Neuroscientifically Challenged

Neuroligin and Autism

2010-09-19T00:37:00.007-04:00

The rapid increase in autism spectrum disorder (ASD) diagnoses over the last 15 years is alarming. A number of reasons for the rise have been suggested, some of which have sparked debate that occasionally becomes laden with vitriol. Many people, surprised and frightened by what they see as the unprecedented appearance of a novel disorder, are looking for answers and pointing fingers at parties they feel may be culpable. The etiology of ASD is unknown, and perhaps we will find that some of the impassioned claims made by groups like Generation Rescue are valid. But the idea that the emergence of such a disorder occurred overnight is not completely accurate.

Perhaps the earliest documented case of autism was that of Hugh Blair in 1747 (he was 39 at the time). Over the years other cases were identified, while many were misdiagnosed (frequently as infantile schizophrenia). In the 1940s, Leo Kanner and Hans Asperger developed the foundation for the modern diagnosis of autism by laying out a clearer description of the disorder. Interestingly, Kanner was disturbed by how quickly the rate of diagnosis of new cases of autism rose after his paper was published. This was in the 1950s. Since then, of course, the diagnosis has been refined and subsequently broadened, resulting in the class of ASDs we are familiar with today. In many ways, the history of autism up to this point is not so different from the history of other debilitating disorders like schizophrenia in that it consists of slow acknowledgement of a unique set of symptoms, followed by attempts at classification and an increase in the number of diagnoses due to clearer diagnostic criteria.

How the story of autism plays out is yet to be seen. But as the debate over vaccines and other potential causes continues to smolder, science is plodding along attempting to develop animal models for the study of the disorder. Several genetic mutations have been associated with ASDs. Mutations in genes that encode for proteins involved in the healthy functioning of synapses, called neuroligins and neurexins, have been directly linked to ASD. The result has been that many now classify the disorder as a synaptopathy, or a disease that is primarily caused by synaptic dysfunction. This has also led to the development of neuroligin-3 knockout (KO) mice as a rodent model for ASD.

A study in this month’s issue of The Journal of Biological Chemistry goes a step further in determining exactly how mutations in neuroligin can result in synaptopathies. The group coerced cultured neurons to express neuroligin mutations, which caused the protein to be folded improperly after it was manufactured. Furthermore, the misfolded proteins were not sent from the cell body out to the limits of the neuron. Thus the dendrites had a dearth of the protein, a factor that could be at least partly responsible for the unhealthy synaptic function that occurs when the neuroligin gene is mutated.

Protein misfolding is a culprit in Alzheimer's and Parkinson's disease as well, among others. While this study is an important step toward understanding autism, there are many more questions to be answered about how dependent the disorder may be upon protein misfolding and what other factors may be contributing to its variety of symptoms. And unfortunately attempts at developing treatments for protein misfolding diseases have not yet met with much success. Regardless, this is a positive development in understanding ASDs, a task that remains important not just for their treatment but for quelling the anxiety of a public struggling to understand the troubling incidence of the disorder.

De Jaco, A., Lin, M., Dubi, N., Comoletti, D., Miller, M., Camp, S., Ellisman, M., Butko, M., Tsien, R., & Taylor, P. (2010). Neuroligin Trafficking Deficiencies Arising from Mutations in the / -Hydrolase Fold Protein Family Journal of Biological Chemistry, 285 (37), 28674-28682 DOI: 10.1074/jbc.M110.139519

The Many Sides of GABA

2010-09-09T16:28:00.004-04:00

If you have a superficial level of knowledge about neuroscience, you probably won’t associate psychostimulants with gamma-aminobutyric acid (more commonly known as GABA). Just as you learn in early biology that a mitochondrion is the “powerhouse of the cell”, you learn in early neuroscience that GABA is the “primary inhibitory neurotransmitter of the brain”. And while this is often true (exceptions are being found on a regular basis), it perhaps doesn’t do justice to the diversity of roles that GABA can play.

There are, for example, many instances of GABA having an inhibitory effect on another inhibitory neuron. This can in effect stop the inhibition, potentially allowing for excitation by another neurotransmitter. Exactly this happens every time you make a voluntary movement. Neurons in the striatum release GABA that inhibits the action of neurons in the globus pallidus. These neurons normally inhibit areas of the thalamus that are necessary for movement but when they are inhibited the thalamus is essentially freed up, allowing us to move.

So, GABA-ergic actions don't necessarily mean inhibition as an end result. This is also true when it comes to the addictive properties of drugs. Dopamine (DA) neurons in the nucleus accumbens (NAc) directly modulate GABAergic connections to the ventral pallidum (VP), which itself sends GABAergic projections back to the NAc. Thus, it is easy to imagine that influencing DA transmission in the NAc, an inevitable outcome of drug use, also has an effect on GABAergic activity throughout the reward system.

Because of this, researchers like Claire Dixon and colleagues have been interested in how GABAa receptors are affected by the administration of drugs like cocaine. In a study published earlier this year in PNAS, Dixon et al. used knockout (KO) mice that had the gene for the alpha2 subunit of the GABAa receptor deleted. GABAa receptors containing these subunits are highly expressed in the NAc.

While these KO mice still demonstrated a stimulant response to cocaine (based on locomotor assays), they failed to show sensitization to the drug, i.e. their activity remained the same on repeated administrations while the wild-type (WT) mice's activity progressively increased. Additionally, cocaine's ability to facilitate conditioned reinforcement (lever pressing) was vastly reduced in the KO mice.

This indicates that GABA may have a role in mediating an addictive response to drugs. The authors hypothesize that the ability of cocaine to increase behaviors associated with environmental cues connected to the drug (lever pressing), and with conditioned activity (sensitization), may depend upon GABAa receptors. Alpha-2 subunits may allow cocaine to strengthen the association between cues and a drug, an association that underlies some of the most compulsive aspects of addiction. Thus, perhaps GABA receptors represent a potential, if not unlikely, target for treating addiction.

Dixon et al. (2010). Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAa receptors. PNAS, 107, 2289-2294.

Encephalon Celebrates its Emerald Anniversary

2008-09-29T01:50:00.007-04:00

Welcome to a landmark edition of Encephalon, the cream of the crop of brain science blog carnivals. This is the 55th edition of Encephalon, an anniversary achieved by less than 5% of married couples. Thus, this edition is a testament to the dedication of neuroscience bloggers: they don’t even take vows, yet they still stay committed to providing their readers with scintillating perspectives on developments in brain science. While more than 95% of married couples give up before their emerald anniversary, brain bloggers keep typing away, upholding their pledge to inform. (We will conveniently disregard the fact that Encephalon occurs biweekly, not annually, which, if considered, would make the analogy to marriage somewhat ridiculous.) Anyway, on to a selection of the best and brightest neuroscience blogs from the last couple of weeks.

Jeremy, a contributor to SharpBrains, provides a superbly written piece about assessing the affects of video games on adolescents. The rational perspective is greatly appreciated.

Greg from Neuroanthropology discusses neuroplasticity, and why the process has been oversimplified, the term overused, and the hype a little unjustified (hmmmm...this reminds me of mirror neurons).

The Neurocritic applies his caustic wit to the sensationalism that surrounds studies of the underlying personality traits of liberals and conservatives.

Cognitive Daily looks at a study of teenagers' sexual behavior. Listen up, abstinence-only advocates...

Dr. Shock MD reviews targets in the brain for deep brain stimulation, an intriguing treatment for highly resistant depression.

Mo at Neurophilosophy has an excellent and thorough discussion of a fascinating disorder: developmental topographagnosia.

Brain Blogger contributes its usual group of insightful posts. One discusses the potential antipsychotics may have in reducing the risk of suicide in depressed patients, something that current antidepressants fail at doing (they sometimes actually increase it). Another examines a little-known treatment for diabetes: the ketogenic diet.

Neuronism continues to impress with well-written contributions to Encephalon. This one is an overview of computational neuroscience, a little-understood but increasingly important field.

Dan at Sports are 80 Percent Mental is exceptional at getting us to consider the neuroscience of sports. This time he describes the success of different cognitive strategies in golf.

The Mouse Trap has two interesting postings about 8 common adaptive problems that drive evolution across species, they are here and here. Another post discusses a suggested expansion of the big five personality traits.

That's it for the emerald edition of Encephalon. Thanks for all your submissions! The next edition will be hosted by Combining Cognits on October 13th. Send your submissions to encephalon {dot} host {at} gmail {dot} com.

Encephalon #55 Call For Submissions

2008-09-22T21:59:00.002-04:00

Encephalon #55 will be hosted here next Monday--I may be too lazy to post original material, but I'm not too lazy to post links to other people's stuff! Please send potential postings to encephalon {dot} host {at} gmail {dot} com.

A Brief Hiatus

2008-09-05T23:20:00.003-04:00

Anyone who reads this blog regularly will have noticed that the frequency of posts has slowed quite a bit over the past few weeks. The truth is, between two jobs, an assistantship, classes, and my thesis I've occasionally had trouble finding time to eat and sleep, much less blog. So, I'm taking a brief hiatus to get my priorities under control. I'm definitely not closing up shop, and will still be hosting the 55th edition of Encephalon here on September 29th. Check back occasionally until then...thanks!

