DATA: Stress can increase or decrease anxiety depending on the timing of the stressor

The following data can be cited using this permanent identifier: You can also find a PDF of the complete data and text there.

The purpose of these experiments was to determine the immediate and delayed effects of stress on anxiety/depressive behavior. For the open field and elevated plus maze experiments male CD1 mice (Charles River) were used (n=6-8 per group; arrived at 7 weeks of age, tested at 9-11 weeks, handled for 5 days prior to testing). The GFAP-tk mice used for the novelty-suppressed feeding test were as described in Snyder, 2011, Nature. Mice were housed 4/cage, kept on a 12 hour light/dark cycle with lights on at 6 am and were tested during the light phase. Testing was performed either directly from the home cage (controls), immediately following 30 min restraint (stress) or following 30 min restraint with a 30 min post-restraint delay interval (stress+delay).

Figure 1: Increased fear/anxiety in the open field immediately following stress. a) The open field was a white plastic box (50cm x 50cm x 50cm) which was divided into outer (o), middle (m), and center (c) regions. Mice were tracked with Ethovision software (Noldus) and latency to approach the center region and time spent in the 3 regions during a 15 min test was calculated. Light intensity was approxmiately 150 lux. b) The presence of an object (~2 cm diameter, 3 cm tall wire metal cylinder containing a marble) in the center of the open field increased time spent in this subregion, and was therefore included in subsequent experiments (i.e. d-h; ****t-test P<0.001 vs. no object). c) The presence of the object did not affect the latency to approach the center of the open field. d) Neither stress condition affected the latency to approach the center of the open field. e) Stress significantly reduced the time spent in the center of the open field but this effect was absent after 30 min (stress+delay group; 1 way ANOVA main effect P=0.001, #Tukey post-test P<0.001 vs. control & P<0.05 vs. stress+delay). f-h) Time spent in the center, middle and outer regions across the test’s 3 x 5 min bins. Compared to controls, stress reduced time spent in the center and middle regions and increased time spent in the outer region (2 way repeated measures ANOVA, main effects of treatment all P<0.01, effect of time and interactions ns; Bonferroni post-test *P<0.05, **P<0.01, ***P<0.001 vs. control). Continue reading DATA: Stress can increase or decrease anxiety depending on the timing of the stressor

How to share all of your data

Figshare is one of the greatest new tools for scientists. It allows you to publish any piece of data, no matter how small or insignificant, in a citable fashion. This is a big deal because ALL scientists have (tons of) data of this sort. Pilot experiments are performed to get the conditions right for the real experiments. And they never get published. The manuscript is written up or the paper is reviewed and some data is judged irrelevant or incomplete and is excluded. And never gets published. An experiment is performed and there is a null result, or the data are hard to interpret without further experiments, or the project doesn’t get funded, and so the project is dropped. And the experiment becomes nonexistent outside of the lab that performed it. There are many reasons why this should not be the case: 1) effort was spent on the experiment and so publishing it gives the scientist credit, 2) taxpayer money was spent on the experiment and so publishing these data gives back to the system that enables us to do this work in the first place, 3) data that are not useful or exciting to the scientist that acquired them can be incredibly useful and time-saving to other scientists that are working on related problems. The list could go on.


Figshare may not be the only option, and others will likely crop up in the near future, but it is a good example of a solution. We all know about the internet, right? A medium for immediately publishing anything you want? I’m a little baffled that this has taken so long.

For my part, in my spare time, I will be scouring my hard drive for findings that have been forgotten. The beauty of publishing in a place like Figshare is that it is easy. Most of these experiments have already been analyzed (I mean, they were graphed so that we could discuss what to do/not do with them, now it’s just a matter of uploading the already-presentable data). Also, there’s no obligation to discuss the data ad nauseum (you’ll see some data descriptions are pretty short) though some degree of explanation is required to make the data useful. Furthermore, should the story evolve, there’s no reason why it can’t be also published in a traditional journal format. Check out Nature Publishing Group’s policy – they’re ok with publishing data (even full manuscripts) on preprint servers prior to submitting to their journals.

Of course, some data may still not be “shareable” such as patient data or data that is closely related to an ongoing project. But interestingness should never be a factor in my mind, because you never know what will be valuable to others.

So, if you’re “just” a summer student who thinks your 2 months of work can’t possibly amount to hard, citable evidence, think again. Ask your boss first, but think again.

In press: The neurogenesis-depression hypothesis, confirmed.

A transgenic tool for eliminating adult neurogenesis.

