The post Brittany defends her PhD! appeared first on The Snyder Lab.

The post Alyssa defends her PhD! appeared first on The Snyder Lab.

¹We don’t have anything against other types of sports and in fact, individually, many of us pursue other types of athletics in our spare time. But collectively, it is interesting that we gravitate towards throwing heavy rocks. Perhaps we should branch out but, before we do, it is worth considering whether there might be other types of heavy object sports that we should try before moving on. Like, shotput would probably qualify. Caber toss anyone?

²Mainly because the lab administrator didn’t get around to organizing the event until curling was all booked up.

The post Bowling 2022 appeared first on The Snyder Lab.

Intermittent theta burst transcranial magnetic stimulation induces hippocampal mossy fiber plasticity in male but not female mice

PAPER ALERT!!! Tian Rui (Brittany) Zhang is a PhD student in the lab who has been studying the effects of various types of non-invasive stimulation (TMS, ECS) on adult neurogenesis, neuronal activity, and behavior in mice. In this new paper she found that a new form of theta-patterned TMS causes growth of presynaptic terminals on adult-born neurons. We know these synaptic terminals are very important for memory, and possibly also for emotional regulation, and so this suggests a possible route by which theta-based TMS might impact behavior. But only in males?? Here is the abstract:

Transcranial magnetic stimulation (TMS) induces electric fields that depolarize or hyperpolarize neurons. Intermittent theta burst stimulation (iTBS), a patterned form of TMS that is delivered at the theta frequency (~5 Hz), induces neuroplasticity in the hippocampus, a brain region that is implicated in memory and learning. One form of plasticity that is unique to the hippocampus is adult neurogenesis, however little is known about whether TMS, or iTBS in particular, affects newborn neurons. Here we therefore applied repeated sessions of iTBS to male and female mice and measured the extent of adult neurogenesis and the morphological features of immature neurons. We found that repeated sessions of iTBS did not significantly increase the amount of neurogenesis or affect the gross dendritic morphology of new neurons, and there were no sex differences in neurogenesis rates or aspects of afferent morphology. In contrast, efferent properties of newborn neurons varied as a function of sex and stimulation. Chronic iTBS increased the size of mossy fiber terminals, which synapse onto CA3 pyramidal neurons, but only in males. iTBS also increased the number of terminal-associated filopodia, putative synapses onto inhibitory interneurons, but only in male mice. This efferent plasticity could be result from a general trophic effect or it could reflect accelerated maturation of immature neurons. Given the important role of mossy fiber synapses in hippocampal learning, our results identify a neurobiological effect of iTBS that might be associated with sex-specific changes in cognition.

The post Sex differences in TMS-induced hippocampal plasticity appeared first on The Snyder Lab.

Happy to announce a new publication that has been many years¹ in the works, “Sex differences in the spatial behavior functions of adult-born neurons in rats“, led by former postdoc Tim O’Leary.

In this study, we inhibited adult neurogenesis in female and male transgenic rats to see what happens to learning ability. We know that hippocampal neurogenesis contributes to learning, and that it also regulates the stress response, but no one has really looked at whether these 2 functions interact. New neurons often aren’t needed to learn in standard spatial learning paradigms like the water maze but we predicted that they might become more important under conditions of stress. So, here we therefore used a cold water maze to induce higher levels of stress. Specifically, we predicted that stress might impair learning when you don’t have neurogenesis, since we had previously found that neurogenesis buffers the effects of stress.

Somewhat consistent with our prediction, our first results indeed found that blocking neurogenesis altered learning under stressful conditions, but we were shocked that the rats actually learned faster without new neurons! I remember thinking, “We must be doing something wrong…but what?”. Well, just like (most) everyone else at the time, when this project began we were mainly using male animals for our projects. And so there ended up being a surplus of female rats that were available for this study. Maybe what we did “wrong” was to use females? And so we decided we really should repeat the experiment in males, since our hypothesis was completely built on data from male subjects (that was all that was available in the literature). And when we did we found what we originally expected, that blocking neurogenesis impaired learning under stress. At first, these results were completely paradoxical. But as is often the case, once you look into the literature you begin to see parallel stories and you actually start to believe your data! In this case, it was prior work, showing that stress can have opposite effects on learning in males and females², that gave me some reassurance in the early stages of this project.

So there you have it: neurogenesis is good for males and bad for females!?! “Faster is better” is the usual interpretation when it comes to maze data, but somehow here it seems less plausible, no? Indeed, once we looked in detail, we found that the more important result might be how stress altered behavioral strategies in males and females. In males, neurogenesis caused rats to adopt similar escape strategies regardless of stress; in females neurogenesis caused rats to shift their strategies depending on stress. This is interesting because it suggests that neurogenesis could be playing equally important but complementary roles in the two sexes. It’s likely that, in a different type of learning situation, blocking neurogenesis would cause males to learn faster and females to learn slower.