Have a Face Only a Mother Could Love? Without Serotonin She Thinks You're Just as Ugly as Everyone Else Does

2008-08-27T22:44:00.007-04:00

As the popularity of antidepressant medication has burgeoned over the past few decades, serotonin has become one of the more publicly recognized neurotransmitters. Along with that popularity has come a trend of attributing a wide variety of behaviors (especially depression) to “serotonin imbalances”. While this is a gross simplification in most cases, it does seem to be clear that there is a correlation between serotonin transmission and behavior.

A group of researchers at Case Western Reserve University has recently shown that the disruption of serotonergic function in mice is powerful enough to inhibit one of their strongest instincts: caring for their young. They used female mice with a mutation that causes a reduction in the expression of serotonergic genes and in the synthesis of the neurotransmitter, and monitored the survival of their young after they gave birth.

99% of the pups of the wild-type (normal) mice lived past the nurturing period of youth, but none of the pups of the serotonin-inhibited mothers survived. In fact, most of them were dead after 3-4 days. When the researchers took pups born to the serotonin-deficient mothers and gave them to the wild-type mothers to raise, the pups survived. The serotonin-deficient mothers failed to nurse their pups, didn't build nests for them, and didn't organize them near her in a huddle (which is necessary for their warmth and survival).

The serotonin-inhibited mothers did not seem to exhibit deficiencies in any other behavioral assay, such as maze-running or olfaction. They were not deemed to be overly anxious as measured by locomotor tasks, but instead of mothering they often simply paced the cage and engaged in repetitive digging. The authors suggest that anxiety behaviors may have been more prominent if not for the relaxing effect lactating has on rodents.

How applicable these findings are to humans is, of course, completely unclear. Postpartum depression is often treated with selective serotonin reuptake inhibitors, but even if untreated doesn’t generally lead to abandonment of one’s children. Regardless, finding a neurochemical substrate for an instinct like caring for one's young is notable, as it is a behavior essential to what is widely considered the goal of existence: high reproductive fitness.

Reference:

Lerch-Haner, J.K., Frierson, D., Crawford, L.K., Beck, S.G., Deneris, E.S. (2008). Serotonergic transcriptional programming determines maternal behavior and offspring survival. Nature Neuroscience, 11(9), 1001-1003. DOI: 10.1038/nn.2176

Cocaine and Glutamate, Part Two

2008-08-18T22:33:00.004-04:00

Ten years ago, if you had asked a neuroscientist what neurotransmitter is most important to the development of an addiction, nine out of ten times they would have said “dopamine”. Ask the same question today, however, and you’ll probably be told that it is impossible to pin such a complex process on one neurotransmitter, as clearly (at least) both dopamine and glutamate are integral to the addiction process.

In hindsight, it is not surprising that glutamate be involved in addiction. Glutamate is the most abundant excitatory neurotransmitter in the brain. It is utilized in a number of cognitive processes, but essential to synaptic plasticity, and thus to learning and memory. And addiction is really just a type of learning—perhaps learning gone haywire, but learning nonetheless. It involves the association of a positive experience with the drug that was taken to induce it, resulting in a seeking of the drug to reproduce the experience. In addiction, however, unlike other learning processes, this seeking becomes obsessive and compulsive.

It is now thought that cocaine use causes glutamatergic synapses on dopamine neurons in the ventral tegmental area (VTA), a midbrain region of the reward system, to become stronger—even after just a single use. This makes the dopamine neurons there more sensitive to glutamate, causing a hyper-sensitivity to cocaine that results in addiction. It is believed the strengthening of these glutamatergic synapses involves changes in the composition of subunits of glutamate receptors.

In order to shed more light on the specifics of this subunit restructuring, a study published last week in the journal Neuron investigates the behavioral results of changes in glutamate receptor structure. The authors created genetically engineered mice that lacked one of three types of glutamate receptor subunits: GluR1, GluR2, or NR1.

As expected, they found that cocaine-induced strengthening of synapses on dopamine neurons was dependent on the functionality of glutamate receptor subunits, specifically the GluR1 and Nr1 subunits. They also, however, made two major discoveries. First, deletion of the GluR1 subunit caused the extinction of cocaine-seeking behavior to be slowed. Thus, these mice continued to seek cocaine long after cocaine had been withheld from them, when normal mice had already “forgotten” about the drug. By extension, this might mean that pharmacological stimulation of this receptor could have potential as a treatment for addiction.

Additionally, they found that the NR1 receptor subunit was necessary for the reinstatement of drug-seeking behavior after extinction. This is analogous to relapse behavior in humans. Once again, this could have pharmacological potential in addiction treatment.

Of course, these pharmacological applications, if viable, will take some time to work out. As you can imagine, it will not be easy to create a treatment that can selectively inhibit specific subunits on glutamate receptors in a particular brain region (although this can and has been done with other receptor subunits). And, with how important glutamate is to learning in general, there is potential that a treatment aimed at glutamate receptors could disrupt other cognitive processes. So, if you’re waiting for a pill to solve your cocaine problem, you may have to wait a while longer. A cocaine vaccine (see here) may be available first.

Reference:

ENGBLOM, D., BILBAO, A., SANCHISSEGURA, C., DAHAN, L., PERREAULENZ, S., BALLAND, B., PARKITNA, J., LUJAN, R., HALBOUT, B., MAMELI, M. (2008). Glutamate Receptors on Dopamine Neurons Control the Persistence of Cocaine Seeking. Neuron, 59(3), 497-508. DOI: 10.1016/j.neuron.2008.07.010

Encephalon #52 at Ouroboros

2008-08-18T16:53:00.003-04:00

Encephalon #52 is up at Ouroboros, a science blog that focuses on the biology of aging--which is also my current area of research! Check it out...

Why You Can't Remember Where Your Keys Are

2008-08-14T22:45:00.004-04:00

Why do we remember? To some this might seem like a ridiculous question. Memory is so intricately intertwined with our conception of existence that it is difficult to objectively ask questions about why we developed the capacity for it, or to imagine the possibility of a life without it. If one is to assume, however, that like every other facet of the human condition, memory evolved from rudimentary beginnings, then “why do we remember?” becomes not only a reasonable question, but an important scientific inquiry.

Looking at memory from an evolutionary standpoint, one must assume that it developed to serve an adaptive purpose. Of course, when one begins to cogitate on what that purpose might be, it is easy to stumble into purely speculative territory. Evolutionary psychologists have received much criticism for this. Examples of hypotheses about evolutionary origins gone wrong shouldn’t serve to negate the efforts of the entire field, however, it should just encourage a more cautious approach.

Two psychologists from Purdue University, James Nairne and Josefa Pandeirada, published an article in this month’s Current Directions in Psychological Science that describes their lab’s approach to the evolution of memory. It attempts to avoid blatant speculation by beginning with simple hypotheses about the purposes of memory, and testing their validity before moving on to more complex explanations.

They start with three basic assumptions that an evolutionarily adaptive perspective on memory would require. The first is that memory probably didn’t evolve just to recall the past. In other words, memory must serve a purpose, allowing us to predict the probability of future events given certain circumstances. Second, memory should be governed by priorities. We shouldn’t remember all environmental stimuli with equal clarity. This would lead to a maladaptive inability to remember the most salient stimuli, and would clutter our memories with unimportant details about our environment. Third, memory should assign the highest salience to environmental stimuli that improve reproductive fitness and evolutionary adaptiveness. So, those things in our environment that have historically proven to be the most important for survival should garner the most mnemonic attention.

Based on these assumptions, Nairne and Pandeirada conducted behavioral experiments to determine if survival-related processing enhances retention. After an initial study indicated that participants were able to remember survival-related words better than other words that required a similar level of processing, the researchers designed a large study that compared survival processing to some of the most renowned mnemonic techniques, like imagery and the use of autobiographical cues. They found that survival processing resulted in higher average recall rates than any of the other techniques tested.

So perhaps we remember because it allows us to predict where danger might lie, who we can trust, successful ways to court a mate, how to obtain food, etc. Maybe this seems obvious, but it only becomes so with a little thought. Our inherent predisposition toward an anthropocentric view of the world often causes us to unconsciously regard our mnemonic abilities as above the laws of science and the progression of evolution. We don’t usually think of our memory as evolving in the same way that our bodies have, but the idea that we have developed context-specific cognitive modules through evolution is becoming hard to ignore. Then again, perhaps there is a reason we have a tendency to ignore such explanations for our cognitive abilities. Anthropocentrism may be adaptive in its own right.

Reference:

Nairne, J.S., Pandeirada, J.N. (2008). Adaptive Memory: Remembering With a Stone-Age Brain. Current Directions in Psychological Science, 17(4), 239-243. DOI: 10.1111/j.1467-8721.2008.00582.x

Cocaine's Addictive Influence Begins Even Before Euphoria

2008-08-11T22:12:00.008-04:00

It has long been known in the addiction field that exposure to drug-associated stimuli, commonly referred to as relapse triggers, is one of the primary causes of relapse in abstinent addicts. Neuroscience studies have added evidential support for this perspective by providing a molecular explanation for it. It is thought to principally involve two neurotransmitters: dopamine and glutamate, and a region of the reward system called the ventral tegmental area (VTA).

