Impaired adult neurogenesis leads to depression – is it realistic?

depressionAbout a year ago we published a paper linking adult neurogenesis to depression. A causal sort of ‘linking’, right? I mean, we found that, when adult neurogenesis was eliminated, mice had elevated glucocorticoids in response to stress and showed depressive-like behaviours1. So doesn’t this mean that impaired adult neurogenesis could lead to depression in humans, in the real world?

Well, it could…and we did end our paper with the following:

Because the production of new granule neurons is itself strongly regulated by stress and glucocorticoids, this system forms a loop through which stress, by inhibiting adult neurogenesis, could lead to enhanced responsiveness to future stress. This type of programming could be adaptive, predisposing animals to behave in ways best suited to the severity of their particular environments. However, maladaptive progression of such a feed-forward loop could potentially lead to increased stress responsiveness and depressive behaviours that persist even in the absence of stressful events.

We had to end it somehow – I was just happy that after 3 years of work we were DONE2! But our final speculation makes it clear that, while this chapter may be done, the story is not. And this fact was rightly pointed out in a recent commentary by Lucassen et al. in Molecular Psychiatry3, where they continue the discussion and bring up some good points. Here is a loose elaboration on some of the outstanding issues they bring up. Continue reading

Neurogenesis and the septotemporal axis at #SFN11

As I’ve alluded, science, and therefore the SFN meeting where much science is unveiled, is a cycle of confusion and clarification. Currently, confusion may be prevailing in the adult hippocampal neurogenesis field since new neurons have been implicated in everything mammals do – spatial and nonspatial memory, anxiety, depression, addiction, social behavior, stress regulation, blinking etc. This should not be entirely surprising since the hippocampus itself, where these young neurons reside, has many different functions. But how can we reconcile these seemingly disparate functions?

Every time I get worked up about all these neurogenesis findings I think about two words that return me to a state of inner peace, calmness, and….mental turmoil that all of my experiments will have to be performed twice: Septal and Temporal. Neurogenesis aside, the septal and temporal ends of the hippocampus are connected to different brain structures that cause the septal hippocampus to be more involved in spatial processing/cognition and the temporal hippocampus to be more involved in regulating stress and emotion. Which has the potential to explain everything. Continue reading

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

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.

Random roundup

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“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.

Decade in review #1: the neurogenesis-depression hypothesis

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At 0.6% of the way into the decade, we’re well beyond the timeframe when most “things of the decade” articles appear. Now that “decade hype” has settled down I thought it would be fun to write a series of posts that discuss some of the major themes in adult neurogenesis over the last decade. A lot has happened in this time; depending on how you birthdate the field (i.e. not counting the work of Joseph Altman), the last decade represents over half the lifetime of the field. BDHXV8966V35

One very influential theme that emerged, only to gain momentum, is the neurogenesis-depression hypothesis. Generally, the idea is that adult hippocampal neurogenesis is protective against depression. This idea was initially quite novel because, 10 years ago, most people were fixated on the hippocampus as a structure involved in learning and memory. Indeed, it’s not implausible that the ability to form rich, detailed memories (which the hippocampus is known for) could enable one to make associations and see perspectives that allow them to escape a depressive funk. But more direct evidence linking the hippocampus to mood has come from studies showing that manipulations to the hippocampus alter stress and anxiety-related behaviors. Continue reading

A list of experiments that relate adult hippocampal neurogenesis to behavior

The list as a Google spreadsheet (also excel | HTML | RSS feed of updates)
List last updated 3/9/2011.

I’ve always enjoyed making lists. As a kid I can remember writing lists of rhyming words, lists of all the Ocean Pacific clothes I owned, lists of all the people I knew. Many years later, I hope I’ve now made a list that is actually useful.

Adult neurogenesis is now undisputed. Pretty much on a weekly basis there is a new paper that examines both levels of adult hippocampal neurogenesis and behavior, attempting to draw a functional connection. The good news is that the argument for a behavioral function for adult neurogenesis continues to get stronger. The bad news is that there’s a massive pileup of data, and it’s becoming hard to filter through the relevant studies – first you have to find them amongst the 1000+ studies of adult neurogenesis. Then you have to read them. What behaviors are examined? Is there an effect of reducing or enhancing neurogenesis? What method is used to manipulate neurogenesis? What do other studies find that performed a similar analysis? Continue reading