We also looked at activity-dependent (immediate-early) gene expression and found big differences between the sexes (suggestive of different strategies and approaches to learning) but no differences related to neurogenesis. Interestingly, new neurons in males were significantly more plastic in males that in females, in response to learning. The consequence of this plasticity is still a bit of a mystery but it fits with previous evidence that males tend to show more (or different) stress-related plasticity in CA3, which is part of the same circuitry as the newborn neurons.

What else? Well, in writing up this manuscript we were aware that there was a huge disparity in how males and females have been included in neurogenesis research. We therefore decided to quantify it (and publish it on Figshare, here):

Clearly, most studies have only examined male subjects. And while things may be improving (more studies are including females), a significant proportion still do not specify the sex of their subjects or actually report/analyze the male vs female data, as has recently been reported for neuroscience more broadly. There are certainly a lot of interesting and important discoveries to be made!

Head over to eNeuro if you want the data in all its juicy details…

¹Aside from the fact that the lab moved during this project (right after the behavioral experiment were completed), including both sexes was one of the reasons this study took so long to complete (about 8 years). A study with behavioral, retrovirus-morphology and neural activity components is one thing but then double it? And have large enough sample sizes that you are really confident in the results?

²for example work by Shors and Bangasser, Luine, Conrad

³In fact, we have included the underlying data as extended material, partly as a result of interactions with reviewers, who prompted us to more comprehensively report our statistics and effect sizes.

The post Sex differences in the function of neurogenesis appeared first on The Snyder Lab.

The lab has 5 presentations to check out at Neuromatch! This is an exciting new venue for online scientific presentation, discussion and collaboration. Interactive talks are short (only 15 min) and supposed to be primarily Q&A, so come with your Qs! Here is a list of our presentations along with links to view them:

Tues Oct 27: Chronic intermittent theta burst stimulation (iTBS) effects on adult hippocampal neurogenesis in males and females, by Tian Rui Zhang et al.

Fri Oct 30: Pathfinder: open source software for analyzing spatial navigation search strategies, by Matthew Cooke et al.

Fri Oct 30: Adult-born Neurons Inhibit Developmentally-born Neurons, by Alyssa Ash et al.

Fri Oct 30: Delayed maturation of input plasticity at lateral perforant path synapses onto adult-born dentate granule neurons, by Nick Vyleta et al.

Fri Oct 30: Adult-born hippocampal neurons undergo extended development and are morphologically distinct from neonatally-born neurons, presented by Jason on behalf of first authors JD Cole and Delane Espinueva, et al.

The post Presentations at Neuromatch appeared first on The Snyder Lab.

Since the original release we have gotten queries from a number of folks whose .csv or .xlsx files weren’t read by Pathfinder, because the x, y or time coordinates weren’t in the expected places. Most of the time this was because people wanted to use Pathfinder to analyze data from non-rodent or non-water maze experiments that used unsupported software, such as studies of human virtual navigation. To address this we added a “define” button, which pulls up a new window where you can tell Pathfinder where the X, Y, and T information is. See the gif below:

The other feature we added is a live preview of your parameter settings, things like maze size, thigmotaxic zone etc. As you change these parameters you will see an updated live preview. We thought this would help people get their settings in the right ballpark, and provide some intuitive feedback about what is being measured.

More details can be found on the Pathfinder Github page.

The post Navigation strategy analyses for all! [aka Pathfinder update] appeared first on The Snyder Lab.

Seib, Désirée R., Espinueva, Delane F., Floresco, Stan B., Snyder, Jason S. A role for neurogenesis in probabilistic reward learning. Behavioral Neuroscience. https://doi.org/10.1037/bne0000370

Abstract: Rewards are often unreliable and optimal choice requires behavioral flexibility and learning about the probabilistic nature of uncertain rewards. Probabilistic learning occurs over multiple trials, often without conscious knowledge, and is traditionally associated with striatal function. While the hippocampus is classically recognized for its role in memory for individual experiences, recent work indicates that it is also involved in probabilistic forms of learning but little is known about the features that support such learning. We hypothesized that adult neurogenesis may be involved, because adult-born neurons contribute to both learning and reward-related behaviors. To test this, we used an appetitive probabilistic reversal learning task where a correct lever is rewarded with 80% probability and an incorrect lever is rewarded with 20% probability. Behavioral flexibility was assessed by switching correct-incorrect lever identities after 8 consecutive correct choices. Transgenic male rats that lacked adult neurogenesis displayed an initial deficit in discriminating the correct and incorrect levers, but they were not impaired at reversing behavior when the reward contingencies switched. When reward was withheld after a correct lever choice, neurogenesis-deficient rats were more likely to choose the incorrect lever on the subsequent trial. Also, rats with intact neurogenesis were more sensitive to reward at the incorrect lever. Differences were not observed in control transgenic rats that had intact neurogenesis. These results identify a novel role for neurogenesis in learning about uncertain, probabilistic rewards. Altered sensitivity to reward and negative feedback furthermore implicates neurogenesis in cognitive phenotypes associated with mood disorders such as depression.