The idea that adult neurogenesis protects individuals from depression is perhaps the single greatest motivator driving neurogenesis research. Not surprisingly, “neurogenesis depression” is the most common behavioral keyword that brings people to this blog (followed closely by “pattern separation”). So I’m excited to say that we will soon be publishing what (I think) is the best evidence that impaired adult neurogenesis actually causes depressive symptoms (in mice). The neurogenesis-depression hypothesis is over 10 years old and yet there is largely only correlational evidence linking neurogenesis to depression and no direct evidence that impaired adult neurogenesis leads to depressive symptoms. Naturally, this has led to skepticism (e.g. see this paper by Robert Sapolsky, and discussion by fellow bloggers: scicurious, neurocritic, neuroskeptic). A key factor in our study was stress: mice that lacked neurogenesis often seemed very normal when they were happily going about their business (as in previous studies by other groups). However, following stress, mice lacking neurogenesis had elevated levels of stress hormones and they also showed more depressive behaviors (or depressive-like, if you prefer). I hope to go into more detail soon.

For now, here is the abstract:

Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Jason S. Snyder, Amélie Soumier, Michelle Brewer, James Pickel & Heather A. Cameron. National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.

Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to specifically inhibit adult neurogenesis, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic–pituitary–adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

*image is of GFAP-driven thymidine kinase in a mouse brain (GFAP in green and thymidine kinase in red). In the presence of ganciclovir, any cell that expresses thymidine kinase dies when it attempts to divide. In this case those cells would be the radial glial stem cells that produce new neurons. These were the mice used to stop neurogenesis in the majority of the experiments.

UPDATE: Ed Yong at Discover Magazine and Scicurious at Scientific American have great summaries of the findings and their significance. And the Drugmonkey blog attacks the question of whether or not a depression study in mice can be relevant for humans.

New neurons mature very slowly in monkeys

ResearchBlogging.orgSo, it turns out that neurogenesis in primates is quite a bit different than in rodents. It’s been over 10 years since adult neurogenesis was first described in the adult primate hippocampus and yet much of the basic work has yet to be done. That’s where this new study by Kohler et al. come in. The data are not so new actually — they were first presented at the Society for Neuroscience meeting back in 2005.

Their question was simple: at what rate do newborn neurons mature in nonhuman primates? Their methods were also simple and easy to compare to previous studies in rodents: they used BrdU to label newborn cells and then they colabeled the BrdU+ cells with immature (DCX) and mature (NeuN) neuronal markers at different cell ages: 2 days, 2 weeks, 6 weeks, 11 weeks and 23 weeks.

First, they found that after labeling with BrdU the number of BrdU+ cells increased over the next 6 weeks. This fits well with the data from Gould and suggests that precursor cells in primates may divide much more infrequently, taking up the BrdU label at injection, retaining it for several days or weeks and then giving rise to additional BrdU+ cells upon redivision, etc etc until the BrdU is diluted. Continue reading New neurons mature very slowly in monkeys

Studies of adult hippocampal neurogenesis in primates

For obvious reasons, studying neurogenesis in primates is useful. Primates are phylogenetically more related to us than rodents, and so understanding their nervous system can better help us to understand our own. For over a decade we have known that neurogenesis continues in adulthood in primates and in many ways, the process is similar to what has been observed in rodents. For example, neurogenesis is reduced with age in primates, is decreased by stress, increased in pathological conditions such as epilepsy, and increased by antidepressant treatment.

My goal in compiling this list was to assess the magnitude of adult neurogenesis in primates. It’s definitely more challenging than assessing the magnitude of neurogenesis in rodents, which we know much more about, and so I had put it off. At this point I haven’t reached a clear conclusion but, in quickly skimming these papers, the number of proliferating cells and/or new neurons averages thousand(s) of cells in the young adult primate hippocampus. The range is much much larger, and many studies cannot be easily compared due to variability in the methods, which is partly understandable since primates are scarce and are often used in multiple studies, thereby limiting the analyses that can be performed.

Download the list

The National Institute of Replicating Discoveries, Y’all (NIRDY)

Sometimes when you say something on Twitter people respond. People don’t respond that much to what I have to say but, now and then, there’s enough of a reaction to help me realize that an idea was meaningful beyond the moment it popped into my mind and made its way onto the keyboard. So, thanks to those people for starting the conversation.

