28:57.675Zstauthor: Jayatissa, year: 2009, journal: Brain Res, title: Decreased cell proliferation in the dentate gyrus does not associate with development of anhedonic-like symptoms in rats., behaviorexamined: depr / anxiety - sucrose consumption, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: rat, abstract: Depressive disorders have been proposed to be caused by stress-induced down-regulation of hippocampal neurogenesis. Nevertheless, several reports have recently pointed out that, in rodent models of depression, suppression of generation of new hippocampal neurons is not by itself sufficient to induce the development of depression-related symptoms. In the present study, we used the cell proliferation blocker methylazoxymethanol (MAM) and the rat chronic mild stress (CMS) model of depression to challenge the neurogenic theory of depression. In order to achieve a comparable reduction in hippocampal cytogenesis, rats were either chronically treated with MAM for 2 weeks, or subjected to an 8 week regime of chronic mild stress. Consumption of a palatable sucrose solution was monitored once a week to assess the development of anhedonic behavior. Prior to terminal perfusion, the animals were injected with bromodeoxyuridine, a marker of proliferating cells. The number of proliferating cells and total cell number and volume were estimated for the granule cell layer of the ventral hippocampal formation. Unlike CMS, chronic injections with MAM did not induce anhedonia-like symptoms in rats. Both MAM-treated and CMS-exposed groups of rats showed a comparable significant reduction in cell proliferation in the granular cell layer of the ventral hippocampal formation. However, the total cell number was reduced for CMS-exposed rats only while the granule cell layer volume was conserved for both groups. Our results show that suppression of cell proliferation in the hippocampal formation is not an absolute factor for induction of an anhedonia-like state in rats. However, it may still represent an important causal factor for vulnerable subjects.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ahx1v2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - sucrose preference, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ajbm82017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - sucrose preference, neurogenesismanipulation: exog. MAM + UCMS, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/akq6p2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - sucrose preference, neurogenesismanipulation: exog. MAM + UCMS + flx, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/aaw7q2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - sucrose preference, neurogenesismanipulation: exog. MAM + UCMS + imi, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/acas72017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - sucrose preference, neurogenesismanipulation: exog. MAM + UCMS + CP156526, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/adpck2017-03-21T21:28:57.675Zstauthor: Bessa, year: 2009, journal: Mol Psychiatry, title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, behaviorexamined: depr / anxiety - sucrose preference, neurogenesismanipulation: exog. MAM + UCMS + SSR149415, neurogenesisassociatedwith: nothing, species: rat, abstract: The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/af3x12017-03-21T21:28:57.675Zstauthor: Noonan, year: 2010, journal: J Neurosci, title: Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction, behaviorexamined: depr / anxiety - sucrose self administration, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/arr0q2017-03-21T21:28:57.675Zstauthor: Singer, year: 2009, journal: J Comp Neurol, title: Conditional ablation and recovery of forebrain neurogenesis in the mouse., behaviorexamined: depr / anxiety - tail suspension, neurogenesismanipulation: transgenic nestin-tk + imi, neurogenesisassociatedwith: nothing, species: mouse, abstract: Forebrain neurogenesis persists throughout life in the rodent subventricular zone (SVZ) and hippocampal dentate gyrus (DG). Several strategies have been employed to eliminate adult neurogenesis and thereby determine whether depleting adult-born neurons disrupts specific brain functions, but some approaches do not specifically target neural progenitors. We have developed a transgenic mouse line to reversibly ablate adult neural stem cells and suppress neurogenesis. The nestin-tk mouse expresses herpes simplex virus thymidine kinase (tk) under the control of the nestin 2nd intronic enhancer, which drives expression in neural progenitors. Administration of ganciclovir (GCV) kills actively dividing cells expressing this transgene. We found that peripheral GCV administration suppressed SVZ-olfactory bulb and DG neurogenesis within 2 weeks but caused systemic toxicity. Intracerebroventricular GCV infusion for 28 days nearly completely depleted proliferating cells and immature neurons in both the SVZ and DG without systemic toxicity. Reversibility of the effects after prolonged GCV infusion was slow and partial. Neurogenesis did not recover 2 weeks after cessation of GCV administration, but showed limited recovery 6 weeks after GCV that differed between the SVZ and DG. Suppression of neurogenesis did not inhibit antidepressant responsiveness of mice in the tail suspension test. These findings indicate that SVZ and DG neural stem cells differ in their capacity for repopulation, and that adult-born neurons are not required for antidepressant responses in a common behavioral test of antidepressant efficacy. The nestin-tk mouse should be useful for studying how reversible depletion of adult neurogenesis influences neurophysiology, other behaviors, and neural progenitor dynamics.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/at5l72017-03-21T21:28:57.675Zstauthor: Shors, year: 2002, journal: Hippocampus, title: Neurogenesis may relate to some but not all types of hippocampal-dependent learning., behaviorexamined: locomotion, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: rat, abstract: The hippocampal formation generates new neurons throughout adulthood. Recent studies indicate that these cells possess the morphology and physiological properties of more established neurons. However, the function of adult generated neurons is still a matter of debate. We previously demonstrated that certain forms of associative learning can enhance the survival of new neurons and a reduction in neurogenesis coincides with impaired learning of the hippocampal-dependent task of trace eyeblink conditioning. Using the toxin methylazoxymethanol acetate (MAM) for proliferating cells, we tested whether reduction of neurogenesis affected learning and performance associated with different hippocampal dependent tasks: spatial navigation learning in a Morris water maze, fear responses to context and an explicit cue after training with a trace fear paradigm. We also examined exploratory behavior in an elevated plus maze. Rats were injected with MAM (7 mg/kg) or saline for 14 days, concurrent with BrdU, to label new neurons on days 10, 12, and 14. After treatment, groups of rats were tested in the various tasks. A significant reduction in new neurons in the adult hippocampus was associated with impaired performance in some tasks, but not with others. Specifically, treatment with the antimitotic agent reduced the amount of fear acquired after exposure to a trace fear conditioning paradigm but did not affect contextual fear conditioning or spatial navigation learning in the Morris water maze. Nor did MAM treatment affect exploration in the elevated plus maze. These results combined with previous ones suggest that neurogenesis may be associated with the formation of some but not all types of hippocampal-dependent memories.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/auk5k2017-03-21T21:28:57.675Zstauthor: Madsen, year: 2003, journal: Neuroscience, title: Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat., behaviorexamined: locomotion, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: The generation of new neurons in the adult mammalian brain has been documented in numerous recent reports. Studies undertaken so far indicate that adult hippocampal neurogenesis is related in a number of ways to hippocampal function.Here, we report that subjecting adult rats to fractionated brain irradiation blocked the formation of new neurons in the dentate gyrus of the hippocampus. At different time points after the termination of the irradiation procedure, the animals were tested in two tests of short-term memory that differ with respect to their dependence on hippocampal function. Eight and 21 days after irradiation, the animals with blocked neurogenesis performed poorer than controls in a hippocampus-dependent place-recognition task, indicating that the presence of newly generated neurons may be necessary for the normal function of this brain area. The animals were never impaired in a hippocampus-independent object-recognition task. These results are in line with other reports documenting the functional significance of newly generated neurons in this region. As our irradiation procedure models prophylactic cranial irradiation used in the treatment of different cancers, we suggest that blocked neurogenesis contributes to the reported deleterious side effects of this treatment, consisting of memory impairment, dysphoria and lethargy.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/avyq12017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: locomotion, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/am4r22017-03-21T21:28:57.675Zstauthor: Dupret, year: 2008, journal: PLoS One, title: Spatial relational memory requires hippocampal adult neurogenesis., behaviorexamined: locomotion, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: nothing, species: mouse, abstract: The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/anjbj2017-03-21T21:28:57.675Zstauthor: Ko, year: 2009, journal: Mol Brain, title: Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory., behaviorexamined: locomotion, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: mouse, abstract: ABSTRACT: Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/aoxvw2017-03-21T21:28:57.675Zstauthor: Ko, year: 2009, journal: Mol Brain, title: Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory., behaviorexamined: locomotion, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: ABSTRACT: Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/aqcgd2017-03-21T21:28:57.675Zstauthor: Ko, year: 2009, journal: Mol Brain, title: Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory., behaviorexamined: locomotion, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: ABSTRACT: Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/b2zk22017-03-21T21:28:57.675Zstauthor: Noonan, year: 2010, journal: J Neurosci, title: Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction, behaviorexamined: locomotion, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/b4e4j2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: locomotion (after UCMS), neurogenesismanipulation: irradiation + UCMS + AVP antag, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/b5sow2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: locomotion (after UCMS), neurogenesismanipulation: irradiation + UCMS + CRF antag, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/b779d2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: locomotion (after UCMS), neurogenesismanipulation: irradiation + UCMS + flx, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/axdae2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: locomotion (after UCMS), neurogenesismanipulation: irradiation + UCMS + imi, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ayruv2017-03-21T21:28:57.675Zstauthor: Surget, year: 2008, journal: Biol Psychiatry, title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal., behaviorexamined: locomotion (after UCMS), neurogenesismanipulation: irradiation + UCMS, neurogenesisassociatedwith: nothing, species: mouse, abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/b06f82017-03-21T21:28:57.675Zstauthor: Fuss, year: 2010, journal: PLoS ONE, title: Deletion of Running-Induced Hippocampal Neurogenesis by Irradiation Prevents Development of an Anxious Phenotype in Mice, behaviorexamined: locomotion (running), neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Recent evidence postulates a role of hippocampal neurogenesis in anxiety behavior. Here we report that elevated levels of neurogenesis elicit increased anxiety in rodents. Mice performing voluntary wheel running displayed both highly elevated levels of neurogenesis and increased anxiety in three different anxiety-like paradigms: the open field, elevated O-maze, and dark-light box. Reducing neurogenesis by focalized irradiation of the hippocampus abolished this exercise-induced increase of anxiety, suggesting a direct implication of hippocampal neurogenesis in this phenotype. On the other hand, irradiated mice explored less frequently the lit compartment of the dark-light box test irrespective of wheel running, suggesting that irradiation per se induced anxiety as well. Thus, our data suggest that intermediate levels of neurogenesis are related to the lowest levels of anxiety. Moreover, using c-Fos immunocytochemistry as cellular activity marker, we observed significantly different induction patterns between runners and sedentary controls when exposed to a strong anxiogenic stimulus. Again, this effect was altered by irradiation. In contrast, the well-known induction of brain-derived neurotrophic factor (BDNF) by voluntary exercise was not disrupted by focal irradiation, indicating that hippocampal BDNF levels were not correlated with anxiety under our experimental conditions. In summary, our data demonstrate to our knowledge for the first time that increased neurogenesis has a causative implication in the induction of anxietyhttps://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/b1kzp2017-03-21T21:28:57.675Zstauthor: Wong-Goodrich, year: 2010, journal: Cancer Res, title: Voluntary running prevents progressive memory decline and increases adult hippocampal neurogenesis and growth factor expression after whole-brain irradiation, behaviorexamined: locomotion (running), neurogenesismanipulation: irradiation, neurogenesisassociatedwith: reduced running, species: mouse, abstract: Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to 4 months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting 1 month after sham or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdUrd) immunolabeling and enzyme-linked immunosorbent assay indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdUrd+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor-1, and occurred despite irradiation-induced elevations in hippocampal proinflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/be8562017-03-21T21:28:57.675Zstauthor: Imayoshi, year: 2008, journal: Nat Neurosci, title: Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain., behaviorexamined: memory - Barnes maze, 7d, neurogenesismanipulation: transgenic Nestin Cre-ER DTA, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Neurogenesis occurs continuously in the forebrain of adult mammals, but the functional importance of adult neurogenesis is still unclear. Here, using a genetic labeling method in adult mice, we found that continuous neurogenesis results in the replacement of the majority of granule neurons in the olfactory bulb and a substantial addition of granule neurons to the hippocampal dentate gyrus. Genetic ablation of newly formed neurons in adult mice led to a gradual decrease in the number of granule cells in the olfactory bulb, inhibition of increases in the granule cell number in the dentate gyrus and impairment of behaviors in contextual and spatial memory, which are known to depend on hippocampus. These results suggest that continuous neurogenesis is required for the maintenance and reorganization of the whole interneuron system in the olfactory bulb, the modulation and refinement of the existing neuronal circuits in the dentate gyrus and the normal behaviors involved in hippocampal-dependent memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bfmpn2017-03-21T21:28:57.675Zstauthor: Wong-Goodrich, year: 2010, journal: Cancer Res, title: Voluntary running prevents progressive memory decline and increases adult hippocampal neurogenesis and growth factor expression after whole-brain irradiation, behaviorexamined: memory - Barnes maze, acquisition, neurogenesismanipulation: irradiation-early, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to 4 months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting 1 month after sham or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdUrd) immunolabeling and enzyme-linked immunosorbent assay indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdUrd+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor-1, and occurred despite irradiation-induced elevations in hippocampal proinflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bh1a02017-03-21T21:28:57.675Zstauthor: Wong-Goodrich, year: 2010, journal: Cancer Res, title: Voluntary running prevents progressive memory decline and increases adult hippocampal neurogenesis and growth factor expression after whole-brain irradiation, behaviorexamined: memory - Barnes maze, acquisition, neurogenesismanipulation: irradiation-late, neurogenesisassociatedwith: nothing, species: mouse, abstract: Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to 4 months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting 1 month after sham or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdUrd) immunolabeling and enzyme-linked immunosorbent assay indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdUrd+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor-1, and occurred despite irradiation-induced elevations in hippocampal proinflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bifuh2017-03-21T21:28:57.675Zstauthor: Wong-Goodrich, year: 2010, journal: Cancer Res, title: Voluntary running prevents progressive memory decline and increases adult hippocampal neurogenesis and growth factor expression after whole-brain irradiation, behaviorexamined: memory - Barnes maze, recent, neurogenesismanipulation: irradiation-late, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to 4 months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting 1 month after sham or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdUrd) immunolabeling and enzyme-linked immunosorbent assay indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdUrd+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor-1, and occurred despite irradiation-induced elevations in hippocampal proinflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/b8lvi2017-03-21T21:28:57.675Zstauthor: Imayoshi, year: 2008, journal: Nat Neurosci, title: Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain., behaviorexamined: memory - Barnes maze, recent, neurogenesismanipulation: transgenic Nestin Cre-ER DTA, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Neurogenesis occurs continuously in the forebrain of adult mammals, but the functional importance of adult neurogenesis is still unclear. Here, using a genetic labeling method in adult mice, we found that continuous neurogenesis results in the replacement of the majority of granule neurons in the olfactory bulb and a substantial addition of granule neurons to the hippocampal dentate gyrus. Genetic ablation of newly formed neurons in adult mice led to a gradual decrease in the number of granule cells in the olfactory bulb, inhibition of increases in the granule cell number in the dentate gyrus and impairment of behaviors in contextual and spatial memory, which are known to depend on hippocampus. These results suggest that continuous neurogenesis is required for the maintenance and reorganization of the whole interneuron system in the olfactory bulb, the modulation and refinement of the existing neuronal circuits in the dentate gyrus and the normal behaviors involved in hippocampal-dependent memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ba0fz2017-03-21T21:28:57.675Zstauthor: Wong-Goodrich, year: 2010, journal: Cancer Res, title: Voluntary running prevents progressive memory decline and increases adult hippocampal neurogenesis and growth factor expression after whole-brain irradiation, behaviorexamined: memory - Barnes maze, recent, neurogenesismanipulation: irradiation-late + running, neurogenesisassociatedwith: nothing, species: mouse, abstract: Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to 4 months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting 1 month after sham or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdUrd) immunolabeling and enzyme-linked immunosorbent assay indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdUrd+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor-1, and occurred despite irradiation-induced elevations in hippocampal proinflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bbf0c2017-03-21T21:28:57.675Zstauthor: Wong-Goodrich, year: 2010, journal: Cancer Res, title: Voluntary running prevents progressive memory decline and increases adult hippocampal neurogenesis and growth factor expression after whole-brain irradiation, behaviorexamined: memory - Barnes maze, recent, neurogenesismanipulation: irradiation-early, neurogenesisassociatedwith: nothing, species: mouse, abstract: Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to 4 months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting 1 month after sham or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdUrd) immunolabeling and enzyme-linked immunosorbent assay indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdUrd+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor-1, and occurred despite irradiation-induced elevations in hippocampal proinflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bctkt2017-03-21T21:28:57.675Zstauthor: Tronel, year: 2010, journal: Hippocampus, title: Adult-born neurons are necessary for extended contextual discrimination, behaviorexamined: memory - contextual fear discrimination, extended, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: New neurons are continuously produced in the adult dentate gyrus of the hippocampus. It has been shown that one of the functions of adult neurogenesis is to support spatial pattern separation, a process that transforms similar memories into nonoverlapping representations. This prompted us to investigate whether adult-born neurons are required for discriminating two contexts, i.e., for identifying a familiar environment and detect any changes introduced in it. We show that depleting adult-born neurons impairs the animal's ability to disambiguate two contexts after extensive training. These data suggest that the continuous production of new dentate neurons plays a crucial role in extracting and separating efficiently contextual representation in order to discriminate features within events.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bpgoi2017-03-21T21:28:57.675Zstauthor: Tronel, year: 2010, journal: Hippocampus, title: Adult-born neurons are necessary for extended contextual discrimination, behaviorexamined: memory - contextual fear discrimination, recent, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: nothing, species: mouse, abstract: New neurons are continuously produced in the adult dentate gyrus of the hippocampus. It has been shown that one of the functions of adult neurogenesis is to support spatial pattern separation, a process that transforms similar memories into nonoverlapping representations. This prompted us to investigate whether adult-born neurons are required for discriminating two contexts, i.e., for identifying a familiar environment and detect any changes introduced in it. We show that depleting adult-born neurons impairs the animal's ability to disambiguate two contexts after extensive training. These data suggest that the continuous production of new dentate neurons plays a crucial role in extracting and separating efficiently contextual representation in order to discriminate features within events.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bqv8z2017-03-21T21:28:57.675Zstauthor: Kitamura, year: 2009, journal: Cell, title: Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory., behaviorexamined: memory - contextual fear, 7d, neurogenesismanipulation: running, neurogenesisassociatedwith: reduced hipp dependence, species: mouse, abstract: Acquired memory initially depends on the hippocampus (HPC) for the process of cortical permanent memory formation. The mechanisms through which memory becomes progressively independent from the HPC remain unknown. In the HPC, adult neurogenesis has been described in many mammalian species, even at old ages. Using two mouse models in which hippocampal neurogenesis is physically or genetically suppressed, we show that decreased neurogenesis is accompanied by a prolonged HPC-dependent period of associative fear memory. Inversely, enhanced neurogenesis by voluntary exercise sped up the decay rate of HPC dependency of memory, without loss of memory. Consistently, decreased neurogenesis facilitated the long-lasting maintenance of rat hippocampal long-term potentiation in vivo. These independent lines of evidence strongly suggest that the level of hippocampal neurogenesis play a role in determination of the HPC-dependent period of memory in adult rodents. These observations provide a framework for understanding the mechanisms of the hippocampal-cortical complementary learning systems.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bs9tc2017-03-21T21:28:57.675Zstauthor: Winocur, year: 2006, journal: Hippocampus, title: Inhibition of neurogenesis interferes with hippocampus-dependent memory function., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: Rats treated with low dose irradiation, to inhibit adult hippocampal neurogenesis, and control rats were administered a non-matching-to-sample (NMTS) task, which measured conditional rule learning and memory for specific events, and a test of fear conditioning in which a discrete CS was paired with an aversive US in a complex environment. Irradiated rats were impaired on the NMTS task when the intervals between sample and test trials were relatively long, and in associating the shock-induced fear with contextual cues in the fear conditioning task. Irradiated rats were not impaired in learning the basic NMTS rule or in performing that task when the intervals between the sample and test trials were short. Nor were there group differences in conditioning the fear response to the CS in the fear conditioning task. The results, which extend the range of hippocampus-dependent tasks that can be said to be vulnerable to the effects of neurogenesis suppression, support the hypothesis that new hippocampal cells generated in adulthood participate in a broad range of hippocampal functions.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/btodt2017-03-21T21:28:57.675Zstauthor: Saxe, year: 2006, journal: Proc Natl Acad Sci U S A, title: Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bjueu2017-03-21T21:28:57.675Zstauthor: Saxe, year: 2006, journal: Proc Natl Acad Sci U S A, title: Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: transgenic GFAP-tk, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bl8zb2017-03-21T21:28:57.675Zstauthor: Warner-Schmidt, year: 2008, journal: Eur J Neurosci, title: Electroconvulsive seizure restores neurogenesis and hippocampus-dependent fear memory after disruption by irradiation, behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: Ongoing neurogenesis in the adult hippocampus is thought to play a role in learning and memory processes, and in response to antidepressant treatments. Low doses of irradiation (IRR) produce a significant long-lasting inhibitory effect on hippocampal neurogenesis that correlates with long-lasting behavioral deficits. Here we report that electroconvulsive seizure (ECS), which robustly increases adult neurogenesis in naïve animals, also reverses the disruption of neurogenesis produced by IRR exposure. Moreover, we find that vascular endothelial growth factor (VEGF) is an essential mediator of this effect. Expression of VEGF in the granule cell layer (GCL) of the hippocampus is decreased by IRR, and ECS administration reverses this deficit in VEGF. There is a corresponding alteration in the number of endothelial cells, which express VEGF, in the hippocampal GCL following IRR and ECS. We also find that blockade of VEGF signaling attenuates ECS-induced proliferation, and VEGF infusion partially restores proliferation in irradiated animals. To examine the functional consequences of IRR and ECS on neurogenesis, hippocampus-dependent contextual fear conditioning was assessed. We found that following disruption by IRR, ECS restores contextual learning to baseline levels at time points consistent with its effects on neurogenesis. These findings demonstrate that ECS, in part via induction of VEGF, can reverse long-term neurogenesis deficits resulting from IRR, and that these effects have functional consequences on hippocampus-dependent fear memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bmnjo2017-03-21T21:28:57.675Zstauthor: Wojtowicz, year: 2008, journal: Eur J Neurosci, title: The effects of running and of inhibiting adult neurogenesis on learning and memory in rats, behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: The presence of ongoing adult neurogenesis within the highly plastic hippocampal circuitry poses questions as to the relevance of new neurons to learning and memory. Correlational and causal evidence suggests that some, but not all, hippocampal tasks involve the new neurons. The evidence with regard to spatial learning in the water maze, one of the most commonly used hippocampal tasks, is contradictory. In this study we examined the effects of irradiation-induced reduction in neurogenesis on spatial learning and another standard hippocampal task, contextual fear conditioning, in rats that experienced normal cage conditions or voluntary running. The results indicate that reduced neurogenesis had little effect on spatial learning but severely impaired contextual fear conditioning. It was suggested that compensatory mechanisms within the hippocampus may have contributed selectively to sparing of spatial function. Performance on the fear conditioning task was weakly related to enhanced neurogenesis or running. The results improve our understanding of the functional role of adult neurogenesis in behaving animals.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bo2452017-03-21T21:28:57.675Zstauthor: Imayoshi, year: 2008, journal: Nat Neurosci, title: Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: transgenic Nestin Cre-ER DTA, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Neurogenesis occurs continuously in the forebrain of adult mammals, but the functional importance of adult neurogenesis is still unclear. Here, using a genetic labeling method in adult mice, we found that continuous neurogenesis results in the replacement of the majority of granule neurons in the olfactory bulb and a substantial addition of granule neurons to the hippocampal dentate gyrus. Genetic ablation of newly formed neurons in adult mice led to a gradual decrease in the number of granule cells in the olfactory bulb, inhibition of increases in the granule cell number in the dentate gyrus and impairment of behaviors in contextual and spatial memory, which are known to depend on hippocampus. These results suggest that continuous neurogenesis is required for the maintenance and reorganization of the whole interneuron system in the olfactory bulb, the modulation and refinement of the existing neuronal circuits in the dentate gyrus and the normal behaviors involved in hippocampal-dependent memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/c0p7u2017-03-21T21:28:57.675Zstauthor: Hernandez-Rabaza, year: 2009, journal: Neuroscience, title: Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: Neurogenesis in the adult dentate gyrus (DG) of the hippocampus has been implicated in neural plasticity and cognition but the specific functions contributed by adult-born neurons remain controversial. Here, we have explored the relationship between adult hippocampal neurogenesis and memory function using tasks which specifically require the participation of the DG. In two separate experiments several groups of rats were exposed to fractionated ionizing radiation (two sessions of 7 Gy each on consecutive days) applied either to the whole brain or focally, aiming at a region overlying the hippocampus. The immunocytochemical assays showed that the radiation significantly reduced the expression of doublecortin (DCX), a marker for immature neurons, in the dorsal DG. Ultrastructural examination of the DG region revealed disruption of progenitor cell niches several weeks after the radiation. In the first experiment, whole-brain and focal irradiation reduced DCX expression by 68% and 43%, respectively. Whole-brain and focally-irradiated rats were unimpaired compared with control rats in a matching-to-place (MTP) working memory task performed in the T-maze and in the long-term retention of the no-alternation rule. In the second experiment, focal irradiation reduced DCX expression by 36% but did not impair performance on (1) a standard non-matching-to-place (NMTP) task, (2) a more demanding NMTP task with increasingly longer within-trial delays, (3) a long-term retention test of the alternation rule and (4) a spatial reversal task. However, rats irradiated focally showed clear deficits in a "purely" contextual fear-conditioning task at short and long retention intervals. These data demonstrate that reduced adult hippocampal neurogenesis produces marked deficits in the rapid acquisition of emotionally relevant contextual information but spares spatial working memory function, the long-term retention of acquired spatial rules and the ability to flexibly modify learned spatial strategies.