The VTA is part of the midbrain, and two major dopamine pathways—the mesolimbic and mesocortical—run through it. It is chock full of dopamine, glutamate, and GABA neurons. When a subject who has acquired the self-administration of a drug like cocaine is exposed to environmental stimuli they have associated with the drug, glutamate and dopamine are released from the VTA. This rush of neurotransmitters activates another area of the reward system, the nucleus accumbens, and usually leads to an attempt to reinstate drug-using behavior.

As might be expected, cocaine use itself also results in increased dopamine and glutamate transmission in the VTA. Interestingly, however, this increased neurotransmitter activity begins before the pharmacological effects of cocaine can occur. While it takes about 10 seconds for cocaine to cross the blood-brain barrier and exert its psychotropic influence, dopamine levels rise almost immediately. Thus, it would seem that the reinforcing qualities of the drug may not be solely attributable to the euphoria it produces.

Roy Wise, Bin Wang, and Zhi-Bing You published an article last week in PloS One that investigates this phenomenon. They injected cocaine methiodide (MI)—an analogue to cocaine that does not cross the blood-brain barrier to have a psychotropic effect—into rats and measured the resultant changes in neurotransmitter levels.

In rats that had never been exposed to cocaine, the MI had no effect. But in those that had previously acquired cocaine self-administration, the MI caused VTA glutamate release. It was also enough to cause these rats to reacquire cocaine-seeking behavior that had been rendered extinct.

This study speaks to the complexity and potency of the inclination toward relapse. While it has been known that external cues can cause changes in brain chemistry that predispose one toward relapse, this is the first evidence that internal cues (besides the actual rewarding mental influences of the drug) may also play a role in reinstating drug use. Fortunately, these added influences can be avoided by continued abstinence from the drug. But once a drug is used, how pleasurable the resultant experience is may have little to do with the re-emergence of drug cravings.

Reference:

Roy A. Wise, Bin Wang, Zhi-Bing You, Antonio Verdejo García (2008). Cocaine Serves as a Peripheral Interoceptive Conditioned Stimulus for Central Glutamate and Dopamine Release. PLoS ONE, 3 (8) DOI: 10.1371/journal.pone.0002846

The Evolution of Schizophrenia

2008-08-07T22:50:00.008-04:00

Schizophrenia is one of the more frightening and debilitating mental disorders. It can cause hallucinations, delusions, and social withdrawal, as well as a variety of other cognitive afflictions. While scientists have yet to decipher the etiology of the disease, its high inheritability rate (60-85%) has led many to look for answers in genetics. Since schizophrenia affects cognitive functions that are distinctly human (like language-related abilities), some have begun to consider ways in which the human brain has evolved, and how this could shed light on the causes of schizophrenia.

A group of researchers published a study this week in Genome Biology that examines the relationship between schizophrenia and the evolution of higher order processes in humans. They first investigated the evolution of molecular mechanisms involved in human cognition. Then they examined the changes that occur in schizophrenic patients, and looked for an overlap between the two data sets.

They found that, of 22 biological processes that show a strong indication of recent positive selection, 6 involve disproportionate numbers of genes that are implicated in schizophrenia. All of those 6 are implicated in energy metabolism, or the regulation of energy flow through the body/brain.

The group then performed comparative analyses between schizophrenic patients, healthy controls, chimpanzees, and rhesus macaques. The reason other primates are used in such a study is to further delineate the evolutionary picture. If an evolutionary change in the brain can be found between a human and a chimpanzee, for example, then one can assume it was a human development that took place after the divergence of chimps and humans.

The researchers saw distinct differences between the four groups, indicating recent evolutionary changes. They again found that metabolites that play key roles in energy metabolism (e.g. lactate, glycine, choline) were affected.

These results caused the scientists to suggest that recent evolutionary changes in our brain’s energy metabolism may have been integral in the development of the higher order processes we associate with the human brain. These changes would have been necessary to meet increased energy demands as the brain went through increases in size, number of synaptic connections, extent of neurotransmitter turnover, etc.

It seems that brain energy metabolism is negatively affected in disorders like schizophrenia. For example, decreases in blood flow to the prefrontal cortex have been reported when schizophrenics attempt cognitive tasks. The researchers in this study suggest that, after the last 2 million years of rapid evolution, the human brain is basically pushing the limits of its metabolic abilities. Thus, any aberrations in the brain’s energy metabolism capabilities could have drastic results, schizophrenia being one example.

According to this perspective, schizophrenia is a by-product of our rapidly evolving brains. Because we are operating at near-capacity levels, any reduction in our ability to produce and process brain energy can be debilitating. In order to verify this hypothesis, however, much more work examining the correlation between evolution, energy metabolism, and brain disorders will need to be done.

Reference:

Khaitovich, P., Lockstone, H.E., Wayland, M.T., Tsang, T.M., Jayatilaka, S.D., Guo, A.J., Zhou, J., Somel, M., Harris, L.W., Holmes, E., Paabo, S., Bahn, S. (2008). Metabolic changes in schizophrenia and human brain evolution. Genome Biology, 9(8), R124. DOI: 10.1186/gb-2008-9-8-r124

Good News for Fruit Fly Truckers

2008-08-04T20:15:00.006-04:00

Science has arrived at credible hypotheses to explain a number of complex waking behaviors. Yet an overtly simpler behavior—one that doesn’t vary much from situation to situation or person to person, and involves a minimal amount of physical and mental activity—baffles us, leaving us with a surfeit of hypotheses that seem to explain some aspect of it, but none that is sufficient to explain it as a whole.

That perplexing behavior is sleep. It comprises 1/3 of our lives, yet we don’t really know why. It seems to play a number of roles. It acts as a restorative influence on the body, bolstering the immune system and our overall feeling of restedness. It also seems to be very important during development, occupying most of an infant’s time as its brain is rapidly maturing. And indications are that it's an important part of memory consolidation.

But none of these purported reasons for sleep can explain on its own why it may have evolved. For example, it seems that the restorative functions of sleep could be achieved without putting ourselves in a state where we are oblivious to our external environment—something that is very dangerous evolutionarily. The necessity of sleep during development doesn’t explain why adults need to continue doing it, and, while it may be less efficient, memory storage is still possible after sleep deprivation.

The unsatisfying nature of each of these hypotheses on their own has caused some to support an explanation of sleep that stresses its adaptive importance in helping our ancestors remain safe from predators. Sleep incapacitates us at a time (in the dark) when we are most vulnerable, keeping ancient humans out of the paths of nocturnal carnivores. While this might be evolutionarily adaptive, however, it doesn’t explain why we experience minimal conscious ability to monitor our environment during sleep (why not just a restful but conscious state?), or why animals that are predators and not generally hunted sometimes sleep a great deal (e.g. lions).

In addition to lacking a clear purpose for sleep, we have yet to understand the physiological mechanisms behind it. This has caused some scientists to turn to the model organism Drosophila for answers. The sleeping state of Drosophila has much in common with that of mammals. It involves homeostatic and circadian regulation, consists of long periods of immobility, becomes more fragmented with age, etc.

While scientists still haven’t come to a consensus on the reason for sleep, Drosophila research has led to several findings that have aided in the elucidation of its physiology. For example, it has helped to explain the role of neurotransmitters, like serotonin, that play a key role in sleep regulation. Recently, it has led to an amazing discovery: a way to reverse the effects of mental fatigue due to sleep deprivation by manipulating gene expression.

The cognitive deficits that Drosophila develop as a result of sleep deprivation are similar to those exhibited by humans. The extent of the impairment is correlated with the amount of time spent awake. Learning in Drosophila has been found to be dependent on a structure known as the mushroom bodies (MBs)—thought to be somewhat homologous to our hippocampus—and a dopamine receptor called the dopamine D1-like receptor (dDA1).

Scientists at the Washington University School of Medicine recently investigated whether sleep-loss induced learning impairments could be reversed in Drosophila. They used a learning task that takes advantage of the flies’ predisposition to fly towards a light. The flies were placed in a T-maze with a lighted tunnel and a dark tunnel. The lighted tunnel also contained a piece of filter paper soaked in quinine, which has a bitter taste and repels flies. On repeated trials, the flies had to learn to resist their urge to fly down the lighted tunnel by associating it with the bitter smell of quinine.

Sleep deprivation led to a decreased ability to perform on the learning assay. Additionally, the researchers found that learning the task at all was heavily dependent on the functionality of the dDA1. When they studied mutant flies with a deficiency in this receptor, learning was significantly reduced. Thus, they manipulated dDA1 in the MBs to be over-expressed and surprisingly found that this caused learning deficits after sleep deprivation to return to baseline levels.

The authors of the study use these findings to make a couple of postulations about sleep and sleep deprivation. First, they suggest that, although sleep deprivation probably affects several pathways, it may target specific brain areas that are essential for functioning (in this case, the MBs). Also, they hypothesize that one of the functions of sleep may be to restore levels of neurotransmitters essential to proper functioning, like dopamine.

While this finding has already led to speculation on popular science sites about a pharmacological method of negating sleep-deprived cognitive impairments, it’s important to remember that this was a study done in fruit flies, and much work would have to be done to find if it is potentially applicable to humans. Regardless, while the overall purpose of sleep continues to be a mystery, this study does add one more piece to the puzzle in understanding its physiological mechanisms.