The post A Role for Neurogenesis in Probabilistic Reward Learning appeared first on The Snyder Lab.

Anyone who has run behavioral experiments knows that after running hundreds (or thousands…millions?*) of trials you begin to see patterns that make you wonder if something else is going on that your analyses are not capturing. For people who study learning, memory and spatial navigation you may have put your mouse in a maze and seen it take turns, detours or routes that make you wonder if it is not quite as smart as you thought (WHY DO YOU KEEP MISSING THE PLATFORM YOU *$#*#%()!). Or maybe it is actually smarter than you thought (DAMN IS SHE SWIMMING TO OTHER PARTS OF THE MAZE BECAUSE OF THAT ONE TIME I FORGOT TO PUT THE PLATFORM IN THE POOL AFTER THE PROBE TRIAL ARGH IM SUCH A *#&%&%#(*(!). Or maybe you are at one with your mouse and ready to take him or her (both?) to the next level of spatial navigational testing?

If you answered yes to any of the above questions then you might be interested in our new Pathfinder software for automatically classifying different patterns of navigation, led by MSc student Matthew Cooke. Pathfinder is inspired by studies of water maze search behavior, which have found that rodents progress from random to procedural to highly spatially-specific search patterns as they learn a spatial goal location in new environment. These types of navigational strategies have distinct advantages, likely depend on different neural circuits, and they are affected in different disease models. But many people don’t analyze navigation strategies because there is no easy way to do so. That’s why we made Pathfinder, an open source, Python-based application. It currently opens files from Ethovision, Watermaze, Anymaze and  the free, open source application ezTrack. While it’s optimized for analyzing rodent navigation in the water maze, it could also be used to analyze all sorts of spatial behaviors in different species and in different mazes, as long timestamped x-y coordinates are available. So, please test it out and let us know how it is working for you, and how we could make it better!

You can get it on Github and here is the abstract:

Spatial navigation is a universal behavior that varies depending on goals, experience and available sensory stimuli. Spatial navigational tasks are routinely used to study learning, memory and goal-directed behavior, in both animals and humans. One popular paradigm for testing spatial memory is the Morris water maze, where subjects learn the location of a hidden platform that offers escape from a pool of water. Researchers typically express learning as a function of the latency to escape, though this reveals little about the underlying navigational strategies. Recently, a number of studies have begun to classify water maze search strategies in order to clarify the precise spatial and mnemonic functions of different brain regions, and to identify which aspects of spatial memory are disrupted in disease models. However, despite their usefulness, strategy analyses have not been widely adopted due to the lack of software to automate analyses. To address this need we developed Pathfinder, an open source application for analyzing spatial navigation behaviors. In a representative dataset, we show that Pathfinder effectively characterizes the development of highly-specific spatial search strategies as male and female mice learn a standard spatial water maze. Pathfinder can read data files from commercially- and freely-available software packages, is optimized for classifying search strategies in water maze paradigms, but can also be used to analyze 2D navigation by other species, and in other tasks, as long as timestamped xy coordinates are available. Pathfinder is simple to use, can automatically determine pool and platform geometry, generates heat maps, analyzes navigation with respect to multiple goal locations, and can be updated to accommodate future developments in spatial behavioral analyses. Given these features, Pathfinder may be a useful tool for studying how navigational strategies are regulated by the environment, depend on specific neural circuits, and are altered by pathology.

*poor souls

The post Pathfinder: software for automatically classifying spatial search strategies appeared first on The Snyder Lab.

!!UPDATE!!

This paper is now published at the Journal of Neuroscience and you can also find it here.

Congratulations to John Darby Cole and Delane Espinueva, two former undergraduate students who led an incredibly detailed study of the morphological development of adult-born neurons. You might read this and think, hasn’t this already been done? It’s true that people have looked at new neuron development but, amazingly, several key aspects are still not know. For example, since few people have examined adult-born neurons at older ages it was never really clear if or when new neurons stop growing (and thus, stop contributing developmental plasticity to the hippocampal circuit). Also, few have directly compared adult-born neuron morphology to neurons born in early development, so it is not entirely clear whether new neurons become the same as existing neurons, or might make up a distinct population. And the answer is….here is the preprint and here is the abstract:

The post New paper: Adult-born neurons undergo extended morphological development appeared first on The Snyder Lab.