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/c23sb2017-03-21T21:28:57.675Zstauthor: Elbeltagy, year: 2009, journal: Behav Brain Res, title: Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: exog. 5-Fluorouracil, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: Cancer patients who have been treated with systemic adjuvant chemotherapy have described experiencing deteriorations in cognition. A widely used chemotherapeutic agent, 5-fluorouracil (5-FU), readily crosses the blood-brain barrier and so could have a direct effect on brain function. In particular this anti mitotic drug could reduce cell proliferation in the neurogenic regions of the adult brain. In contrast reports indicate that hippocampal dependent neurogenesis and cognition are enhanced by the SSRI antidepressant Fluoxetine. In this investigation the behavioural effects of chronic (two week) treatment with 5-FU and (three weeks) with Fluoxetine either separately or in combination with 5-FU were tested on adult Lister hooded rats. Behavioural effects were tested using a context dependent conditioned emotional response test (CER) which showed that animals treated with 5-FU had a significant reduction in freezing time compared to controls. A separate group of animals was tested using a hippocampal dependent spatial working memory test, the object location recognition test (OLR). Animals treated only with 5-FU showed significant deficits in their ability to carry out the OLR task but co administration of Fluoxetine improved their performance. 5-FU chemotherapy caused a significant reduction in the number of proliferating cells in the sub granular zone of the dentate gyrus compared to controls. This reduction was eliminated when Fluoxetine was co administered with 5-FU. Fluoxetine on its own had no effect on proliferating cell number or behaviour. These findings suggest that 5-FU can negatively affect both cell proliferation and hippocampal dependent working memory and that these deficits can be reversed by the simultaneous administration of the antidepressant Fluoxetine.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/c3ico2017-03-21T21:28:57.675Zstauthor: Snyder, year: 2009, journal: J Neurosci, title: Adult-born hippocampal neurons are more numerous, faster maturing, and more involved in behavior in rats than in mice., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: Neurons are born throughout adulthood in the hippocampus and show enhanced plasticity compared with mature neurons. However, there are conflicting reports on whether or not young neurons contribute to performance in behavioral tasks, and there is no clear relationship between the timing of maturation of young neurons and the duration of neurogenesis reduction in studies showing behavioral deficits. We asked whether these discrepancies could reflect differences in the properties of young neurons in mice and rats. We report that young neurons in adult rats show a mature neuronal marker profile and activity-induced immediate early gene expression 1-2 weeks earlier than those in mice. They are also twice as likely to escape cell death, and are 10 times more likely to be recruited into learning circuits. This comparison holds true in two different strains of mice, both of which show high rates of neurogenesis relative to other background strains. Differences in adult neurogenesis are not limited to the hippocampus, as the density of new neocortical neurons was 5 times greater in rats than in mice. Finally, in a test of function, we find that the contribution of young neurons to fear memory is much greater in rats than in mice. These results reveal substantial differences in new neuron plasticity and function between these two commonly studied rodent species.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/c4wx52017-03-21T21:28:57.675Zstauthor: Shors, year: 2002, journal: Hippocampus, title: Neurogenesis may relate to some but not all types of hippocampal-dependent learning., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: rat, abstract: The hippocampal formation generates new neurons throughout adulthood. Recent studies indicate that these cells possess the morphology and physiological properties of more established neurons. However, the function of adult generated neurons is still a matter of debate. We previously demonstrated that certain forms of associative learning can enhance the survival of new neurons and a reduction in neurogenesis coincides with impaired learning of the hippocampal-dependent task of trace eyeblink conditioning. Using the toxin methylazoxymethanol acetate (MAM) for proliferating cells, we tested whether reduction of neurogenesis affected learning and performance associated with different hippocampal dependent tasks: spatial navigation learning in a Morris water maze, fear responses to context and an explicit cue after training with a trace fear paradigm. We also examined exploratory behavior in an elevated plus maze. Rats were injected with MAM (7 mg/kg) or saline for 14 days, concurrent with BrdU, to label new neurons on days 10, 12, and 14. After treatment, groups of rats were tested in the various tasks. A significant reduction in new neurons in the adult hippocampus was associated with impaired performance in some tasks, but not with others. Specifically, treatment with the antimitotic agent reduced the amount of fear acquired after exposure to a trace fear conditioning paradigm but did not affect contextual fear conditioning or spatial navigation learning in the Morris water maze. Nor did MAM treatment affect exploration in the elevated plus maze. These results combined with previous ones suggest that neurogenesis may be associated with the formation of some but not all types of hippocampal-dependent memories.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bv2y62017-03-21T21:28:57.675Zstauthor: Zhang, year: 2008, journal: Nature, title: A role for adult TLX-positive neural stem cells in learning and behaviour, behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: transgenic TLX, neurogenesisassociatedwith: nothing, species: mouse, abstract: Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bwhin2017-03-21T21:28:57.675Zstauthor: Dupret, year: 2008, journal: PLoS One, title: Spatial relational memory requires hippocampal adult neurogenesis., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: nothing, species: mouse, abstract: The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bxw302017-03-21T21:28:57.675Zstauthor: Ko, year: 2009, journal: Mol Brain, title: Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: mouse, abstract: ABSTRACT: Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/bzanh2017-03-21T21:28:57.675Zstauthor: Ko, year: 2009, journal: Mol Brain, title: Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: ABSTRACT: Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cbxr62017-03-21T21:28:57.675Zstauthor: Jaholkowski, year: 2009, journal: Learn Mem, title: New hippocampal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning, behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: transgenic Cyclin D2, neurogenesisassociatedwith: nothing, species: mouse, abstract: The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs known for their side effects and the results obtained vary greatly. We used a novel approach, cyclin D2 knockout mice (D2 KO mice), specifically lacking adult brain neurogenesis to verify its importance in learning and memory. D2 KO mice and their wild-type siblings were tested in several behavioral paradigms, including those in which the role of adult neurogenesis has been postulated. D2 KO mice showed no impairment in sensorimotor tests, with only sensory impairment in an olfaction-dependent task. However, D2 KO mice showed proper procedural learning as well as learning in context (including remote memory), cue, and trace fear conditioning, Morris water maze, novel object recognition test, and in a multifunctional behavioral system-IntelliCages. D2 KO mice also demonstrated correct reversal learning. Our results suggest that adult brain neurogenesis is not obligatory in learning, including the kinds of learning where the role of adult neurogenesis has previously been strongly suggested.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cdcbn2017-03-21T21:28:57.675Zstauthor: Kitamura, year: 2009, journal: Cell, title: Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Acquired memory initially depends on the hippocampus (HPC) for the process of cortical permanent memory formation. The mechanisms through which memory becomes progressively independent from the HPC remain unknown. In the HPC, adult neurogenesis has been described in many mammalian species, even at old ages. Using two mouse models in which hippocampal neurogenesis is physically or genetically suppressed, we show that decreased neurogenesis is accompanied by a prolonged HPC-dependent period of associative fear memory. Inversely, enhanced neurogenesis by voluntary exercise sped up the decay rate of HPC dependency of memory, without loss of memory. Consistently, decreased neurogenesis facilitated the long-lasting maintenance of rat hippocampal long-term potentiation in vivo. These independent lines of evidence strongly suggest that the level of hippocampal neurogenesis play a role in determination of the HPC-dependent period of memory in adult rodents. These observations provide a framework for understanding the mechanisms of the hippocampal-cortical complementary learning systems.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ceqw02017-03-21T21:28:57.675Zstauthor: Kitamura, year: 2009, journal: Cell, title: Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: transgenic follistatin, neurogenesisassociatedwith: nothing, species: mouse, abstract: Acquired memory initially depends on the hippocampus (HPC) for the process of cortical permanent memory formation. The mechanisms through which memory becomes progressively independent from the HPC remain unknown. In the HPC, adult neurogenesis has been described in many mammalian species, even at old ages. Using two mouse models in which hippocampal neurogenesis is physically or genetically suppressed, we show that decreased neurogenesis is accompanied by a prolonged HPC-dependent period of associative fear memory. Inversely, enhanced neurogenesis by voluntary exercise sped up the decay rate of HPC dependency of memory, without loss of memory. Consistently, decreased neurogenesis facilitated the long-lasting maintenance of rat hippocampal long-term potentiation in vivo. These independent lines of evidence strongly suggest that the level of hippocampal neurogenesis play a role in determination of the HPC-dependent period of memory in adult rodents. These observations provide a framework for understanding the mechanisms of the hippocampal-cortical complementary learning systems.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/cg5gh2017-03-21T21:28:57.675Zstauthor: Snyder, year: 2009, journal: J Neurosci, title: Adult-born hippocampal neurons are more numerous, faster maturing, and more involved in behavior in rats than in mice., behaviorexamined: memory - contextual fear, recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Neurons are born throughout adulthood in the hippocampus and show enhanced plasticity compared with mature neurons. However, there are conflicting reports on whether or not young neurons contribute to performance in behavioral tasks, and there is no clear relationship between the timing of maturation of young neurons and the duration of neurogenesis reduction in studies showing behavioral deficits. We asked whether these discrepancies could reflect differences in the properties of young neurons in mice and rats. We report that young neurons in adult rats show a mature neuronal marker profile and activity-induced immediate early gene expression 1-2 weeks earlier than those in mice. They are also twice as likely to escape cell death, and are 10 times more likely to be recruited into learning circuits. This comparison holds true in two different strains of mice, both of which show high rates of neurogenesis relative to other background strains. Differences in adult neurogenesis are not limited to the hippocampus, as the density of new neocortical neurons was 5 times greater in rats than in mice. Finally, in a test of function, we find that the contribution of young neurons to fear memory is much greater in rats than in mice. These results reveal substantial differences in new neuron plasticity and function between these two commonly studied rodent species.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/c6bhi2017-03-21T21:28:57.675Zstauthor: Drew, year: 2010, journal: Behav Neurosci, title: Arrest of adult hippocampal neurogenesis in mice impairs single- but not multiple-trial contextual fear conditioning, behaviorexamined: memory - contextual fear, recent, 1 shock, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: The role of adult hippocampal neurogenesis in contextual fear conditioning (CFC) is debated. Several studies demonstrated that blocking adult hippocampal neurogenesis in rodents impairs CFC, while several other studies failed to observe an impairment. We sought to determine whether different CFC methods vary in their sensitivity to the arrest of adult neurogenesis. Adult neurogenesis was arrested in mice using low-dose, targeted x-irradiation, and the effects of irradiation were assayed in conditioning procedures that varied in the use of a discrete conditioned stimulus, the number of trials administered, and the final level of conditioning produced. We demonstrate that irradiation impairs CFC in mice when a single-trial CFC procedure is used but not when multiple-trial procedures are used, regardless of the final level of contextual fear produced. In addition, we show that the irradiation-induced deficit in single-trial CFC can be rescued by providing preexposure to the conditioning context. These results indicate that adult hippocampal neurogenesis is required for CFC in mice only when brief training is provided.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/c7q1z2017-03-21T21:28:57.675Zstauthor: Drew, year: 2010, journal: Behav Neurosci, title: Arrest of adult hippocampal neurogenesis in mice impairs single- but not multiple-trial contextual fear conditioning, behaviorexamined: memory - contextual fear, recent, 2 shocks, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: The role of adult hippocampal neurogenesis in contextual fear conditioning (CFC) is debated. Several studies demonstrated that blocking adult hippocampal neurogenesis in rodents impairs CFC, while several other studies failed to observe an impairment. We sought to determine whether different CFC methods vary in their sensitivity to the arrest of adult neurogenesis. Adult neurogenesis was arrested in mice using low-dose, targeted x-irradiation, and the effects of irradiation were assayed in conditioning procedures that varied in the use of a discrete conditioned stimulus, the number of trials administered, and the final level of conditioning produced. We demonstrate that irradiation impairs CFC in mice when a single-trial CFC procedure is used but not when multiple-trial procedures are used, regardless of the final level of contextual fear produced. In addition, we show that the irradiation-induced deficit in single-trial CFC can be rescued by providing preexposure to the conditioning context. These results indicate that adult hippocampal neurogenesis is required for CFC in mice only when brief training is provided.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/c94mc2017-03-21T21:28:57.675Zstauthor: Drew, year: 2010, journal: Behav Neurosci, title: Arrest of adult hippocampal neurogenesis in mice impairs single- but not multiple-trial contextual fear conditioning, behaviorexamined: memory - contextual fear, recent, 3 tone-shocks w varied shock intensity, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: The role of adult hippocampal neurogenesis in contextual fear conditioning (CFC) is debated. Several studies demonstrated that blocking adult hippocampal neurogenesis in rodents impairs CFC, while several other studies failed to observe an impairment. We sought to determine whether different CFC methods vary in their sensitivity to the arrest of adult neurogenesis. Adult neurogenesis was arrested in mice using low-dose, targeted x-irradiation, and the effects of irradiation were assayed in conditioning procedures that varied in the use of a discrete conditioned stimulus, the number of trials administered, and the final level of conditioning produced. We demonstrate that irradiation impairs CFC in mice when a single-trial CFC procedure is used but not when multiple-trial procedures are used, regardless of the final level of contextual fear produced. In addition, we show that the irradiation-induced deficit in single-trial CFC can be rescued by providing preexposure to the conditioning context. These results indicate that adult hippocampal neurogenesis is required for CFC in mice only when brief training is provided.