Reference:

SEUGNET, L., SUZUKI, Y., VINE, L., GOTTSCHALK, L., SHAW, P. (2008). D1 Receptor Activation in the Mushroom Bodies Rescues Sleep-Loss-Induced Learning Impairments in Drosophila. Current Biology DOI: 10.1016/j.cub.2008.07.028

Dopamine and the Bruce Effect

2008-07-30T23:59:00.006-04:00

If you take a recently impregnated female mouse and place her in a cage with an unfamiliar male, something curious often happens. The female, upon smelling the new male's urine, spontaneously aborts the fetus as her body drastically reduces its production of prolactin (PRL), a hormone responsible for progesterone secretion and thus essential to maintaining a pregnancy. The embryo fails to implant and the female begins ovulating again, making her receptive to copulation attempts by the new male. This strange phenomenon was first noticed by biologist Hilda Margaret Bruce in 1959, and is referred to as the Bruce effect.

The Bruce effect has been a curiosity to biologists since its discovery, as many have sought to explain why the female mouse’s body would seemingly be programmed to destroy her own offspring. After all, isn’t reproduction supposed to be the “goal” of evolution, and thus of life?

Several explanations have been offered to make sense of the Bruce effect. One is that it is an adaptive mechanism to protect the female’s potential maternal investment from being lost to infanticide. Infanticide is a fairly common practice among many species, and is usually committed by the male.

A male often cannot visibly determine if a female is pregnant when he encounters her (if her fertilization has been recent). Thus, upon copulating with her, he takes a risk that she may already be pregnant. If she were to produce offspring from another male, he might mistake them for his own and invest his resources in raising them (whatever “raising” may mean in the particular species). The risk being, if they are not his offspring he makes the investment but does not gain the benefit of his genes being passed on to a new generation. This is evolutionary suicide, and some biologists believe the males of many species instinctually go to great lengths to avoid it.

One way to make sure none of one’s resources go to raising another’s offspring is to simply get rid of the offspring. Male mice will frequently be infanticidal for the first three weeks after copulating with a female. Then they act paternally for about two months, after which they regress to their infanticidal tendencies. Coincidentally (not really), the mouse gestation period is three weeks and the weaning period is about two months. So the male times his infanticidal behavior perfectly to ensure that any offspring he helps to wean are his (note again that this is instinctual, not conscious behavior).

So, many biologists have suggested the Bruce effect may be a way for the female to avoid going through a pregnancy and investing all of her resources in it, just to have her progeny killed by a new male. Instead, she can abort the fetus and be receptive to him, in the process ensuring that she will have the opportunity to raise offspring into adulthood.

An alternative explanation for the Bruce effect involves mate selection. In this hypothesis, blocking the pregnancy is beneficial to the female by providing her with a novel mating partner. In highly territorial animals like rodents, a female may be more inclined to mate with the mouse whose urine she can currently smell, as he is most likely dominant in that territory.

Whatever the reason for the effect, a female also seems to reach a point when she has too much invested in the pregnancy already for it to be beneficial to abort. In mice, this occurs after the first few days of pregnancy, when the embryo becomes implanted. After this point, the Bruce effect no longer occurs. This is thought to involve a type of evolutionary weighing of the pros and cons. After three days of pregnancy, the female “decides” she has put enough time into her fetus that it would be counter-productive to start over. She must take the risk.

While the evolutionary cause of the Bruce effect may not be known for some time, a study published in July's Nature Neuroscience brings us closer to understanding the neural mechanism behind it. It seems to be dependent upon the versatile neurotransmitter dopamine.

When the female mouse smells another male’s urine, two sense organs in the nasal cavity are involved in processing the scent. One, called the vomeronasal organ (VNO), has pheremone-sensing capabilities. The other, the main olfactory epithelium (MOE), detects odorants. Both organs project fibers to the main olfactory bulb (MOB) and accessory olfactory bulb (AOB). The MOB contains a large population of dopaminergic interneurons, known as the juxtaglomerular dopaminergic interneurons (JGD).

As these dopamine interneurons are highly involved with olfaction, the scientists involved in the study wondered if they might also play a role in blocking pregnancy through urine odor detection. When they measured dopamine levels in the female mouse brain, they found a surge in dopamine occurred after the third day of the pregnancy—the time at which male odor no longer has an abortive effect on the fetus.

When they administered a dopamine antagonist, which blocks dopamine transmission, spontaneous abortion again occurred, even after implantation on the third day. Therefore, dopamine appears to interfere with the perception of the male urine odors, and is responsible for the suppression of the Bruce effect after the third day of a mouse pregnancy.

These findings represent a new understanding of the roles of the olfactory bulb, implicating it in the control of reproduction and social behavior in rodents. While not really applicable to humans, making sense of the Bruce effect is important in comprehending social behavior that, without knowledge of evolutionary theory, seems otherwise inexplicable.

Reference:

Che Serguera, Viviana Triaca, Jakki Kelly-Barrett, Mumna Al Banchaabouchi, Liliana Minichiello (2008). Increased dopamine after mating impairs olfaction and prevents odor interference with pregnancy Nature Neuroscience, 11 (8), 949-956 DOI: 10.1038/nn.2154

Gene Therapy for Prion Diseases

2008-07-26T13:44:00.007-04:00

Prion diseases are relatively rare in humans. The most common, Creutzfeldt-Jakob disease (CJD), afflicts only about one in every million people. Despite their low prevalence, however, these diseases (also known as transmissible spongiform encephalopathies, or TSEs) receive a fair amount of attention from the media and the scientific community. This interest is probably due to their enigmatic mechanism, potential for epidemic spreading, frightening neurodegenerative features, and (as of yet) incurability.

TSEs are neurodegenerative diseases thought to be the result of a prion infection. This distinguishes them from most other sicknesses, which are caused by microbial infections. Prions are infectious agents made up entirely of proteins (the word itself comes from a combination of proteinaceous and infectious).

A prion protein called PrPC (the C stands for cellular, and actually should be in superscript but I can't get Blogger to do this) is commonly present on the membranes of our cells, although its function has not yet been fully resolved. PrPSc (the Sc is for Scrapie, the first identified prion disease—in sheep) is an isoform of PrPC and the toxic form of PrP. When it enters the brain it can cause conformational changes in PrPC, turning it into PrPSc.

PrPSc is extremely resistant to being broken down. Thus, it accumulates in the brain, forming protein aggregates known as amyloid fibers. These are toxic to brain cells, and eventually kill them. Astrocytes, which perform a number of supporting functions in the cell (one of which is cleaning up), find the dead neurons and digest them.

This creates actual holes in the brain, giving it a sponge-like appearance (and the reason for these disorders being referred to as spongiform). This continued neurodegeneration leads to a number of clinical symptoms, like changes in personality, depression, involuntary movements, lack of coordination, dementia, and eventually the complete loss of the ability to move or speak. TSEs are currently incurable, and an effective method of therapeutic treatment has not been found. The aggregation of PrPScs occurs over a long period of time, giving the diseases incubation periods that range from 10-60 years depending on the disease type.

TSEs can be the result of genetic or sporadic (non-genetic) causes. A mutation in the prion protein (PRNP) gene can cause the production of PrPSc instead of PrPC, leading to a prion disease. TSEs are also contagious—not through the air or normal contact, but through exposure to infected tissue, body fluids, or contaminated medical instruments (due to the durability of prions, they can survive normal sterilization procedures).

Unfortunately, we have learned about how TSEs are spread by witnessing several deadly epidemics. Around the middle of the twentieth century, a TSE arose in a New Guinean tribal people called the Fore. It is thought to have spread through cannibalistic ritual practices, and killed over 1,000 of their people. In the 1980s 60 deaths were linked to the transmission of CJD through contaminated medical instruments. Around the same time, 85 people died after receiving prion-infected growth hormone injections. In the 1990s, a type of CJD called variant CJD (vCJD) was linked to eating beef infected with the bovine form of TSE, bovine spongiform encephalitis (BSE), or mad cow’s disease. vCJD has a shorter incubation period than CJD, with the median age at death being 28, versus 68 for CJD. The illness also has a longer duration, with a median of 15 months for vCJD and only 4-5 months for CJD. Up to 200 people worldwide have died from vCJD.

BSE is thought to be caused by feeding cattle the remains of other infected cattle. This practice was stopped in 1989. Due to the long incubation period of the disease, however, some fear that the real mad cow disease epidemic has yet to manifest itself.

An article in PloS One this month addresses a possible way to control such an outbreak, with the successful application of a gene therapy treatment for TSEs. A natural resistance to prion diseases has been discovered in both animals and humans, and specific mutant forms of the mouse Prnp gene have been found to reduce the replication of prions in infected cells.

The researchers involved in the study injected this mutant gene into the brains of mice infected with prions. In order to make the study more relevant to human TSEs, they did this during late stages of the disease, at 80 and 95 days post infection. This increases relevance because, due to the long incubation period of TSEs, most people are unaware they have contracted them until serious symptoms develop.

They found that, after two injections, treated mice survived 20% longer than non-treated mice. They exhibited substantial improvements in behavioral symptoms, as well as a significant reduction of spongiosis and astrocytic activity in the brain.