The idea I had today is that some scientific disciplines could benefit from more replication. And what better way to do it than to have Big Brother audit your science and see if they can replicate in their lab what you did in yours. The idea stemmed from my own feelings about my field. I’ve had serious thoughts lately about trying to replicate a couple findings that have had a lot of influence in the field. They’re important findings. They reveal key functions of new neurons that could be relevant for human health. For this reason the whole field is aware of them, cites them, uses them as justification for additional research. Sooo, then why haven’t they been replicated?   Continue reading The National Institute of Replicating Discoveries, Y’all (NIRDY)

Dorsoventral vs. Septotemporal hippocampus

Everybody knows what the hippocampus is for: memory. And…maybe something about anxiety or depression? Yes – over the last 10 years or so many studies have been published showing that the hippocampus has these two roles and that the mnemonic and emotional functions of the hippocampus are associated with its septal (dorsal) and temporal (ventral) ends, respectively. This new knowledge means that we’ve had to reorient our perspective. What we see when we consider the septal hippocampus may not be the same if we only consider its temporal end. My goal here is not to provide a review of the memory vs. emotional functions of the hippocampus (btw this dichotomy is a vast oversimplification). Instead, I’d like to talk about how people have differentiated these two ends of the hippocampus in their analyses. I’m also happy to showcase a bunch of pretty anatomical images that will probably never be published in a traditional journal article. Continue reading Dorsoventral vs. Septotemporal hippocampus

Random roundup

random roundup banner

“Random” roundup because any posts linking to articles or ideas I’ve recently found noteworthy will never occur on a regular basis (as others manage to do – I applaud you) but only when enough interesting material has accrued and I have a spare moment. The links will, however, not be random. For example, you can expect many links to point to articles on adult neurogenesis or hippocampal function but will likely find few links directing you to photos of puppy dogs.

Dopaminergic Modulation of Cortical Inputs during Maturation of Adult-Born Dentate Granule Cells. A pretty thorough examination of dopaminergic modulation of synaptic transmission and synaptic plasticity in the dentate gyrus. Dopamine reduced synaptic transmission in both immature and mature granule neurons, but through different receptor subtypes. Additionally, dopamine reduced long-term plasticity in immature neurons but not mature neurons. Given the suggestion that dopamine could gate the entry of information into long-term memory, these findings suggest young and old neurons could have quite different behavioral functions.

Mu Y, Zhao C, & Gage FH (2011). Dopaminergic Modulation of Cortical Inputs during Maturation of Adult-Born Dentate Granule Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (11), 4113-23 PMID: 21411652


Lidocaine attenuates anisomycin-induced amnesia and release of norepinephrine in the amygdala. Memory consolidation is the phenomenon by which memories are encoded through enduring structural changes in the brain and is often demonstrated by showing that memory loss occurs when you inhibit protein synthesis around the time of learning. This paper shows that one of the most commonly-used protein synthesis inhibitors, anisomycin, leads to increased norepinephrine release in the amygdala which could, by itself, impair memory.  The interesting final experiment showed that the effects of anisomycin on memory and norepiniphrine were reduced when the amygdala was totally shut down with lidocaine.

Sadowski RN, Canal CE, & Gold PE (2011). Lidocaine attenuates anisomycin-induced amnesia and release of norepinephrine in the amygdala. Neurobiology of learning and memory PMID: 21453778


Evidence for the Re-Enactment of a Recently Learned Behavior during Sleepwalking. I’ve written a number of times about how neuronal firing patterns observed during waking experience are replayed during sleep, and could therefore reflect consolidation of memory and even dream content. Of course no one knows what rats are experiencing during sleep or whether they dream like us. To get around this problem, these authors trained sleepwalkers on a motor task with very defined arm movements and then examined sleepwalking behavior on the following night. Indeed, a video shows one subject who wakes up the following night and, for a few seconds, seems to be performing the same stereotyped task movements. Only one subject but tantalizing evidence and a cool experimental strategy nonetheless.

Oudiette D, Constantinescu I, Leclair-Visonneau L, Vidailhet M, Schwartz S, & Arnulf I (2011). Evidence for the Re-Enactment of a Recently Learned Behavior during Sleepwalking. PloS one, 6 (3) PMID: 21445313


Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. One of the biggest questions in the neurogenesis field is whether adult-born neurons are important for behavior. Usually this is tested by examining behavior in animals that lack adult neurogenesis but many studies have correlated increased neurogenesis in enriched or athletic animals with “improved” behavior (smarter, less depressed etc). Of course, the major confound is that enrichment and exercise do many other things besides increasing neurogenesis. To get around this Sahay et al. made a mouse in which neurogenesis could be specifically increased in adulthood. These mice were better at discriminating between related contexts and, after exercise, showed much greater exploratory activity in an open field.

Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, & Hen R (2011). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature PMID: 21460835


Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates. This study potentially bridges a big big gap by extending the role of adult neurogenesis in the antidepressant response from rodents all the way to monkeys. Chronic stress induced anhedonic and subordinate behaviors and these effects could be reversed with fluoxetine, but not in irradiated monkeys that had reduced neurogenesis. Could someone follow this up with a transgenic model?