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/caj6t2017-03-21T21:28:57.675Zstauthor: Drew, year: 2010, journal: Behav Neurosci, title: Arrest of adult hippocampal neurogenesis in mice impairs single- but not multiple-trial contextual fear conditioning, behaviorexamined: memory - contextual fear, recent, pre-exposure + 1 shock, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: The role of adult hippocampal neurogenesis in contextual fear conditioning (CFC) is debated. Several studies demonstrated that blocking adult hippocampal neurogenesis in rodents impairs CFC, while several other studies failed to observe an impairment. We sought to determine whether different CFC methods vary in their sensitivity to the arrest of adult neurogenesis. Adult neurogenesis was arrested in mice using low-dose, targeted x-irradiation, and the effects of irradiation were assayed in conditioning procedures that varied in the use of a discrete conditioned stimulus, the number of trials administered, and the final level of conditioning produced. We demonstrate that irradiation impairs CFC in mice when a single-trial CFC procedure is used but not when multiple-trial procedures are used, regardless of the final level of contextual fear produced. In addition, we show that the irradiation-induced deficit in single-trial CFC can be rescued by providing preexposure to the conditioning context. These results indicate that adult hippocampal neurogenesis is required for CFC in mice only when brief training is provided.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hmyxm2017-03-21T21:28:57.675Zstauthor: Winocur, year: 2006, journal: Hippocampus, title: Inhibition of neurogenesis interferes with hippocampus-dependent memory function., behaviorexamined: memory - contextual fear, remote, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: Rats treated with low dose irradiation, to inhibit adult hippocampal neurogenesis, and control rats were administered a non-matching-to-sample (NMTS) task, which measured conditional rule learning and memory for specific events, and a test of fear conditioning in which a discrete CS was paired with an aversive US in a complex environment. Irradiated rats were impaired on the NMTS task when the intervals between sample and test trials were relatively long, and in associating the shock-induced fear with contextual cues in the fear conditioning task. Irradiated rats were not impaired in learning the basic NMTS rule or in performing that task when the intervals between the sample and test trials were short. Nor were there group differences in conditioning the fear response to the CS in the fear conditioning task. The results, which extend the range of hippocampus-dependent tasks that can be said to be vulnerable to the effects of neurogenesis suppression, support the hypothesis that new hippocampal cells generated in adulthood participate in a broad range of hippocampal functions.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hodi32017-03-21T21:28:57.675Zstauthor: Ko, year: 2009, journal: Mol Brain, title: Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory., behaviorexamined: memory - contextual fear, remote, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: ABSTRACT: Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hps2g2017-03-21T21:28:57.675Zstauthor: Jaholkowski, year: 2009, journal: Learn Mem, title: New hippocampal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning, behaviorexamined: memory - contextual fear, remote, neurogenesismanipulation: transgenic Cyclin D2, neurogenesisassociatedwith: nothing, species: mouse, abstract: The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs known for their side effects and the results obtained vary greatly. We used a novel approach, cyclin D2 knockout mice (D2 KO mice), specifically lacking adult brain neurogenesis to verify its importance in learning and memory. D2 KO mice and their wild-type siblings were tested in several behavioral paradigms, including those in which the role of adult neurogenesis has been postulated. D2 KO mice showed no impairment in sensorimotor tests, with only sensory impairment in an olfaction-dependent task. However, D2 KO mice showed proper procedural learning as well as learning in context (including remote memory), cue, and trace fear conditioning, Morris water maze, novel object recognition test, and in a multifunctional behavioral system-IntelliCages. D2 KO mice also demonstrated correct reversal learning. Our results suggest that adult brain neurogenesis is not obligatory in learning, including the kinds of learning where the role of adult neurogenesis has previously been strongly suggested.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hr6mx2017-03-21T21:28:57.675Zstauthor: Kitamura, year: 2009, journal: Cell, title: Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory., behaviorexamined: memory - contextual fear, remote, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: reduced hipp dependence, species: mouse, abstract: Acquired memory initially depends on the hippocampus (HPC) for the process of cortical permanent memory formation. The mechanisms through which memory becomes progressively independent from the HPC remain unknown. In the HPC, adult neurogenesis has been described in many mammalian species, even at old ages. Using two mouse models in which hippocampal neurogenesis is physically or genetically suppressed, we show that decreased neurogenesis is accompanied by a prolonged HPC-dependent period of associative fear memory. Inversely, enhanced neurogenesis by voluntary exercise sped up the decay rate of HPC dependency of memory, without loss of memory. Consistently, decreased neurogenesis facilitated the long-lasting maintenance of rat hippocampal long-term potentiation in vivo. These independent lines of evidence strongly suggest that the level of hippocampal neurogenesis play a role in determination of the HPC-dependent period of memory in adult rodents. These observations provide a framework for understanding the mechanisms of the hippocampal-cortical complementary learning systems.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hhcny2017-03-21T21:28:57.675Zstauthor: Kitamura, year: 2009, journal: Cell, title: Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory., behaviorexamined: memory - contextual fear, remote, neurogenesismanipulation: transgenic follistatin, neurogenesisassociatedwith: reduced hipp dependence, species: mouse, abstract: Acquired memory initially depends on the hippocampus (HPC) for the process of cortical permanent memory formation. The mechanisms through which memory becomes progressively independent from the HPC remain unknown. In the HPC, adult neurogenesis has been described in many mammalian species, even at old ages. Using two mouse models in which hippocampal neurogenesis is physically or genetically suppressed, we show that decreased neurogenesis is accompanied by a prolonged HPC-dependent period of associative fear memory. Inversely, enhanced neurogenesis by voluntary exercise sped up the decay rate of HPC dependency of memory, without loss of memory. Consistently, decreased neurogenesis facilitated the long-lasting maintenance of rat hippocampal long-term potentiation in vivo. These independent lines of evidence strongly suggest that the level of hippocampal neurogenesis play a role in determination of the HPC-dependent period of memory in adult rodents. These observations provide a framework for understanding the mechanisms of the hippocampal-cortical complementary learning systems.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hir8f2017-03-21T21:28:57.675Zstauthor: Goodman, year: 2010, journal: Neuroscience, title: Young hippocampal neurons are critical for recent and remote spatial memory in adult mice, behaviorexamined: memory - cued water maze recent, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: mouse, abstract: New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functionhttps://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hk5ss2017-03-21T21:28:57.675Zstauthor: Goodman, year: 2010, journal: Neuroscience, title: Young hippocampal neurons are critical for recent and remote spatial memory in adult mice, behaviorexamined: memory - cued water maze remote, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: mouse, abstract: New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functionhttps://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hlkd92017-03-21T21:28:57.675Zstauthor: Snyder, year: 2005, journal: Neuroscience, title: A role for adult neurogenesis in spatial long-term memory., behaviorexamined: memory - cued water maze remote, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: Adult hippocampal neurogenesis has been linked to learning but details of the relationship between neuronal production and memory formation remain unknown. Using low dose irradiation to inhibit adult hippocampal neurogenesis we show that new neurons aged 4-28 days old at the time of training are required for long-term memory in a spatial version of the water maze. This effect of irradiation was specific since long-term memory for a visibly cued platform remained intact. Furthermore, irradiation just before or after water maze training had no effect on learning or long-term memory. Relationships between learning and new neuron survival, as well as proliferation, were investigated but found non-significant. These results suggest a new role for adult neurogenesis in the formation and/or consolidation of long-term, hippocampus-dependent, spatial memories.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hy7gy2017-03-21T21:28:57.675Zstauthor: Deng, year: 2009, journal: J Neurosci, title: Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain., behaviorexamined: memory - extinction contextual fear recent, neurogenesismanipulation: transgenic nestin-tk, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Adult-born dentate granule cells (DGCs) contribute to learning and memory, yet it remains unknown when adult-born DGCs become involved in the cognitive processes. During neurogenesis, immature DGCs display distinctive physiological characteristics while undergoing morphological maturation before final integration into the neural circuits. The survival and activity of the adult-born DGCs can be influenced by the experience of the animal during a critical period when newborn DGCs are still immature. To assess the temporal importance of adult neurogenesis, we developed a transgenic mouse model that allowed us to transiently reduce the numbers of adult-born DGCs in a temporally regulatable manner. We found that mice with a reduced population of adult-born DGCs at the immature stage were deficient in forming robust, long-term spatial memory and displayed impaired performance in extinction tasks. These results suggest that immature DGCs that undergo maturation make important contributions to learning and memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hzm1f2017-03-21T21:28:57.675Zstauthor: Ko, year: 2009, journal: Mol Brain, title: Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory., behaviorexamined: memory - extinction contextual fear recent, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: mouse, abstract: ABSTRACT: Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/i10ls2017-03-21T21:28:57.675Zstauthor: Ko, year: 2009, journal: Mol Brain, title: Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory., behaviorexamined: memory - extinction contextual fear recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: ABSTRACT: Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/i2f692017-03-21T21:28:57.675Zstauthor: Ko, year: 2009, journal: Mol Brain, title: Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory., behaviorexamined: memory - extinction contextual fear remote, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: ABSTRACT: Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hsl7a2017-03-21T21:28:57.675Zstauthor: Meshi, year: 2006, journal: Nat Neurosci, title: Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment., behaviorexamined: memory - habituation, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Environmental enrichment increases adult hippocampal neurogenesis and alters hippocampal-dependent behavior in rodents. To investigate a causal link between these two observations, we analyzed the effect of enrichment on spatial learning and anxiety-like behavior while blocking adult hippocampal neurogenesis. We report that environmental enrichment alters behavior in mice regardless of their hippocampal neurogenic capability, providing evidence that the newborn cells do not mediate these effects of enrichment.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/htzrr2017-03-21T21:28:57.675Zstauthor: Meshi, year: 2006, journal: Nat Neurosci, title: Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment., behaviorexamined: memory - habituation, neurogenesismanipulation: irradiation + EE, neurogenesisassociatedwith: nothing, species: mouse, abstract: Environmental enrichment increases adult hippocampal neurogenesis and alters hippocampal-dependent behavior in rodents. To investigate a causal link between these two observations, we analyzed the effect of enrichment on spatial learning and anxiety-like behavior while blocking adult hippocampal neurogenesis. We report that environmental enrichment alters behavior in mice regardless of their hippocampal neurogenic capability, providing evidence that the newborn cells do not mediate these effects of enrichment.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hvec42017-03-21T21:28:57.675Zstauthor: Pollak, year: 2008, journal: Neuron, title: An animal model of a behavioral intervention for depression., behaviorexamined: memory - learned safety, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Although conditioned inhibition of fear (or learned safety) is a learning process critical for preventing chronic stress, a predisposing factor for depression and other psychopathologies, little is known about its functional purposes or molecular mechanisms. To obtain better insight into learned safety, we investigated its behavioral and molecular characteristics and found that it acts as a behavioral antidepressant in two animal models. Learned safety promotes the survival of newborn cells in the dentate gyrus of the hippocampus, while its antidepressant effect is abolished in mice with ablated hippocampal neurogenesis. Learned safety also increases the expression of BDNF in the hippocampus and leads to downregulation of genes involved in the dopaminergic and neuropeptidergic but not the serotonergic system in the basolateral amygdala. These data suggest that learned safety is an animal model of a behavioral antidepressant that shares some neuronal hallmarks of pharmacological antidepressants but is mediated by different molecular pathways.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/hwswl2017-03-21T21:28:57.675Zstauthor: Hernandez-Rabaza, year: 2009, journal: Neuroscience, title: Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal., behaviorexamined: memory - match to place (T maze), neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: Neurogenesis in the adult dentate gyrus (DG) of the hippocampus has been implicated in neural plasticity and cognition but the specific functions contributed by adult-born neurons remain controversial. Here, we have explored the relationship between adult hippocampal neurogenesis and memory function using tasks which specifically require the participation of the DG. In two separate experiments several groups of rats were exposed to fractionated ionizing radiation (two sessions of 7 Gy each on consecutive days) applied either to the whole brain or focally, aiming at a region overlying the hippocampus. The immunocytochemical assays showed that the radiation significantly reduced the expression of doublecortin (DCX), a marker for immature neurons, in the dorsal DG. Ultrastructural examination of the DG region revealed disruption of progenitor cell niches several weeks after the radiation. In the first experiment, whole-brain and focal irradiation reduced DCX expression by 68% and 43%, respectively. Whole-brain and focally-irradiated rats were unimpaired compared with control rats in a matching-to-place (MTP) working memory task performed in the T-maze and in the long-term retention of the no-alternation rule. In the second experiment, focal irradiation reduced DCX expression by 36% but did not impair performance on (1) a standard non-matching-to-place (NMTP) task, (2) a more demanding NMTP task with increasingly longer within-trial delays, (3) a long-term retention test of the alternation rule and (4) a spatial reversal task. However, rats irradiated focally showed clear deficits in a "purely" contextual fear-conditioning task at short and long retention intervals. These data demonstrate that reduced adult hippocampal neurogenesis produces marked deficits in the rapid acquisition of emotionally relevant contextual information but spares spatial working memory function, the long-term retention of acquired spatial rules and the ability to flexibly modify learned spatial strategies.