The authors suggest this effect occurred because the mutated Prpn gene produces a protein that cannot be converted into PrPSc. Additionally, the protein it makes competes with PrPC for PrPSc, slowing the conversion of existing PrPC to the toxic form. Basically, this means that the PrPSc doesn’t realize the new proteins can’t be transformed, and still attaches itself to them. This delays the overall disease progression, as many of these PrPScs are busy trying to make conformational changes to no avail.

These results are promising not only because they slow down the aggregation of toxic prions, but because the effect was demonstrated at such a late stage of disease. Unfortunately, the disease was slowed but not cured. Regardless, the hint of a successful method of treatment for prion diseases might be comforting to nervous meat eaters who are fearing a future vCJD outbreak. I’m a vegetarian (and have been for a long time), so as long as the soybeans in my tofu weren’t grown with meat and bone meal fertilizer, I feel reasonably safe.

Reference:

Karine Toupet, Valérie Compan, Carole Crozet, Chantal Mourton-Gilles, Nadine Mestre-Francés, Françoise Ibos, Pierre Corbeau, Jean-Michel Verdier, Véronique Perrier, Alfred Lewin (2008). Effective Gene Therapy in a Mouse Model of Prion Diseases PLoS ONE, 3 (7), 0- DOI: 10.1371/journal.pone.0002773

The Singing Bass: Kitschy or Insightful?

2008-07-22T23:18:00.000-04:00

If you were listening in on a discussion about the evolutionary origins of language, you might expect to hear theories bandied about concerning evidence for language-like processes in apes. You probably wouldn’t be too shocked to hear someone bring up an example of language in parrots. You might, however, be a little surprised if the conversation turned to the origins of human vocalization in toadfish.

Perhaps this isn’t that surprising, though, when one considers how much of our evolutionary beginnings are shared with fishes. While (of course) fish don’t have language in a human sense, some species do have the ability to make vocalizations in certain situations, like courtship or defense of territory. Although they lack an air tube leading to the mouth, and a larynx to create the vibrational variations more common to land animal utterances, some are able to make noises with an air sac used primarily for buoyancy control and secondary respiration, known as the gas bladder. Fish of the batrachoidid family in particular (i.e. the midshipman and toadfish) have a diverse group of vocalizations. They vary depending on the context, with specific calls for aggression, surprise, or mating (among others).

This leads to a couple of different hypotheses. One is that the ability to vocalize evolved independently a number of times throughout history: in fish, amphibians, reptiles, mammals, and birds. Another is that there is a common origin for the ability to vocalize that can be traced back millions of years to a piscine ancestor. A study published in this week’s Science explores the latter hypothesis by investigating the development of the neural circuitry for vocalization in larval fish.

Studying embryos or larvae is a method used in evolutionary developmental biology. Similarities in the embryonic development of two organisms are considered evidence of a common ancestor. This conclusion is based on the fact that evolution works by the alteration of existing structures. Thus, two related organisms will theoretically have similar embryonic development to a certain point, where it will then diverge in order to form the structures that make the two creatures taxonomically different. A commonly given example of this is the vestigial pharyngeal pouches (gill slits) that human embryos possess early in development.

The authors of the study in Science found that the vocal motor neurons in batrachoidid fish develop in a segmental region that spans the caudal hindbrain and rostral spinal cord. This is similar to the pattern of development found in other vertebrates like frogs and birds. Adult phenotypes seem to indicate a comparable developmental process in reptiles and mammals as well, although embryological studies here are lacking.

The authors conclude that these analogies in the distribution of vocal neurons indicate a conserved developmental pathway that involves Hox gene expression. They suggest this pathway predates the radiation of fish, originating over 400 million years ago. Thus, perhaps the Big Mouth Billy Bass is a more astutely-developed toy than it first appears to be…no, it’s still stupid.

Reference:

Bass, A.H., Gilland, E.H., Baker, R. (2008). Evolutionary Origins for Social Vocalization in a Vertebrate Hindbrain-Spinal Compartment. Science, 321(5887), 417-421. DOI: 10.1126/science.1157632

Mirror Neurons May Be Responsible For Global Warming & U.S. Economic Woes

2008-07-18T00:59:00.009-04:00

Since their discovery in the 1990s, mirror neurons have experienced a degree of fanfare uncommon to findings in the field of neuroscience. Mirror neurons are so named because they are activated both when a primate participates in a task, and while watching another complete the same task, thus “mirroring” the behavior of the other animal. This unique activation pattern has led some to suggest that mirror neurons are integral not only to imitation, but also to understanding that others have their own mental states (theory of mind). By extension, it has been hypothesized that mirror neurons are necessary for language acquisition and social interaction. Dysfunctions in mirror neurons have even been offered as a possible cause of autism.

Thus, they have come to be viewed as a very special kind of neuron, with a versatility and importance to brain function that is unrivaled by other types of brain cells. But, do mirror neurons deserve the exalted status that some have ascribed to them? In short: probably not.

Mirror neurons do seem the play an interesting role in cognition. Primate studies have found mirror neurons to be activated in correlation with focusing on a particular goal or intention of movement. They are also activated in a selective fashion, with specific groups corresponding to different goals of an action, e.g. grasping to move vs. grasping to eat. Of additional interest, they have been found to respond to sounds associated with an observed action.

fMRI studies in humans have revealed specific activity in areas where mirror neurons are thought to be located, such as the ventral premotor (vPM) and anterior intraparietal sulcus (alPS), during observation and imitation of movement.

But, while these findings in humans and non-human primates are intriguing, they don’t support the rampant speculation that has followed about the role of mirror neurons in overall cognitive function. Experiments with monkeys to date haven’t assessed the ability to imitate, experience empathy, display theory of mind, or use language. Of course, it is debatable to what extent some of these attributes even exist in non-human primates, or if they can be studied if they do.

As for humans, neuroimaging experiments have allowed scientists to determine which regions of the brain are active during imitation or observation of an action. The specific neurons that are utilized, however, and any physiological characteristics that make them unique, cannot be assessed with current imaging technology.

Thus, the roles attributed to mirror neurons in the last decade since their discovery may have been an overly ambitious attempt to describe their function. By extension, implying that their malfunction is critical in autism could really be jumping the gun.

In an essay in last week’s Nature, Antonio Damasio and Kaspar Meyer discuss the exaggerated claims about mirror neurons, and suggest a rational hypothesis for how they may work. Twenty years ago Damasio proposed a theory known as “time-locked multimodal activation” to explain the development of complex memories. The theory is based on the proposed existence of groups of neurons that, during the encoding of memories, receive input from a number of different sites. Damasio termed these neuronal groups convergence-divergence zones (CDZ). He suggested there are two types of CDZs: local CDZs, which collect information from areas close to a sensory cortex (e.g. the visual cortex), and non-local CDZs, which are higher-order structures of the brain where the information from local CDZs converges.

According to this theory, when a memory is formed—Damasio and Meyer use the example of a monkey opening a peanut shell—all the information about the event converges on a non-local CDZ. Then, if the monkey hears a peanut shell opened in the future, this would activate a local auditory CDZ, as well as the non-local CDZ where memories associated with the noise are stored. Signals are sent out from the non-local CDZ to all local CDZs that were involved in the original experience of the event, activating these sites and resulting in a sort of recreation of the original peanut-cracking.

Mirror neurons are represented by the non-local CDZs. In this scenario, however, mirror neurons are not physiologically unique. They are normal neurons involved in a network that has less to do with “mirroring” than with integrating and syncing the various aspects of elaborate memories. This does not take away from the role and function of this network, but should detract a little from the aggrandized status attributed to individual mirror neurons, in favor of an appreciation of the holistic complexity of the brain.

The CDZ hypothesis, however, has not been tested, although research does indicate that networks involved in observing and imitating behavior spread beyond purported mirror neuron sites. Regardless of whether the specifics of the CDZ hypothesis come to be supported by future studies, I feel it represents a more sensible approach to mirror neurons. To credit mirror neurons alone with a function that carries such importance, like the ability to infer the mental states of others, seems to oppose much of what has been learned thus far about neuroscience. We have never found language neurons, love neurons, or fear neurons. Instead we have found networks that spread throughout brain regions that correlate with the ability to experience these aspects of cognition. I suspect we will soon say the same about mirror neuron networks and their involvement in social interaction.

References:

Damasio, A., Meyer, K. (2008). Behind the looking-glass. Nature, 454(7201), 167-168. DOI: 10.1038/454167a

Dinstein, I., Thomas, C., Behrmann, M., & Heeger, D.J. (2008). A mirror up to nature. Current Biology, 18 (1), 13-17.

If I Beat Up a Robot, Will I Feel Remorse?

2008-07-14T22:49:00.009-04:00

At times, when my computer's performance has transformed it from an essential tool into a source of frustration, I will find myself getting increasingly angry at it. Eventually I may begin cursing it, roughly shoving the keyboard around, violently pressing the reset button, etc. And I can’t help noticing that, during these moments of anger, I have actually begun to blame my computer for the way it is working—as if there were a homunculus inside the machine who had decided that it was a good time to frustrate me and then started fiddling with the wires and circuitry.