Perera, T., Dwork, A., Keegan, K., Thirumangalakudi, L., Lipira, C., Joyce, N., Lange, C., Higley, J., Rosoklija, G., Hen, R., Sackeim, H., & Coplan, J. (2011). Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates PLoS ONE, 6 (4) DOI: 10.1371/journal.pone.0017600


Systemic 5-bromo-2-deoxyuridine induces conditioned flavor aversion and c-Fos in the visceral neuraxis. OH NOOO! Rats don’t like BrdU! These authors show that pairing a BrdU injection with exposure to a sweet palatable drink causes rats to avoid that drink in the future. It also leads to a mildly elevated stress response and elevated c-fos expression in areas of the brain that represent viscera, consistent with the possibility that BrdU could be exerting unpleasant effects in the gut, where there is a lot of cell division. The authors conclude that the effects on behavior in subsequent days and weeks are probably minimal (phew!), but I’d certainly keep these data in mind when considering injecting BrdU around the time of behavioral testing.

Kimbrough A, Kwon B, Eckel LA, & Houpt TA (2011). Systemic 5-bromo-2-deoxyuridine induces conditioned flavor aversion and c-Fos in the visceral neuraxis. Learning & memory (Cold Spring Harbor, N.Y.), 18 (5), 292-5 PMID: 21498563


Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice. In an interesting study of plasticity following neurogenesis reduction, these authors find that LTP was dramatically reduced after arresting neurogenesis, but only transiently. LTP recovered within weeks, possibly because of compensatory reductions in inhibition and enhanced survival of neurons born before neurogenesis ablation. Hat tip to Sil for this one.

Singer BH, Gamelli AE, Fuller CL, Temme SJ, Parent JM, & Murphy GG (2011). Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice. Proceedings of the National Academy of Sciences of the United States of America, 108 (13), 5437-42 PMID: 21402918


That’s it.

Are new neurons really more excitable? (yes)

ResearchBlogging.orgSome facts on neuronal excitability:

  1. Excitable: the ability to fire action potentials.
  2. More excitable: fires action potentials, but more.
  3. More LTP: not the same as more excitable.
  4. Less inhibition: also not the same as more excitable, though the two may go hand in hand.
  5. The Scholarpedia page on neuronal excitability, which was last modified on 13 August 2009, has been accessed 49,025 times, and contains no information (peer review is slow).

One of the claims that is often made is that adult-born neurons are more plastic and more excitable than older neurons.  This despite there being little evidence (until recently) that new neurons indeed are more excitable. But, hey, “excitable” sounds great alongside “plastic”. The Schmidt-Hieber paper did show that new neurons are more excitable, though it wasn’t their main focus and it is only occasionally referenced as evidence for greater excitability.

My misunderstanding that there are no thorough investigations of new neuron excitability was brought to an end recently when I was fortunate to have an infant-free moment (In which I was able to read two papers in the same evening, plus an entire New Yorker article over breakfast. Amazing.) One of the papers was Reliable Activation of Immature Neurons in the Adult Hippocampus by Mongiat et al. from Alejandro Schinder’s lab, which I really should have read long ago. Continue reading Are new neurons really more excitable? (yes)

How does the brain pick which neurons to use?

ResearchBlogging.orgWiring. That’s one answer to this question. We know this from topographic maps in the thalamus and neocortex, where the basic units of sensory information are neatly represented in spatially-arranged populations of neurons – the various body parts are represented in specific locations, as are the different frequencies of sound, the different parts of the retina, and different odors and tastes. This basic sensory information has to be represented (i.e. we all need a faithful representation of visual elements, we all need to hear the various frequencies of sound that make up human speech etc.) so why not hard-wire it and make its representation the same for all of us?

It’s often thought that things change as you move into parts of the brain that represent more complex and abstract concepts. For example, in the hippocampus, many neurons receive the same inputs so it’s generally assumed that different neurons are equally capable of representing a given piece of information. While wiring between neurons must play a role in determining which neurons are activated, the diffuseness of the wiring means that related information need not be stored in spatially neighboring neurons as in the sensory regions of neocortex. Indeed, if you look at hippocampal neurons activated by a given experience they don’t appear to have any particular spatial arrangement but are randomly distributed, anatomically. Alternatively, it could be that certain hippocampal neurons are hard-wired to respond to specific stimuli, it’s just that we don’t understand the wiring. Continue reading How does the brain pick which neurons to use?

New neurons in the adult brain. How they work and what they're good for.