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/i9g0a2017-03-21T21:28:57.675Zstauthor: Saxe, year: 2006, journal: Proc Natl Acad Sci U S A, title: Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus., behaviorexamined: memory - match to place (water maze), neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/iaukr2017-03-21T21:28:57.675Zstauthor: Hernandez-Rabaza, year: 2009, journal: Neuroscience, title: Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal., behaviorexamined: memory - match to place 1w retention (T maze), neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: Neurogenesis in the adult dentate gyrus (DG) of the hippocampus has been implicated in neural plasticity and cognition but the specific functions contributed by adult-born neurons remain controversial. Here, we have explored the relationship between adult hippocampal neurogenesis and memory function using tasks which specifically require the participation of the DG. In two separate experiments several groups of rats were exposed to fractionated ionizing radiation (two sessions of 7 Gy each on consecutive days) applied either to the whole brain or focally, aiming at a region overlying the hippocampus. The immunocytochemical assays showed that the radiation significantly reduced the expression of doublecortin (DCX), a marker for immature neurons, in the dorsal DG. Ultrastructural examination of the DG region revealed disruption of progenitor cell niches several weeks after the radiation. In the first experiment, whole-brain and focal irradiation reduced DCX expression by 68% and 43%, respectively. Whole-brain and focally-irradiated rats were unimpaired compared with control rats in a matching-to-place (MTP) working memory task performed in the T-maze and in the long-term retention of the no-alternation rule. In the second experiment, focal irradiation reduced DCX expression by 36% but did not impair performance on (1) a standard non-matching-to-place (NMTP) task, (2) a more demanding NMTP task with increasingly longer within-trial delays, (3) a long-term retention test of the alternation rule and (4) a spatial reversal task. However, rats irradiated focally showed clear deficits in a "purely" contextual fear-conditioning task at short and long retention intervals. These data demonstrate that reduced adult hippocampal neurogenesis produces marked deficits in the rapid acquisition of emotionally relevant contextual information but spares spatial working memory function, the long-term retention of acquired spatial rules and the ability to flexibly modify learned spatial strategies.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ic9542017-03-21T21:28:57.675Zstauthor: Clelland, year: 2009, journal: Science, title: A functional role for adult hippocampal neurogenesis in spatial pattern separation., behaviorexamined: memory - non-match to place, neurogenesismanipulation: exog. Wnt inhibition, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: The dentate gyrus (DG) of the mammalian hippocampus is hypothesized to mediate pattern separation-the formation of distinct and orthogonal representations of mnemonic information-and also undergoes neurogenesis throughout life. How neurogenesis contributes to hippocampal function is largely unknown. Using adult mice in which hippocampal neurogenesis was ablated, we found specific impairments in spatial discrimination with two behavioral assays: (i) a spatial navigation radial arm maze task and (ii) a spatial, but non-navigable, task in the mouse touch screen. Mice with ablated neurogenesis were impaired when stimuli were presented with little spatial separation, but not when stimuli were more widely separated in space. Thus, newborn neurons may be necessary for normal pattern separation function in the DG of adult mice.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/idnpl2017-03-21T21:28:57.675Zstauthor: Clelland, year: 2009, journal: Science, title: A functional role for adult hippocampal neurogenesis in spatial pattern separation., behaviorexamined: memory - non-match to place, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: The dentate gyrus (DG) of the mammalian hippocampus is hypothesized to mediate pattern separation-the formation of distinct and orthogonal representations of mnemonic information-and also undergoes neurogenesis throughout life. How neurogenesis contributes to hippocampal function is largely unknown. Using adult mice in which hippocampal neurogenesis was ablated, we found specific impairments in spatial discrimination with two behavioral assays: (i) a spatial navigation radial arm maze task and (ii) a spatial, but non-navigable, task in the mouse touch screen. Mice with ablated neurogenesis were impaired when stimuli were presented with little spatial separation, but not when stimuli were more widely separated in space. Thus, newborn neurons may be necessary for normal pattern separation function in the DG of adult mice.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/i3tqm2017-03-21T21:28:57.675Zstauthor: Hernandez-Rabaza, year: 2009, journal: Neuroscience, title: Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal., behaviorexamined: memory - non-match to place (T maze), neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: Neurogenesis in the adult dentate gyrus (DG) of the hippocampus has been implicated in neural plasticity and cognition but the specific functions contributed by adult-born neurons remain controversial. Here, we have explored the relationship between adult hippocampal neurogenesis and memory function using tasks which specifically require the participation of the DG. In two separate experiments several groups of rats were exposed to fractionated ionizing radiation (two sessions of 7 Gy each on consecutive days) applied either to the whole brain or focally, aiming at a region overlying the hippocampus. The immunocytochemical assays showed that the radiation significantly reduced the expression of doublecortin (DCX), a marker for immature neurons, in the dorsal DG. Ultrastructural examination of the DG region revealed disruption of progenitor cell niches several weeks after the radiation. In the first experiment, whole-brain and focal irradiation reduced DCX expression by 68% and 43%, respectively. Whole-brain and focally-irradiated rats were unimpaired compared with control rats in a matching-to-place (MTP) working memory task performed in the T-maze and in the long-term retention of the no-alternation rule. In the second experiment, focal irradiation reduced DCX expression by 36% but did not impair performance on (1) a standard non-matching-to-place (NMTP) task, (2) a more demanding NMTP task with increasingly longer within-trial delays, (3) a long-term retention test of the alternation rule and (4) a spatial reversal task. However, rats irradiated focally showed clear deficits in a "purely" contextual fear-conditioning task at short and long retention intervals. These data demonstrate that reduced adult hippocampal neurogenesis produces marked deficits in the rapid acquisition of emotionally relevant contextual information but spares spatial working memory function, the long-term retention of acquired spatial rules and the ability to flexibly modify learned spatial strategies.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/i58b32017-03-21T21:28:57.675Zstauthor: Winocur, year: 2006, journal: Hippocampus, title: Inhibition of neurogenesis interferes with hippocampus-dependent memory function., behaviorexamined: memory - non-match to place (water maze), neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: Rats treated with low dose irradiation, to inhibit adult hippocampal neurogenesis, and control rats were administered a non-matching-to-sample (NMTS) task, which measured conditional rule learning and memory for specific events, and a test of fear conditioning in which a discrete CS was paired with an aversive US in a complex environment. Irradiated rats were impaired on the NMTS task when the intervals between sample and test trials were relatively long, and in associating the shock-induced fear with contextual cues in the fear conditioning task. Irradiated rats were not impaired in learning the basic NMTS rule or in performing that task when the intervals between the sample and test trials were short. Nor were there group differences in conditioning the fear response to the CS in the fear conditioning task. The results, which extend the range of hippocampus-dependent tasks that can be said to be vulnerable to the effects of neurogenesis suppression, support the hypothesis that new hippocampal cells generated in adulthood participate in a broad range of hippocampal functions.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/i6mvg2017-03-21T21:28:57.675Zstauthor: Hernandez-Rabaza, year: 2009, journal: Neuroscience, title: Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal., behaviorexamined: memory - non-match to place 1w retention (T maze), neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: Neurogenesis in the adult dentate gyrus (DG) of the hippocampus has been implicated in neural plasticity and cognition but the specific functions contributed by adult-born neurons remain controversial. Here, we have explored the relationship between adult hippocampal neurogenesis and memory function using tasks which specifically require the participation of the DG. In two separate experiments several groups of rats were exposed to fractionated ionizing radiation (two sessions of 7 Gy each on consecutive days) applied either to the whole brain or focally, aiming at a region overlying the hippocampus. The immunocytochemical assays showed that the radiation significantly reduced the expression of doublecortin (DCX), a marker for immature neurons, in the dorsal DG. Ultrastructural examination of the DG region revealed disruption of progenitor cell niches several weeks after the radiation. In the first experiment, whole-brain and focal irradiation reduced DCX expression by 68% and 43%, respectively. Whole-brain and focally-irradiated rats were unimpaired compared with control rats in a matching-to-place (MTP) working memory task performed in the T-maze and in the long-term retention of the no-alternation rule. In the second experiment, focal irradiation reduced DCX expression by 36% but did not impair performance on (1) a standard non-matching-to-place (NMTP) task, (2) a more demanding NMTP task with increasingly longer within-trial delays, (3) a long-term retention test of the alternation rule and (4) a spatial reversal task. However, rats irradiated focally showed clear deficits in a "purely" contextual fear-conditioning task at short and long retention intervals. These data demonstrate that reduced adult hippocampal neurogenesis produces marked deficits in the rapid acquisition of emotionally relevant contextual information but spares spatial working memory function, the long-term retention of acquired spatial rules and the ability to flexibly modify learned spatial strategies.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/i81fx2017-03-21T21:28:57.675Zstauthor: Hernandez-Rabaza, year: 2009, journal: Neuroscience, title: Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal., behaviorexamined: memory - non-match to place reversal (T maze), neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: Neurogenesis in the adult dentate gyrus (DG) of the hippocampus has been implicated in neural plasticity and cognition but the specific functions contributed by adult-born neurons remain controversial. Here, we have explored the relationship between adult hippocampal neurogenesis and memory function using tasks which specifically require the participation of the DG. In two separate experiments several groups of rats were exposed to fractionated ionizing radiation (two sessions of 7 Gy each on consecutive days) applied either to the whole brain or focally, aiming at a region overlying the hippocampus. The immunocytochemical assays showed that the radiation significantly reduced the expression of doublecortin (DCX), a marker for immature neurons, in the dorsal DG. Ultrastructural examination of the DG region revealed disruption of progenitor cell niches several weeks after the radiation. In the first experiment, whole-brain and focal irradiation reduced DCX expression by 68% and 43%, respectively. Whole-brain and focally-irradiated rats were unimpaired compared with control rats in a matching-to-place (MTP) working memory task performed in the T-maze and in the long-term retention of the no-alternation rule. In the second experiment, focal irradiation reduced DCX expression by 36% but did not impair performance on (1) a standard non-matching-to-place (NMTP) task, (2) a more demanding NMTP task with increasingly longer within-trial delays, (3) a long-term retention test of the alternation rule and (4) a spatial reversal task. However, rats irradiated focally showed clear deficits in a "purely" contextual fear-conditioning task at short and long retention intervals. These data demonstrate that reduced adult hippocampal neurogenesis produces marked deficits in the rapid acquisition of emotionally relevant contextual information but spares spatial working memory function, the long-term retention of acquired spatial rules and the ability to flexibly modify learned spatial strategies.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ikojm2017-03-21T21:28:57.675Zstauthor: Goodman, year: 2010, journal: Neuroscience, title: Young hippocampal neurons are critical for recent and remote spatial memory in adult mice, behaviorexamined: memory - object location, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functionhttps://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/im3432017-03-21T21:28:57.675Zstauthor: Mustafa, year: 2008, journal: Eur J Neurosci, title: 5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus., behaviorexamined: memory - object location, neurogenesismanipulation: exog. 5-Fluorouracil, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: Chemotherapy-associated memory deficits in adults are prevalent with systemic treatment utilizing 5-fluorouracil (5-Fu). 5-Fu disrupts cell proliferation and readily crosses the blood-brain barrier. Proliferating cells within the adult dentate gyrus of the hippocampus give rise to new neurons involved in memory and learning and require neurotrophic factors such as brain-derived neurotrophic factor (BDNF) to nurture this process of adult neurogenesis. Some of these proliferating cells are anatomically and functionally supported by vascular endothelial cells. We propose that systemically administered 5-Fu chemotherapy will cause deficits in hippocampal memory that are associated with altered BDNF levels and proliferating cells (particularly vascular-associated cells) in the dentate gyrus. This was tested by determining the effect of 5-Fu on spatial working memory as modelled by the object location recognition test. Numbers of vascular-associated (VA) and non-vascular-associated (NVA) proliferating cells in the dentate gyrus were measured using double-labelling immunohistochemistry with markers of proliferation (Ki67) and endothelial cells (RECA-1). 5-Fu-induced changes in hippocampal BDNF and doublecortin (DCX) protein levels were quantified using Western immunoblotting. 5-Fu chemotherapy caused a marginal disruption in spatial working memory and did not alter the total proliferating cell counts or the percentage of VA and NVA proliferating cells in the dentate gyrus. In contrast, 5-Fu significantly reduced BDNF and DCX levels in the hippocampus, indicating alterations in neurotrophin levels and neurogenesis. These findings highlight the usefulness of animal models of 'chemobrain' for understanding the mechanisms that underlie chemotherapy-associated declines in cognitive performance and memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/inhog2017-03-21T21:28:57.675Zstauthor: Elbeltagy, year: 2009, journal: Behav Brain Res, title: Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil., behaviorexamined: memory - object location, neurogenesismanipulation: exog. 5-Fluorouracil, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: Cancer patients who have been treated with systemic adjuvant chemotherapy have described experiencing deteriorations in cognition. A widely used chemotherapeutic agent, 5-fluorouracil (5-FU), readily crosses the blood-brain barrier and so could have a direct effect on brain function. In particular this anti mitotic drug could reduce cell proliferation in the neurogenic regions of the adult brain. In contrast reports indicate that hippocampal dependent neurogenesis and cognition are enhanced by the SSRI antidepressant Fluoxetine. In this investigation the behavioural effects of chronic (two week) treatment with 5-FU and (three weeks) with Fluoxetine either separately or in combination with 5-FU were tested on adult Lister hooded rats. Behavioural effects were tested using a context dependent conditioned emotional response test (CER) which showed that animals treated with 5-FU had a significant reduction in freezing time compared to controls. A separate group of animals was tested using a hippocampal dependent spatial working memory test, the object location recognition test (OLR). Animals treated only with 5-FU showed significant deficits in their ability to carry out the OLR task but co administration of Fluoxetine improved their performance. 