I’m sure I’m not alone. Human beings have a general tendency to attribute mental states, or intentionality, to inanimate objects. There could be several reasons for this attribution, known as mentalizing, being a general human strategy that we overuse and mistakenly apply to nonliving things. One is that our knowledge of human behavior is more richly developed than other types of knowledge, due to the early age at which we acquire it and the large role it plays in our lives. Thus, perhaps we are predisposed to turn to this knowledge to interpret actions of any kind, sometimes causing us to anthropomorphize when examining non-human actions.

Another reason may be that assigning intentionality to an action in our environment is the safest and quickest way to interpret it. For example, if one is walking in tall grass and the grass a few feet ahead of them begins rustling, it would be more adaptive to think there is a predator behind that movement than to assume it is just the wind. Someone who decides it is the wind may end up being wrong, and getting killed or injured. Someone who assigns intention to it may also be wrong, but in either scenario has a better chance of being safe because their erroneous conclusion probably resulted in them using a defensive or evasive, instead of a nonchalant, strategy.

One more possible reason for our overuse of Theory of Mind (the understanding that others have their own mental states) may be based on our need for social interaction. Studies have indicated that people who feel socially isolated tend to anthropomorphize to a greater extent. Thus, perhaps part of the reason we assign intentionality so readily is that we have a desire for other intentional agents to be present in our environment, so we can interact with them.

A study published this month in PloS ONE further explores our behavioral and neural responses when we interact with humans and machines that vary in their resemblance to humans. Twenty subjects participated in the study and engaged in a game called prisoner’s dilemma (PD), a contest that has been extensively used in studying social interaction, competition, and cooperation.

PD is so called because it is based on a hypothetical scenario where two men are arrested for involvement in the same crime. The police approach each individual separately and offer him a deal in which he would have to betray the other. The prisoners are faced with the decision to remain silent or to betray their partner. If both stay silent, they face a very minor sentence because the police don’t have enough evidence to make the greater charge stick. If both betray, however, they each face a 10-year sentence. If one betrays and the other remains silent, the betrayer goes free and the silent accomplice receives the full sentence. The game is usually modified to involve repeated situations of cooperate or betray, in which the players can base their decision on the actions of their opponent in the previous round.

In the PloS ONE study, participants played PD against a computer partner (CP) (just a commercial laptop set up across the room from them), a functional robot (FR) consisting of two button-pressing mechanisms with no human form, an anthropomorphic robot (AR) with a human-like shape, hands, and face, and a human partner (HP). Unbeknownst to the participants, the form of their opponent did not have any relationship to the responses given. All were random. The participants’ impression of their partners was gauged after the experiment with a questionnaire. The survey measured how much fun the participants’ reported when playing against each partner, as well as how intelligent and competitive they felt each player to be. Participants indicated that they enjoyed the interactions more the more human-like their partner was. They also rated the partners progressively more intelligent from the least human (CP) up to the most human (HP). They judged that the AR was more competitive than its less-human counterparts, despite the fact that its responses were randomly generated, just as the others were.

The brain activity of the participants during their interactions was also measured using fMRI. Previous research has indicated that mentalizing involves at least two brain regions: the right posterior superior temporal sulcus (pSTS) at the temporo-parietal junction (TPJ), and the medial prefrontal cortex (mPFC). In the present study, these regions were activated during every interaction, but activity increased linearly as the partners became more human-like.

These results indicate that the more a machine resembles a human, the more we may treat it as if it has its own mental state. This doesn’t seem to be surprising, but I guess what intrigued me more about the study was that there was activity in the mentalizing areas of the brain even during the interaction with the CP, as compared to controls. The activity also increased significantly with each new partner, even when the increase in human likeness was minimal (see picture of the partners above). These examples are evidence of our proclivity to mentalize, as even a slight indication of responsiveness by an object in our environment makes us more inclined to treat it as a conscious entity.

The authors of the study point out that these results may be even more significant when robots become a larger part of our lives. If the frustration I experience with my computer is any indication, I foresee human on robot violence being an epidemic by the year 2050.

Reference:

Krach, S., Hegel, F., Wrede, B., Sagerer, G., Binkofski, F., Kircher, T., Robertson, E. (2008). Can Machines Think? Interaction and Perspective Taking with Robots Investigated via fMRI. PLoS ONE, 3(7), e2597. DOI: 10.1371/journal.pone.0002597

Computational Neuroscience and Systems Biology

2008-07-11T23:26:00.004-04:00

In 1952, Alan Hodgkin and Andrew Huxley published a paper that was the result of several years of experimentation on the axon of the giant squid. They had been measuring action potentials, a task made easier in the giant squid due to the large diameter of its axons (up to 1mm, compared to 1 micrometer, or millionth of a meter, in humans). Using a device (known as a voltage clamp) that allowed them to manipulate the voltage of the axon membrane and measure the resultant current that flowed through its ion channels, they developed a mathematical model that could be used to calculate current flow across excitable membranes. They won the Nobel Prize in 1963 for their work, and amazingly their equations are still used today in their original form.

This mathematical modeling of neuronal function might be considered the first historical step in the creation of a field that is known today as computational neuroscience. Computational neuroscience involves the translation of brain function into quantifiable models. This usually necessitates drawing from a number of different fields, such as neuroscience, cognitive psychology, electrophysiology, mathematics, and computer programming.

A recent article in PloS Computational Biology summarizes the history of computational neuroscience and examines the interaction of the field with another: systems biology. Systems biology is an approach to studying biology that emphasizes looking at a biological system as a whole. This is in contrast to a reductionist methodology, which involves breaking something down into its constituent parts in order to understand how it functions.

Biology has had to rely on reductionism for much of its history, simply because there has not been enough information to understand whole systems. Now, however, sub-fields like genomics and proteomics have led to drastic gains in the extensiveness of our knowledge of biological processes, allowing complex computational modeling of biological systems to occur for the first time.

As pointed out in the PloS article, however, these two fields that use computational methods to explore neuroscience and biology, respectively, are distinctly separate from one another, and have little interaction or overlap. Why is this?

One reason is that the information available to systems biology is much more comprehensive. Data like an entire genome is accessible to use in computational modeling. Neuroscience, on the other hand, usually has to take a more theoretical approach. For example, computational neuroscientists do a lot of work with neural network models. These models, however, are usually general examples and don’t attempt to mimic specific networks in the brain. At this point, accurate modeling of distinct networks is a little too ambitious of an endeavor. The disparity in the information available to the two fields has led to differences in methods and tools (e.g. the software used for modeling), which make integration of the areas even more difficult.

It seems, however, that this chasm between computational neuroscience and systems biology will eventually be abolished. At this point it may be unavoidable, as knowledge of neuroscience lags behind that of other biological areas for various reasons that range from the complexity of the brain to the history of our philosophical approach to studying it. But the understanding of biological processes like gene expression and protein synthesis that makes systems biology capable of large-scale modeling attempts will eventually lead to an improved elucidation of how the brain works. This will inevitably allow for the integration of computational neuroscience and systems biology. After all, the brain is a pretty important part of the overall system.

Reference:

De Schutter, E., Friston, K.J. (2008). Why Are Computational Neuroscience and Systems Biology So Separate?. PLoS Computational Biology, 4(5), e1000078. DOI: 10.1371/journal.pcbi.1000078

Foreign Accent Syndrome

2008-07-10T22:23:00.004-04:00

Watching someone you know recover from a stroke or other serious brain insult can be extremely difficult. Cognitive deficits (including dementia), apraxia, and speech problems are among the disabilities that these patients may have to endure. At times, these impairments can make it hard to find the individual you knew before the incident in the post-accident patient. This is perhaps the most trying aspect of the experience.

Well imagine if, when you attempt to speak to a stroke survivor you knew before the stroke, you find not that they have difficulty producing speech, but that they have strangely adopted a new British (or German, Dutch, etc.) accent. While it may seem to be the lesser of two evils, you can certainly envision that it might be also be a disconcerting experience (for all parties involved).

This rare (but real) disorder is known as foreign accent syndrome. It occurs after a severe brain injury or stroke. The patient develops an abnormality of speech that seems, to most listeners, to resemble a foreign accent. A recent case, one of the first in Canada, involved a woman who had a stroke, then adopted an accent that sounded like Maritime Canadian English—a dialect the woman was previously unfamiliar with.

What exactly is going on here? At first an enigma, recent investigations into foreign accent syndrome have begun to shed some light on the mechanisms underlying the problem. According to a review article in the Journal of Neurolinguistics, “foreign accent syndrome” is actually something of a misnomer, as patients do not demonstrate a speech pattern that consistently corresponds to a particular foreign accent. Instead, they display general changes in linguistic prosody that listeners mistakenly attribute to a different dialect.

Prosody is the rhythm, stress, and intonation of speech, and disruption has an effect on overall speaking ability, but is particularly problematic to vowel production, pitch, and syllable stressing. According to the review, phoneticians who have listened to foreign accent syndrome patients have asserted that their speech doesn’t consistently resemble a foreign dialect. Instead, it fluctuates in its similarity to various languages, and even to different families of languages. Thus, the foreign accent syndrome tag may be a simplification.

It is not a surprise to learn that most cases of foreign accent syndrome appear to be associated with lesions to the left hemisphere of the brain, which is typically correlated with language. Patients usually have damage to Broca’s area, the motor strip adjacent and inferior to this region, and/or the middle frontal gyrus. Details beyond these general areas are scarce, however, leaving the specific neural basis of the syndrome largely unknown.

Probably the important take-home message at this point is that the syndrome doesn’t involve the mysterious acquisition of a foreign accent. Instead, it is a general affliction of speech that causes distortions in prosody, which are interpreted as foreign dialects by listeners. All in all, it is perhaps one of the less debilitating effects of brain injury/stroke. Regardless, one can imagine the upset it must cause at an already difficult time. Perhaps some of that distress will be assuaged in new patients by an improved understanding of the syndrome.

Reference:

BLUMSTEIN, S., KUROWSKI, K. (2006). The foreign accent syndrome: A perspective. Journal of Neurolinguistics, 19(5), 346-355. DOI: 10.1016/j.jneuroling.2006.03.003

Encephalon #49 Celebrates Independence! (from Lamarckism)

2008-07-07T00:45:00.009-04:00

The first week in July is a time of great significance—one that reminds us of change, revolution, and how an age-old view of the world can be drastically altered by the persistent belief in one's own novel ideas. This, of course, is because July 1st marks the anniversary of the presentation of Charles Darwin and Alfred Russel Wallace's independently-developed theories of evolution and natural selection to the Linnean Society of London. The reading represented the first public explanation of the theory, which would eventually come to be the foundation upon which the world of science rests. Last week's anniversary is a special one, marking the 150th year since the publication. So, as you peruse Encephalon's round-up of the latest and greatest neuroscience blogging, remember that all roads in science today lead back to July 1st, 1858, at the Linnean Society.

Darwin developed his theory without the luxury of knowing anything about genes. Brain Stimulant skeptically discusses the use of gene therapy in psychiatry. Just the ability to have the conversation, however, is representative of how far our understanding of genetics has come in 150 years.

Mind Hacks questions whether our rapidly improved methods of imaging the brain are resulting in sensationalized reporting on experimental results.

Cognitive Daily describes what makes voices more or less attractive.

Neurophilosophy provides an intriguing look at the brain's ability to reorganize itself after a cerebrovascular accident. It appears that cells in the brain are much more versatile than once thought.

Neuroanthropology looks at the relationship between music and movement, and how it is manifested in the drumming that accompanies Sundanese martial arts demonstrations, as well as gives us a rational perspective on the debate over the biological origins of homosexuality, and a good reason to relax.

Sharp Brains discusses how physical exercise and mental exercise compare in improving the health of your brain. An interview with Dr. Art Kramer from the University of Illinois provides a way to engage in both forms of exercise at the same time: walking book clubs! And, tests to determine "brain age" are called into question.

The Winding Path provides an in-depth description of the co-evolution of the brain and culture, and then focuses specifically on the evolution of complex social interaction.

Brain Blogger asks if religion has neural or supernatural roots, and looks at the ramifications of implanting microchips containing medical information in patients.

Finally, The Neurocritic takes Science to task for not practicing what it preaches about fMRI translation. He also summarizes a unique review article that uses Dilbert cartoons to help explain the neural correlates of prediction error signals.

Be sure to check out the next edition of Encephalon at Sharp Brains on July 21st. Send your submissions to encephalon{dot}host{at}gmail{dot}com.

Bisexuality in Drosophila

2008-07-03T01:18:00.005-04:00

The fruit fly, like many organisms, has a stereotypical courtship ritual that precedes mating. After noticing a female, a male fly will follow her with a persistence that is strangely reminiscent to me of behavior that can be observed in any local pub on a busy night. The male will then tap the female with his foreleg, which allows him to sense her pheromones through chemoreceptors on his leg, and verify whether she is sexually receptive. If so, he will extend one wing and vibrate it, producing a species-specific courtship song. He also licks her genitalia to further test her pheromones. Of course these last few steps aren’t as noticeable at the local bar, and if they are you may be in the wrong place (perhaps a strange fetish pub). If she doesn’t reject him, he mounts her and attempts to copulate.

See the ritual here:

A fruit fly’s ability to discriminate between males and females is based on visual, auditory, and chemical cues, such as the pheromones 7-tricosene and cis-vaccenyl acetate (cVA). Flies that don’t produce these pheromones are deemed female and courted by other males. Mutant flies that cannot sense the pheromones attempt to copulate indiscriminately with males and females. Normally, however, homosexual behavior in drosophila is relatively rare.

Earlier this year, a joint research team from France and America set out to determine what the biological difference between bisexual and heterosexual flies is. Is it that bisexual flies have difficulty sensing pheromones like 7-tricosone and cVA, or that they are sense the pheromones and are attracted to the opposite sex? What is the mechanism that causes that difference in attraction?

The group identified a mutation in drosophila that drastically increased homosexual encounters. They named it genderblind (gb) due to the resulting phenotype, which exhibited bisexual behavior. They determined, using an immunoblot, that the gb mutation causes a reduction in gb protein quantity. An immunoblot is also known as a western blot, and involves separating proteins with gel electrophoresis and then probing for specific proteins with antibodies that have been raised against them (presence of the protein will invoke an antibody response).

In order to determine if homosexual behavior in flies was simply a result of the misinterpretation of sensory cues, the group manipulated visual and chemosensory cues and measured fly response. They found that, although reducing the availability of visual cues affects the ability of the fly to discriminate between sexes, it was not enough of an effect to explain gb behavior. When they exposed the gb flies to mutant males that did not produce 7-tricosene and cVA, homosexual behavior was reduced to wild-type levels. When they applied these pheromones topically to the mutants, however, homosexual behavior from the gb flies was restored. This suggested that gb flies sense the pheromones, but interpret them differently than wild-type flies.

The group was able to identify the genderblind protein as a glial amino-acid transporter subunit and a regulator of glutamate in the central nervous system (CNS) of the fly. One function of glutamate is to reduce the strength of glutamatergic synapses through desensitization. The gb mutants had reduced genderblind protein levels and lower levels of extracellular glutamate. This resulted in increased glutamatergic synapse strength in the CNS. A glutamate antagonist administered to gb flies caused them to revert back to wild-type sexual behavior, indicating that the stimulation of glutamatergic circuits is responsible for the homosexual behavior. Additionally, inducing the overexpression of glutamate in the CNS of the fly caused an increase in homosexual behavior in both gb and wild-type flies.

Amazingly, the homosexual behavior could basically be turned on or off by manipulating glutamate transmission. The researchers suggest that this implies there is a physiological model for drosophila sexuality in which flies are pre-wired for both heterosexual and homosexual behavior. The homosexual behavior, however, is normally suppressed by genderblind proteins. A similar model has been proposed for mice.

So, the natural question is: what, if anything, does this say about homosexuality or bisexuality in humans? Well, the authors of the study state that genderblind has a high homology to a mammalian protein, the xCT protein. This is a cystine/glutamate transporter and may be an important regulator of glutamate in the CNS, similar to genderblind in the fly.

Despite this similarity, however, in my opinion it is improbable that a relationship between xCT protein levels and bisexuality/homosexuality that is similar to the one in drosophila and genderblind protein exists in humans. This isn’t to say there couldn’t be a correlation, just that the direct connection seen in fruit flies would appear too simple to be a basis for human sexual orientation, which is probably governed by a number of gene-protein relationships. So, while glutamate levels could play a part in suppressing homosexual behavior, they probably couldn’t act like a “bisexuality-switch” they way they do in the fruit fly.

Reference:

Grosjean, Y., Grillet, M., Augustin, H., Ferveur, J., Featherstone, D.E. (2008). A glial amino-acid transporter controls synapse strength and courtship in Drosophila. Nature Neuroscience, 11(1), 54-61. DOI: 10.1038/nn2019

Send in Submissions for Encephalon #49!

2008-07-02T19:02:00.004-04:00

Encephalon #49 will be at Neuroscientifically Challenged on Monday, July 7th. Please send your posts in by 6pm on Sunday the 6th to encephalon {dot} host {at} gmail {dot} com.

The Commonalities of Buffalo Wings, Szechuan Peppers, and Ritalin Snorting

2008-06-30T00:11:00.008-04:00

Spicy food—you either love it or hate it. Whichever group you fall into, though, there’s a good chance you’ve never thought about how intriguing a natural deception it really is. When we eat spicy food we may experience a variety of sensations (depending on the specific cuisine) ranging from tingling to numbness to painful burning. Yet, a short time later the feeling disappears, leaving no redness, scarring, or irritation behind, indicating that the previous unpleasantness we experienced was—literally—all in our heads.

The substance responsible for the burning sensation one may experience when eating chili or buffalo wings is known as capsaicin. It was identified in the 1800s, and a whole family of similar molecules, called capsaicinoids, were discovered in chili peppers in the 1960s. While capsaicin is an irritant to mammals, it has analgesic properties in birds when they consume it. Chili pepper seeds are broken down in the digestive tracts of mammals. Birds, however, pass the seeds intact. Thus, the capsaicin deters mammalian feeders and makes the peppers more palatable to birds, allowing the seeds to be dispersed efficiently through bird migrations. Hence, the burning feeling caused by capsaicin is probably a mechanism that evolved to promote seed dispersal.