5-FU chemotherapy caused a significant reduction in the number of proliferating cells in the sub granular zone of the dentate gyrus compared to controls. This reduction was eliminated when Fluoxetine was co administered with 5-FU. Fluoxetine on its own had no effect on proliferating cell number or behaviour. These findings suggest that 5-FU can negatively affect both cell proliferation and hippocampal dependent working memory and that these deficits can be reversed by the simultaneous administration of the antidepressant Fluoxetine.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/iow8x2017-03-21T21:28:57.675Zstauthor: Jessberger, year: 2009, journal: Learn Mem, title: Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats., behaviorexamined: memory - object recognition, neurogenesismanipulation: exog. Wnt inhibition, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons with hippocampal function used ablation strategies that were not exclusive to the hippocampus or that were associated with substantial side effects, such as inflammation. We here used a lentiviral approach to specifically block neurogenesis in the dentate gyrus of adult male rats by inhibiting WNT signaling, which is critically involved in the generation of newborn neurons, using a dominant-negative WNT (dnWNT). We found a level-dependent effect of adult neurogenesis on the long-term retention of spatial memory in the water maze task, as rats with substantially reduced levels of newborn neurons showed less preference for the target zone in probe trials >2 wk after acquisition compared with control rats. Furthermore, animals with strongly reduced levels of neurogenesis were impaired in a hippocampus-dependent object recognition task. Social transmission of food preference, a behavioral test that also depends on hippocampal function, was not affected by knockdown of neurogenesis. Here we identified a role for newborn neurons in distinct aspects of hippocampal function that will set the ground to further elucidate, using experimental and computational strategies, the mechanism by which newborn neurons contribute to behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/if29y2017-03-21T21:28:57.675Zstauthor: Goodman, year: 2010, journal: Neuroscience, title: Young hippocampal neurons are critical for recent and remote spatial memory in adult mice, behaviorexamined: memory - object recognition, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: mouse, abstract: New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functionhttps://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/igguf2017-03-21T21:28:57.675Zstauthor: Madsen, year: 2003, journal: Neuroscience, title: Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat., behaviorexamined: memory - object recognition, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: The generation of new neurons in the adult mammalian brain has been documented in numerous recent reports. Studies undertaken so far indicate that adult hippocampal neurogenesis is related in a number of ways to hippocampal function.Here, we report that subjecting adult rats to fractionated brain irradiation blocked the formation of new neurons in the dentate gyrus of the hippocampus. At different time points after the termination of the irradiation procedure, the animals were tested in two tests of short-term memory that differ with respect to their dependence on hippocampal function. Eight and 21 days after irradiation, the animals with blocked neurogenesis performed poorer than controls in a hippocampus-dependent place-recognition task, indicating that the presence of newly generated neurons may be necessary for the normal function of this brain area. The animals were never impaired in a hippocampus-independent object-recognition task. These results are in line with other reports documenting the functional significance of newly generated neurons in this region. As our irradiation procedure models prophylactic cranial irradiation used in the treatment of different cancers, we suggest that blocked neurogenesis contributes to the reported deleterious side effects of this treatment, consisting of memory impairment, dysphoria and lethargy.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ihves2017-03-21T21:28:57.675Zstauthor: Revest, year: 2009, journal: Mol Psychiatry, title: Adult hippocampal neurogenesis is involved in anxiety-related behaviors, behaviorexamined: memory - object recognition, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: nothing, species: mouse, abstract: Adult hippocampal neurogenesis is a unique example of structural plasticity, the functional role of which has been a matter of intense debate. New transgenic models have recently shown that neurogenesis participates in hippocampus-mediated learning. Here, we show that transgenic animals, in which adult hippocampal neurogenesis has been specifically impaired, exhibit a striking increase in anxiety-related behaviors. Our results indicate that neurogenesis plays an important role in the regulation of affective states and could be the target of new treatments for anxiety disorders.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ij9z92017-03-21T21:28:57.675Zstauthor: Jaholkowski, year: 2009, journal: Learn Mem, title: New hippocampal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning, behaviorexamined: memory - object recognition, neurogenesismanipulation: transgenic Cyclin D2, neurogenesisassociatedwith: nothing, species: mouse, abstract: The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs known for their side effects and the results obtained vary greatly. We used a novel approach, cyclin D2 knockout mice (D2 KO mice), specifically lacking adult brain neurogenesis to verify its importance in learning and memory. D2 KO mice and their wild-type siblings were tested in several behavioral paradigms, including those in which the role of adult neurogenesis has been postulated. D2 KO mice showed no impairment in sensorimotor tests, with only sensory impairment in an olfaction-dependent task. However, D2 KO mice showed proper procedural learning as well as learning in context (including remote memory), cue, and trace fear conditioning, Morris water maze, novel object recognition test, and in a multifunctional behavioral system-IntelliCages. D2 KO mice also demonstrated correct reversal learning. Our results suggest that adult brain neurogenesis is not obligatory in learning, including the kinds of learning where the role of adult neurogenesis has previously been strongly suggested.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ivx4q2017-03-21T21:28:57.675Zstauthor: Bruel-Jungerman, year: 2005, journal: Eur J Neurosci, title: New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment., behaviorexamined: memory - object recognition, LTM, neurogenesismanipulation: exog. MAM + environmental enrichment, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: Although thousands of new neurons are continuously produced in the dentate gyrus of rodents each day, the function of these newborn cells remains unclear. An increasing number of reports have provided correlational evidence that adult hippocampal neurogenesis is involved in learning and memory. Exposure of animals to an enriched environment leads to improvement of performance in several learning tasks and enhances neurogenesis specifically in the hippocampus. These data raise the question of whether new neurons participate in memory improvement induced by enrichment. To address this issue, we have examined whether the increase in the number of surviving adult-generated cells following environmental enrichment contributes to improved memory function. To this end, neurogenesis was substantially reduced throughout the environmental enrichment period using the antimitotic agent methylazoxymethanol acetate (MAM). Recognition memory performance of MAM-treated enriched rats was evaluated in a novel object recognition task and compared with that of naive and nontreated enriched rats. Injections of 5-bromo-2'-deoxyuridine were used to label dividing cells, together with double immunofluorescent labelling using glial or neuronal cell-specific markers. We found that enrichment led to improved long-term recognition memory and increased hippocampal neurogenesis, and that MAM treatment during environmental enrichment completely prevented both the increase in neurogenesis and enrichment-induced long-term memory improvement. These results establish that newborn cells in the dentate gyrus contribute to the expression of the promnesic effects of behavioural enrichment, and they provide further support for the idea that adult-generated neurons participate in modulating memory function.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/ixbp72017-03-21T21:28:57.675Zstauthor: Bruel-Jungerman, year: 2005, journal: Eur J Neurosci, title: New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment., behaviorexamined: memory - object recognition, STM, neurogenesismanipulation: exog. MAM + environmental enrichment, neurogenesisassociatedwith: nothing, species: rat, abstract: Although thousands of new neurons are continuously produced in the dentate gyrus of rodents each day, the function of these newborn cells remains unclear. An increasing number of reports have provided correlational evidence that adult hippocampal neurogenesis is involved in learning and memory. Exposure of animals to an enriched environment leads to improvement of performance in several learning tasks and enhances neurogenesis specifically in the hippocampus. These data raise the question of whether new neurons participate in memory improvement induced by enrichment. To address this issue, we have examined whether the increase in the number of surviving adult-generated cells following environmental enrichment contributes to improved memory function. To this end, neurogenesis was substantially reduced throughout the environmental enrichment period using the antimitotic agent methylazoxymethanol acetate (MAM). Recognition memory performance of MAM-treated enriched rats was evaluated in a novel object recognition task and compared with that of naive and nontreated enriched rats. Injections of 5-bromo-2'-deoxyuridine were used to label dividing cells, together with double immunofluorescent labelling using glial or neuronal cell-specific markers. We found that enrichment led to improved long-term recognition memory and increased hippocampal neurogenesis, and that MAM treatment during environmental enrichment completely prevented both the increase in neurogenesis and enrichment-induced long-term memory improvement. These results establish that newborn cells in the dentate gyrus contribute to the expression of the promnesic effects of behavioural enrichment, and they provide further support for the idea that adult-generated neurons participate in modulating memory function.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/iyq9k2017-03-21T21:28:57.675Zstauthor: Jaholkowski, year: 2009, journal: Learn Mem, title: New hippocampal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning, behaviorexamined: memory - place preference intellicage, neurogenesismanipulation: transgenic Cyclin D2, neurogenesisassociatedwith: nothing, species: mouse, abstract: The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs known for their side effects and the results obtained vary greatly. We used a novel approach, cyclin D2 knockout mice (D2 KO mice), specifically lacking adult brain neurogenesis to verify its importance in learning and memory. D2 KO mice and their wild-type siblings were tested in several behavioral paradigms, including those in which the role of adult neurogenesis has been postulated. D2 KO mice showed no impairment in sensorimotor tests, with only sensory impairment in an olfaction-dependent task. However, D2 KO mice showed proper procedural learning as well as learning in context (including remote memory), cue, and trace fear conditioning, Morris water maze, novel object recognition test, and in a multifunctional behavioral system-IntelliCages. D2 KO mice also demonstrated correct reversal learning. Our results suggest that adult brain neurogenesis is not obligatory in learning, including the kinds of learning where the role of adult neurogenesis has previously been strongly suggested.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/j04u12017-03-21T21:28:57.675Zstauthor: Madsen, year: 2003, journal: Neuroscience, title: Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat., behaviorexamined: memory - place recognition T maze, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: The generation of new neurons in the adult mammalian brain has been documented in numerous recent reports. Studies undertaken so far indicate that adult hippocampal neurogenesis is related in a number of ways to hippocampal function.Here, we report that subjecting adult rats to fractionated brain irradiation blocked the formation of new neurons in the dentate gyrus of the hippocampus. At different time points after the termination of the irradiation procedure, the animals were tested in two tests of short-term memory that differ with respect to their dependence on hippocampal function. Eight and 21 days after irradiation, the animals with blocked neurogenesis performed poorer than controls in a hippocampus-dependent place-recognition task, indicating that the presence of newly generated neurons may be necessary for the normal function of this brain area. The animals were never impaired in a hippocampus-independent object-recognition task. These results are in line with other reports documenting the functional significance of newly generated neurons in this region. As our irradiation procedure models prophylactic cranial irradiation used in the treatment of different cancers, we suggest that blocked neurogenesis contributes to the reported deleterious side effects of this treatment, consisting of memory impairment, dysphoria and lethargy.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/iqav22017-03-21T21:28:57.675Zstauthor: Saxe, year: 2006, journal: Proc Natl Acad Sci U S A, title: Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus., behaviorexamined: memory - place recognition Y maze, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/irpfj2017-03-21T21:28:57.675Zstauthor: Jessberger, year: 2009, journal: Learn Mem, title: Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats., behaviorexamined: memory - social transmission of food preference, neurogenesismanipulation: exog. Wnt inhibition, neurogenesisassociatedwith: nothing, species: rat, abstract: New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons with hippocampal function used ablation strategies that were not exclusive to the hippocampus or that were associated with substantial side effects, such as inflammation. We here used a lentiviral approach to specifically block neurogenesis in the dentate gyrus of adult male rats by inhibiting WNT signaling, which is critically involved in the generation of newborn neurons, using a dominant-negative WNT (dnWNT). We found a level-dependent effect of adult neurogenesis on the long-term retention of spatial memory in the water maze task, as rats with substantially reduced levels of newborn neurons showed less preference for the target zone in probe trials >2 wk after acquisition compared with control rats. Furthermore, animals with strongly reduced levels of neurogenesis were impaired in a hippocampus-dependent object recognition task. Social transmission of food preference, a behavioral test that also depends on hippocampal function, was not affected by knockdown of neurogenesis. Here we identified a role for newborn neurons in distinct aspects of hippocampal function that will set the ground to further elucidate, using experimental and computational strategies, the mechanism by which newborn neurons contribute to behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/it3zw2017-03-21T21:28:57.675Zstauthor: Clelland, year: 2009, journal: Science, title: A functional role for adult hippocampal neurogenesis in spatial pattern separation., behaviorexamined: memory - spatial discrimination on touch screen, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: The dentate gyrus (DG) of the mammalian hippocampus is hypothesized to mediate pattern separation-the formation of distinct and orthogonal representations of mnemonic information-and also undergoes neurogenesis throughout life. How neurogenesis contributes to hippocampal function is largely unknown. Using adult mice in which hippocampal neurogenesis was ablated, we found specific impairments in spatial discrimination with two behavioral assays: (i) a spatial navigation radial arm maze task and (ii) a spatial, but non-navigable, task in the mouse touch screen. Mice with ablated neurogenesis were impaired when stimuli were presented with little spatial separation, but not when stimuli were more widely separated in space. Thus, newborn neurons may be necessary for normal pattern separation function in the DG of adult mice.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/iuikd2017-03-21T21:28:57.675Zstauthor: Shors, year: 2001, journal: Nature, title: Neurogenesis in the adult is involved in the formation of trace memories., behaviorexamined: memory - trace eyeblink conditioning, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: The vertebrate brain continues to produce new neurons throughout life. In the rat hippocampus, several thousand are produced each day, many of which die within weeks. Associative learning can enhance their survival; however, until now it was unknown whether new neurons are involved in memory formation. Here we show that a substantial reduction in the number of newly generated neurons in the adult rat impairs hippocampal-dependent trace conditioning, a task in which an animal must associate stimuli that are separated in time. A similar reduction did not affect learning when the same stimuli are not separated in time, a task that is hippocampal-independent. The reduction in neurogenesis did not induce death of mature hippocampal neurons or permanently alter neurophysiological properties of the CA1 region, such as long-term potentiation. Moreover, recovery of cell production was associated with the ability to acquire trace memories. These results indicate that newly generated neurons in the adult are not only affected by the formation of a hippocampal-dependent memory, but also participate in it.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/j75o22017-03-21T21:28:57.675Zstauthor: Shors, year: 2002, journal: Hippocampus, title: Neurogenesis may relate to some but not all types of hippocampal-dependent learning., behaviorexamined: memory - trace fear conditioning, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: The hippocampal formation generates new neurons throughout adulthood. Recent studies indicate that these cells possess the morphology and physiological properties of more established neurons. However, the function of adult generated neurons is still a matter of debate. We previously demonstrated that certain forms of associative learning can enhance the survival of new neurons and a reduction in neurogenesis coincides with impaired learning of the hippocampal-dependent task of trace eyeblink conditioning. Using the toxin methylazoxymethanol acetate (MAM) for proliferating cells, we tested whether reduction of neurogenesis affected learning and performance associated with different hippocampal dependent tasks: spatial navigation learning in a Morris water maze, fear responses to context and an explicit cue after training with a trace fear paradigm. We also examined exploratory behavior in an elevated plus maze. Rats were injected with MAM (7 mg/kg) or saline for 14 days, concurrent with BrdU, to label new neurons on days 10, 12, and 14. After treatment, groups of rats were tested in the various tasks. A significant reduction in new neurons in the adult hippocampus was associated with impaired performance in some tasks, but not with others. Specifically, treatment with the antimitotic agent reduced the amount of fear acquired after exposure to a trace fear conditioning paradigm but did not affect contextual fear conditioning or spatial navigation learning in the Morris water maze. Nor did MAM treatment affect exploration in the elevated plus maze. These results combined with previous ones suggest that neurogenesis may be associated with the formation of some but not all types of hippocampal-dependent memories.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/j8k8j2017-03-21T21:28:57.675Zstauthor: Deng, year: 2009, journal: J Neurosci, title: Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain., behaviorexamined: memory - water maze 7d, neurogenesismanipulation: transgenic nestin-tk, neurogenesisassociatedwith: enhanced memory (immature cells), species: mouse, abstract: Adult-born dentate granule cells (DGCs) contribute to learning and memory, yet it remains unknown when adult-born DGCs become involved in the cognitive processes. During neurogenesis, immature DGCs display distinctive physiological characteristics while undergoing morphological maturation before final integration into the neural circuits. The survival and activity of the adult-born DGCs can be influenced by the experience of the animal during a critical period when newborn DGCs are still immature. To assess the temporal importance of adult neurogenesis, we developed a transgenic mouse model that allowed us to transiently reduce the numbers of adult-born DGCs in a temporally regulatable manner. We found that mice with a reduced population of adult-born DGCs at the immature stage were deficient in forming robust, long-term spatial memory and displayed impaired performance in extinction tasks. These results suggest that immature DGCs that undergo maturation make important contributions to learning and memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/j9ysw2017-03-21T21:28:57.675Zstauthor: Deng, year: 2009, journal: J Neurosci, title: Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain., behaviorexamined: memory - water maze 7d, neurogenesismanipulation: transgenic nestin-tk, neurogenesisassociatedwith: nothing (mature cells), species: mouse, abstract: Adult-born dentate granule cells (DGCs) contribute to learning and memory, yet it remains unknown when adult-born DGCs become involved in the cognitive processes. During neurogenesis, immature DGCs display distinctive physiological characteristics while undergoing morphological maturation before final integration into the neural circuits. The survival and activity of the adult-born DGCs can be influenced by the experience of the animal during a critical period when newborn DGCs are still immature. To assess the temporal importance of adult neurogenesis, we developed a transgenic mouse model that allowed us to transiently reduce the numbers of adult-born DGCs in a temporally regulatable manner. We found that mice with a reduced population of adult-born DGCs at the immature stage were deficient in forming robust, long-term spatial memory and displayed impaired performance in extinction tasks. These results suggest that immature DGCs that undergo maturation make important contributions to learning and memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jbddd2017-03-21T21:28:57.675Zstauthor: Goodman, year: 2010, journal: Neuroscience, title: Young hippocampal neurons are critical for recent and remote spatial memory in adult mice, behaviorexamined: memory - water maze recent, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functionhttps://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/j1jee2017-03-21T21:28:57.675Zstauthor: Zhang, year: 2008, journal: Nature, title: A role for adult TLX-positive neural stem cells in learning and behaviour, behaviorexamined: memory - water maze recent, neurogenesismanipulation: transgenic TLX, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/j2xyv2017-03-21T21:28:57.675Zstauthor: Dupret, year: 2008, journal: PLoS One, title: Spatial relational memory requires hippocampal adult neurogenesis., behaviorexamined: memory - water maze recent, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/j4cj82017-03-21T21:28:57.675Zstauthor: Garthe, year: 2009, journal: PLoS One, title: Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies., behaviorexamined: memory - water maze recent, neurogenesismanipulation: exog. TMZ, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Despite enormous progress in the past few years the specific contribution of newly born granule cells to the function of the adult hippocampus is still not clear. We hypothesized that in order to solve this question particular attention has to be paid to the specific design, the analysis, and the interpretation of the learning test to be used. We thus designed a behavioral experiment along hypotheses derived from a computational model predicting that new neurons might be particularly relevant for learning conditions, in which novel aspects arise in familiar situations, thus putting high demands on the qualitative aspects of (re-)learning.In the reference memory version of the water maze task suppression of adult neurogenesis with temozolomide (TMZ) caused a highly specific learning deficit. Mice were tested in the hidden platform version of the Morris water maze (6 trials per day for 5 days with a reversal of the platform location on day 4). Testing was done at 4 weeks after the end of four cycles of treatment to minimize the number of potentially recruitable new neurons at the time of testing. The reduction of neurogenesis did not alter longterm potentiation in CA3 and the dentate gyrus but abolished the part of dentate gyrus LTP that is attributed to the new neurons. TMZ did not have any overt side effects at the time of testing, and both treated mice and controls learned to find the hidden platform. Qualitative analysis of search strategies, however, revealed that treated mice did not advance to spatially precise search strategies, in particular when learning a changed goal position (reversal). New neurons in the dentate gyrus thus seem to be necessary for adding flexibility to some hippocampus-dependent qualitative parameters of learning.Our finding that a lack of adult-generated granule cells specifically results in the animal's inability to precisely locate a hidden goal is also in accordance with a specialized role of the dentate gyrus in generating a metric rather than just a configurational map of the environment. The discovery of highly specific behavioral deficits as consequence of a suppression of adult hippocampal neurogenesis thus allows to link cellular hippocampal plasticity to well-defined hypotheses from theoretical models.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/j5r3p2017-03-21T21:28:57.675Zstauthor: Deng, year: 2009, journal: J Neurosci, title: Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain., behaviorexamined: memory - water maze recent, neurogenesismanipulation: transgenic nestin-tk, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Adult-born dentate granule cells (DGCs) contribute to learning and memory, yet it remains unknown when adult-born DGCs become involved in the cognitive processes. During neurogenesis, immature DGCs display distinctive physiological characteristics while undergoing morphological maturation before final integration into the neural circuits. The survival and activity of the adult-born DGCs can be influenced by the experience of the animal during a critical period when newborn DGCs are still immature. To assess the temporal importance of adult neurogenesis, we developed a transgenic mouse model that allowed us to transiently reduce the numbers of adult-born DGCs in a temporally regulatable manner. We found that mice with a reduced population of adult-born DGCs at the immature stage were deficient in forming robust, long-term spatial memory and displayed impaired performance in extinction tasks. These results suggest that immature DGCs that undergo maturation make important contributions to learning and memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jie7e2017-03-21T21:28:57.675Zstauthor: Shors, year: 2002, journal: Hippocampus, title: Neurogenesis may relate to some but not all types of hippocampal-dependent learning., behaviorexamined: memory - water maze recent, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: nothing, species: rat, abstract: The hippocampal formation generates new neurons throughout adulthood. Recent studies indicate that these cells possess the morphology and physiological properties of more established neurons. However, the function of adult generated neurons is still a matter of debate. We previously demonstrated that certain forms of associative learning can enhance the survival of new neurons and a reduction in neurogenesis coincides with impaired learning of the hippocampal-dependent task of trace eyeblink conditioning. Using the toxin methylazoxymethanol acetate (MAM) for proliferating cells, we tested whether reduction of neurogenesis affected learning and performance associated with different hippocampal dependent tasks: spatial navigation learning in a Morris water maze, fear responses to context and an explicit cue after training with a trace fear paradigm. We also examined exploratory behavior in an elevated plus maze. Rats were injected with MAM (7 mg/kg) or saline for 14 days, concurrent with BrdU, to label new neurons on days 10, 12, and 14. After treatment, groups of rats were tested in the various tasks. A significant reduction in new neurons in the adult hippocampus was associated with impaired performance in some tasks, but not with others. Specifically, treatment with the antimitotic agent reduced the amount of fear acquired after exposure to a trace fear conditioning paradigm but did not affect contextual fear conditioning or spatial navigation learning in the Morris water maze. Nor did MAM treatment affect exploration in the elevated plus maze. These results combined with previous ones suggest that neurogenesis may be associated with the formation of some but not all types of hippocampal-dependent memories.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jjsrv2017-03-21T21:28:57.675Zstauthor: Snyder, year: 2005, journal: Neuroscience, title: A role for adult neurogenesis in spatial long-term memory., behaviorexamined: memory - water maze recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: Adult hippocampal neurogenesis has been linked to learning but details of the relationship between neuronal production and memory formation remain unknown. Using low dose irradiation to inhibit adult hippocampal neurogenesis we show that new neurons aged 4-28 days old at the time of training are required for long-term memory in a spatial version of the water maze. This effect of irradiation was specific since long-term memory for a visibly cued platform remained intact. Furthermore, irradiation just before or after water maze training had no effect on learning or long-term memory. Relationships between learning and new neuron survival, as well as proliferation, were investigated but found non-significant. These results suggest a new role for adult neurogenesis in the formation and/or consolidation of long-term, hippocampus-dependent, spatial memories.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jl7c82017-03-21T21:28:57.675Zstauthor: Meshi, year: 2006, journal: Nat Neurosci, title: Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment., behaviorexamined: memory - water maze recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Environmental enrichment increases adult hippocampal neurogenesis and alters hippocampal-dependent behavior in rodents. To investigate a causal link between these two observations, we analyzed the effect of enrichment on spatial learning and anxiety-like behavior while blocking adult hippocampal neurogenesis. We report that environmental enrichment alters behavior in mice regardless of their hippocampal neurogenic capability, providing evidence that the newborn cells do not mediate these effects of enrichment.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jmlwp2017-03-21T21:28:57.675Zstauthor: Madsen, year: 2003, journal: Neuroscience, title: Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat., behaviorexamined: memory - water maze recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: The generation of new neurons in the adult mammalian brain has been documented in numerous recent reports. Studies undertaken so far indicate that adult hippocampal neurogenesis is related in a number of ways to hippocampal function.Here, we report that subjecting adult rats to fractionated brain irradiation blocked the formation of new neurons in the dentate gyrus of the hippocampus. At different time points after the termination of the irradiation procedure, the animals were tested in two tests of short-term memory that differ with respect to their dependence on hippocampal function. Eight and 21 days after irradiation, the animals with blocked neurogenesis performed poorer than controls in a hippocampus-dependent place-recognition task, indicating that the presence of newly generated neurons may be necessary for the normal function of this brain area. The animals were never impaired in a hippocampus-independent object-recognition task. These results are in line with other reports documenting the functional significance of newly generated neurons in this region. As our irradiation procedure models prophylactic cranial irradiation used in the treatment of different cancers, we suggest that blocked neurogenesis contributes to the reported deleterious side effects of this treatment, consisting of memory impairment, dysphoria and lethargy.