It wasn’t until the late 1990s, however, that scientists began to unravel the mystery behind the phantom sensation caused by capsaicin. To understand it necessitates a little knowledge about neurophysiology. So, I’ll try to summarize half a semester of neurophys in a few short paragraphs.

Neurons (and some other types of cells) communicate with one another through pulses of voltage called action potentials. A neuron maintains a certain regular voltage, known as its resting potential. The membrane of a neuron is broken up by apertures called ion channels. When they are open, certain charged particles can pass in or out of them (which particles and to what extent depends on the type of channel and a number of other factors).

Neurons are influenced primarily by four types of ions: K+ and organic anions (A-) that are concentrated inside the cell, and Na+ and Cl-, which are for the most part outside of the cell. The resting potential across a neuron’s membrane is usually about –70mV. This potential is maintained by a sensitive pump that constantly pulls K+ in, while sending Na+ out.

When a neuron is excited, voltage-dependent ion channels quickly open that allow floods of Na+ into the cell. This causes a change in the voltage of the neuron, referred to as depolarization. The rapid depolarization is the trigger that sends a wave of voltage, the action potential, down the axon of the neuron. If it is strong enough, it will reach the end of the neuron, causing the release of neurotransmitter, which binds to surrounding neurons to open their ion channels, resulting in depolarization, and so on.

So, back to buffalo wings, chili, and capsaicin. Capsaicin is a ligand that binds to a specific receptor, the TRP vanilloid receptor subtype 1 (TRPV1). This receptor can also be stimulated with actual heat and physical injury. When it is activated, it opens ion channels that depolarize nerve cells by allowing an influx of Na+. This produces action potentials that travel to the brain and produce what is, in this case, a false sense of pain.

If you’ve ever eaten Szechuan peppers, you’ll know that the feeling they evoke is different than that of chili peppers. Szechuan peppers cause a tingling, sometimes numbing, feeling. Instead of capsaicin, their active ingredient is hydroxy-alhpa-sanshool (sanshool). How sanshool acts to produce its numbing effect was somewhat of an enigma until a study published last week in Nature Neuroscience offered an explanation.

According to the authors of the study, sanshool acts on a different group of neurons than capsaicin. Capsaicin affects small-diameter sensory neurons that express proinflammatory peptides (which are responsible for the pain), but sanshool acts on large diameter neurons usually associated with proprioception and detection of touch or vibration.

Sanshool was thought to have an effect by opening Na+ channels, in a manner similar to capsaicin. The Nature study, however, found that sanshool actually inhibits K+ channels. The result is still an action potential, but through a different mechanism.

You may be thinking this is a lot of research money being wasted to figure out why food is spicy. But understanding these subtleties of the sensory system is important in that it brings us closer to an overall comprehension of how our senses work. Also, both capsaicin and sanshool have applications as analgesics (ironically capsaicin can reduce pain when applied topically, possibly because it floods the sensory neurons to the point where they go numb).

A side note: A couple of years ago a Harvard researcher, Clifford Woolf, made a novel suggestion. Since the most highly abused prescription drugs like OxyContin and Ritalin generally lead to addiction when users begin snorting them, why not mix capsaicin in with them? This, Dr. Woolf asserted, would not affect the oral digestion of the pills but would make snorting them like “snorting an extract of 50 jalapeno peppers”.

One thing that has always amazed me about pills like these is how amenable they are to being crushed up and snorted. Elizabeth Wurtzel, in her book about Ritalin addiction More, Now Again: A Memoir of Addiction implies that pharmaceutical companies purposely make their drugs like this in order to increase demand and black market consumption. I don’t know if I agree with her or not yet, but when there seem to be options to change the consistency of the pill, or when deterrents like adding capsaicin are available, and they are ignored, it does become suspicious.

Reference:

Bautista, D.M., Sigal, Y.M., Milstein, A.D., Garrison, J.L., Zorn, J.A., Tsuruda, P.R., Nicoll, R.A., Julius, D. (2008). Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nature Neuroscience, 11(7), 772-779. DOI: 10.1038/nn.2143

Encephalon #49 Will Be Right Here--Send in Your Submissions

2008-06-27T00:02:00.004-04:00

Neuroscientifically Challenged will host its first Encephalon Blog Carnival on July 7th and needs submissions! Please send your post on brain science or related topics to encephalon {dot} host {at} gmail {dot}com by 6pm on July 6th.

It's All About Timing: Circadian Rhythms and Behavior

2008-06-26T23:30:00.008-04:00

Anyone who has ever tried to drastically alter his or her sleep schedule (e.g. going from working days to working nights) knows that it is one of the more difficult biological tasks we can take on. Even altering one’s sleep patterns by a couple of hours (such as the shift experienced by cross-country travelers) can be disruptive, and enough to make us feel tired, mentally unclear, and grumpy. But why are we so inflexible when it comes to our daily routine? Why are our otherwise diverse bodies so sensitive to an adjustment of our biological clocks by just a few hours? Perhaps it is because millions of years of evolution have led to a daily body clock so fine-tuned that this sensitivity is adaptive.

Circadian (from the Latin for “around” and “day”) rhythms are endogenous biological patterns that revolve around a daily cycle. They are found in all organisms that have a lifespan that lasts more than a day. They are adaptive in the sense that they allow an organism to anticipate changes in their environment based on the time of day, instead of just being a passive victim to them. Thus, to foster that readiness, they usually involve the coordination of a number of physiological activities, such as eating/drinking behavior, hormonal secretion, locomotor activity, and temperature regulation.

A major nucleus of the mammalian brain, located in the hypothalamus and called the suprachiasmatic nucleus (SCN), is responsible for acting as the master time-keeper in mammals. When the SCN is lesioned (i.e. in rodents), it results in a complete disruption of circadian rhythms. The animals will demonstrate no adherence to a daily schedule, sleeping and waking randomly (although still sleeping the same total amount of time each day).

The SCN receives information from ganglion cells in the retina, which keep it appraised of whether it is light or dark out, and maintain its synchrony with a diurnal schedule. It is not, however, completely dependent on visual input for keeping time. A number of other environmental cues, such as food availability, social interaction, and information about the physical environment (other than light) are thought to play an important role in the SCN’s ability to maintain regular daily rhythms.

Although the SCN is the center for circadian rhythms, it seems that many individual cells are not directly controlled by the SCN. Instead, they are thought to maintain their own time-keeping mechanisms. Known as peripheral oscillators, these cells are present in a number of organs throughout the body, and can be sensitive to environmental cues as well as the signals of the SCN.

So, how do the neurons of the SCN actually “keep time”? They appear to be controlled by a cycle of gene expression, which consists of a natural negative feedback mechanism. Throughout the day, a gene known as CLOCK (circadian locomotor output cycles kaput) is activated based on daytime environmental cues. This gene acts with another, BMAL1, as a transcription factor, driving the transcription of proteins period (PER) and cryptochrome (CRY). When large amounts of PER and CRY have been created, they form a complex, and act on the CLOCK and BMAL1 genes to inhibit their own expression. This occurs during the night, and the result is that PER and CRY proteins become diminished, allowing CLOCK and BMAL1 to begin transcribing them again. This happens around the morning of the next day. Thus, the feedback loop is synchronized with a 24-hour cycle, allowing the clock in the SCN to oscillate at a regular rate.

Disorders of the SCN can result in disruptive sleep problems, such as advanced sleep phase syndrome (early sleep and wake times) or delayed sleep phase syndrome (preference for evenings and delayed falling asleep). More attention is now being focused on the role a dysfunctional circadian system may play in already identified behavioral problems. A recent review in PloS Genetics examines the potential influence circadian rhythm disturbances may have in disorders like depression, schizophrenia, and even autism.

Circadian disruptions are present in all major affective disorders, including depression, bipolar disorder, and schizophrenia. Although the exact role circadian rhythms play in these disorders is not yet known, it may be substantial. This is supported by the influence changes in sleep patterns can have on the alleviation of primary symptoms of these disorders. For example, sleep deprivation has been demonstrated to have an antidepressant effect (albeit short-lived) in patients. And some affective disorders, such as seasonal affective disorder, seem to have a basis in the length of the day, and shape emotional states.

Autism spectrum disorders (ASD) are correlated with low melatonin levels, and a gene responsible for the synthesis of melatonin is considered a susceptibility gene for autism. Mice with a mutant form of this gene demonstrate deficits in social interaction, anxiety, and increased occurrence of seizures. It is postulated that behavioral problems in ASD may be influenced by the failure of an individual’s circadian clock to effectively take note of social and environmental cues.

Variants of a number of time-keeping genes, such as PER1, CLOCK, and CRY have been found to be associated with behavioral disorders. It has yet to be determined if these variations are causative, contributive, or unrelated to the disorders. Keeping in mind how influential a disturbance of circadian rhythms can be in our daily lives, however, it seems logical to investigate the possibility of their contribution to pathologies.

Reference:

Barnard, A.R., Nolan, P.M., Fisher, E.M. (2008). When Clocks Go Bad: Neurobehavioural Consequences of Disrupted Circadian Timing. PLoS Genetics, 4(5), e1000040. DOI: 10.1371/journal.pgen.1000040