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jcrxq2017-03-21T21:28:57.675Zstauthor: Meshi, year: 2006, journal: Nat Neurosci, title: Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment., behaviorexamined: memory - water maze recent, neurogenesismanipulation: irradiation + EE, neurogenesisassociatedwith: nothing, species: mouse, abstract: Environmental enrichment increases adult hippocampal neurogenesis and alters hippocampal-dependent behavior in rodents. To investigate a causal link between these two observations, we analyzed the effect of enrichment on spatial learning and anxiety-like behavior while blocking adult hippocampal neurogenesis. We report that environmental enrichment alters behavior in mice regardless of their hippocampal neurogenic capability, providing evidence that the newborn cells do not mediate these effects of enrichment.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/je6i72017-03-21T21:28:57.675Zstauthor: Saxe, year: 2006, journal: Proc Natl Acad Sci U S A, title: Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus., behaviorexamined: memory - water maze recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jfl2k2017-03-21T21:28:57.675Zstauthor: Wojtowicz, year: 2008, journal: Eur J Neurosci, title: The effects of running and of inhibiting adult neurogenesis on learning and memory in rats, behaviorexamined: memory - water maze recent, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: rat, abstract: The presence of ongoing adult neurogenesis within the highly plastic hippocampal circuitry poses questions as to the relevance of new neurons to learning and memory. Correlational and causal evidence suggests that some, but not all, hippocampal tasks involve the new neurons. The evidence with regard to spatial learning in the water maze, one of the most commonly used hippocampal tasks, is contradictory. In this study we examined the effects of irradiation-induced reduction in neurogenesis on spatial learning and another standard hippocampal task, contextual fear conditioning, in rats that experienced normal cage conditions or voluntary running. The results indicate that reduced neurogenesis had little effect on spatial learning but severely impaired contextual fear conditioning. It was suggested that compensatory mechanisms within the hippocampus may have contributed selectively to sparing of spatial function. Performance on the fear conditioning task was weakly related to enhanced neurogenesis or running. The results improve our understanding of the functional role of adult neurogenesis in behaving animals.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jgzn12017-03-21T21:28:57.675Zstauthor: Jessberger, year: 2009, journal: Learn Mem, title: Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats., behaviorexamined: memory - water maze recent, neurogenesismanipulation: exog. Wnt inhibition, neurogenesisassociatedwith: nothing, species: rat, abstract: New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons with hippocampal function used ablation strategies that were not exclusive to the hippocampus or that were associated with substantial side effects, such as inflammation. We here used a lentiviral approach to specifically block neurogenesis in the dentate gyrus of adult male rats by inhibiting WNT signaling, which is critically involved in the generation of newborn neurons, using a dominant-negative WNT (dnWNT). We found a level-dependent effect of adult neurogenesis on the long-term retention of spatial memory in the water maze task, as rats with substantially reduced levels of newborn neurons showed less preference for the target zone in probe trials >2 wk after acquisition compared with control rats. Furthermore, animals with strongly reduced levels of neurogenesis were impaired in a hippocampus-dependent object recognition task. Social transmission of food preference, a behavioral test that also depends on hippocampal function, was not affected by knockdown of neurogenesis. Here we identified a role for newborn neurons in distinct aspects of hippocampal function that will set the ground to further elucidate, using experimental and computational strategies, the mechanism by which newborn neurons contribute to behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jtmqq2017-03-21T21:28:57.675Zstauthor: Jaholkowski, year: 2009, journal: Learn Mem, title: New hippocampal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning, behaviorexamined: memory - water maze recent, neurogenesismanipulation: transgenic Cyclin D2, neurogenesisassociatedwith: nothing, species: mouse, abstract: The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs known for their side effects and the results obtained vary greatly. We used a novel approach, cyclin D2 knockout mice (D2 KO mice), specifically lacking adult brain neurogenesis to verify its importance in learning and memory. D2 KO mice and their wild-type siblings were tested in several behavioral paradigms, including those in which the role of adult neurogenesis has been postulated. D2 KO mice showed no impairment in sensorimotor tests, with only sensory impairment in an olfaction-dependent task. However, D2 KO mice showed proper procedural learning as well as learning in context (including remote memory), cue, and trace fear conditioning, Morris water maze, novel object recognition test, and in a multifunctional behavioral system-IntelliCages. D2 KO mice also demonstrated correct reversal learning. Our results suggest that adult brain neurogenesis is not obligatory in learning, including the kinds of learning where the role of adult neurogenesis has previously been strongly suggested.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jv1b72017-03-21T21:28:57.675Zstauthor: Goodman, year: 2010, journal: Neuroscience, title: Young hippocampal neurons are critical for recent and remote spatial memory in adult mice, behaviorexamined: memory - water maze remote, neurogenesismanipulation: exog. MAM, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functionhttps://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jwfvk2017-03-21T21:28:57.675Zstauthor: Snyder, year: 2005, journal: Neuroscience, title: A role for adult neurogenesis in spatial long-term memory., behaviorexamined: memory - water maze remote, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: Adult hippocampal neurogenesis has been linked to learning but details of the relationship between neuronal production and memory formation remain unknown. Using low dose irradiation to inhibit adult hippocampal neurogenesis we show that new neurons aged 4-28 days old at the time of training are required for long-term memory in a spatial version of the water maze. This effect of irradiation was specific since long-term memory for a visibly cued platform remained intact. Furthermore, irradiation just before or after water maze training had no effect on learning or long-term memory. Relationships between learning and new neuron survival, as well as proliferation, were investigated but found non-significant. These results suggest a new role for adult neurogenesis in the formation and/or consolidation of long-term, hippocampus-dependent, spatial memories.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jxug12017-03-21T21:28:57.675Zstauthor: Jessberger, year: 2009, journal: Learn Mem, title: Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats., behaviorexamined: memory - water maze remote, neurogenesismanipulation: exog. Wnt inhibition, neurogenesisassociatedwith: enhanced memory, species: rat, abstract: New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons with hippocampal function used ablation strategies that were not exclusive to the hippocampus or that were associated with substantial side effects, such as inflammation. We here used a lentiviral approach to specifically block neurogenesis in the dentate gyrus of adult male rats by inhibiting WNT signaling, which is critically involved in the generation of newborn neurons, using a dominant-negative WNT (dnWNT). We found a level-dependent effect of adult neurogenesis on the long-term retention of spatial memory in the water maze task, as rats with substantially reduced levels of newborn neurons showed less preference for the target zone in probe trials >2 wk after acquisition compared with control rats. Furthermore, animals with strongly reduced levels of neurogenesis were impaired in a hippocampus-dependent object recognition task. Social transmission of food preference, a behavioral test that also depends on hippocampal function, was not affected by knockdown of neurogenesis. Here we identified a role for newborn neurons in distinct aspects of hippocampal function that will set the ground to further elucidate, using experimental and computational strategies, the mechanism by which newborn neurons contribute to behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jo0h22017-03-21T21:28:57.675Zstauthor: Saxe, year: 2006, journal: Proc Natl Acad Sci U S A, title: Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus., behaviorexamined: memory - water maze remote, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: nothing, species: mouse, abstract: Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jpf1j2017-03-21T21:28:57.675Zstauthor: Zhang, year: 2008, journal: Nature, title: A role for adult TLX-positive neural stem cells in learning and behaviour, behaviorexamined: memory - water maze reversal, neurogenesismanipulation: transgenic TLX, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/jqtlw2017-03-21T21:28:57.675Zstauthor: Garthe, year: 2009, journal: PLoS One, title: Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies., behaviorexamined: memory - water maze reversal, neurogenesismanipulation: exog. TMZ, neurogenesisassociatedwith: enhanced memory, species: mouse, abstract: Despite enormous progress in the past few years the specific contribution of newly born granule cells to the function of the adult hippocampus is still not clear. We hypothesized that in order to solve this question particular attention has to be paid to the specific design, the analysis, and the interpretation of the learning test to be used. We thus designed a behavioral experiment along hypotheses derived from a computational model predicting that new neurons might be particularly relevant for learning conditions, in which novel aspects arise in familiar situations, thus putting high demands on the qualitative aspects of (re-)learning.In the reference memory version of the water maze task suppression of adult neurogenesis with temozolomide (TMZ) caused a highly specific learning deficit. Mice were tested in the hidden platform version of the Morris water maze (6 trials per day for 5 days with a reversal of the platform location on day 4). Testing was done at 4 weeks after the end of four cycles of treatment to minimize the number of potentially recruitable new neurons at the time of testing. The reduction of neurogenesis did not alter longterm potentiation in CA3 and the dentate gyrus but abolished the part of dentate gyrus LTP that is attributed to the new neurons. TMZ did not have any overt side effects at the time of testing, and both treated mice and controls learned to find the hidden platform. Qualitative analysis of search strategies, however, revealed that treated mice did not advance to spatially precise search strategies, in particular when learning a changed goal position (reversal). New neurons in the dentate gyrus thus seem to be necessary for adding flexibility to some hippocampus-dependent qualitative parameters of learning.Our finding that a lack of adult-generated granule cells specifically results in the animal's inability to precisely locate a hidden goal is also in accordance with a specialized role of the dentate gyrus in generating a metric rather than just a configurational map of the environment. The discovery of highly specific behavioral deficits as consequence of a suppression of adult hippocampal neurogenesis thus allows to link cellular hippocampal plasticity to well-defined hypotheses from theoretical models.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/js86d2017-03-21T21:28:57.675Zstauthor: Jessberger, year: 2009, journal: Learn Mem, title: Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats., behaviorexamined: memory - water maze reversal, neurogenesismanipulation: exog. Wnt inhibition, neurogenesisassociatedwith: nothing, species: rat, abstract: New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons with hippocampal function used ablation strategies that were not exclusive to the hippocampus or that were associated with substantial side effects, such as inflammation. We here used a lentiviral approach to specifically block neurogenesis in the dentate gyrus of adult male rats by inhibiting WNT signaling, which is critically involved in the generation of newborn neurons, using a dominant-negative WNT (dnWNT). We found a level-dependent effect of adult neurogenesis on the long-term retention of spatial memory in the water maze task, as rats with substantially reduced levels of newborn neurons showed less preference for the target zone in probe trials >2 wk after acquisition compared with control rats. Furthermore, animals with strongly reduced levels of neurogenesis were impaired in a hippocampus-dependent object recognition task. Social transmission of food preference, a behavioral test that also depends on hippocampal function, was not affected by knockdown of neurogenesis. Here we identified a role for newborn neurons in distinct aspects of hippocampal function that will set the ground to further elucidate, using experimental and computational strategies, the mechanism by which newborn neurons contribute to behavior.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/f52je2017-03-21T21:28:57.675Zstauthor: Saxe, year: 2007, journal: Proc Natl Acad Sci U S A, title: Paradoxical influence of hippocampal neurogenesis on working memory., behaviorexamined: memory - working memory, neurogenesismanipulation: irradiation, neurogenesisassociatedwith: impaired memory, species: mouse, abstract: To explore the function of adult hippocampal neurogenesis, we ablated cell proliferation by using two independent and complementary methods: (i) a focal hippocampal irradiation and (ii) an inducible and reversible genetic elimination of neural progenitor cells. Previous studies using these methods found a weakening of contextual fear conditioning but no change in spatial reference memory, suggesting a supportive role for neurogenesis in some, but not all, hippocampal-dependent memory tasks. In the present study, we examined hippocampal-dependent and -independent working memory using different radial maze tasks. Surprisingly, ablating neurogenesis caused an improvement of hippocampal-dependent working memory when repetitive information was presented in a single day. These findings suggest that adult-born cells in the dentate gyrus have different, and in some cases, opposite roles in distinct types of memory.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/f6h3v2017-03-21T21:28:57.675Zstauthor: Tronel, year: 2010, journal: Hippocampus, title: Adult-born neurons are necessary for extended contextual discrimination, behaviorexamined: odor discrimination, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: nothing, species: mouse, abstract: New neurons are continuously produced in the adult dentate gyrus of the hippocampus. It has been shown that one of the functions of adult neurogenesis is to support spatial pattern separation, a process that transforms similar memories into nonoverlapping representations. This prompted us to investigate whether adult-born neurons are required for discriminating two contexts, i.e., for identifying a familiar environment and detect any changes introduced in it. We show that depleting adult-born neurons impairs the animal's ability to disambiguate two contexts after extensive training. These data suggest that the continuous production of new dentate neurons plays a crucial role in extracting and separating efficiently contextual representation in order to discriminate features within events.https://spreadsheets.google.com/feeds/list/1dJghaqrTBHEWphiJqDPoszoPfEp6T4n8GnMKZBjFLkc/od7/public/basic/f7vo82017-03-21T21:28:57.675Zstauthor: Tronel, year: 2010, journal: Hippocampus, title: Adult-born neurons are necessary for extended contextual discrimination, behaviorexamined: pain sensitivity, neurogenesismanipulation: transgenic nestin-Bax, neurogenesisassociatedwith: nothing, species: mouse, abstract: New neurons are continuously produced in the adult dentate gyrus of the hippocampus. It has been shown that one of the functions of adult neurogenesis is to support spatial pattern separation, a process that transforms similar memories into nonoverlapping representations. This prompted us to investigate whether adult-born neurons are required for discriminating two contexts, i.e., for identifying a familiar environment and detect any changes introduced in it. We show that depleting adult-born neurons impairs the animal's ability to disambiguate two contexts after extensive training. These data suggest that the continuous production of new dentate neurons plays a crucial role in extracting and separating efficiently contextual representation in order to discriminate features within events.