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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 Impaired adult neurogenesis leads to depression – is it realistic?

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.

Everything you always wanted to know about neurogenesis timecourses (but were afraid to ask)

Most studies of adult neurogenesis are concerned with neuronal age. Or at least they should be. This is because new neurons develop from a stage where they have no excitatory synapses to one where they have many. If we assume the traditional view that information is stored at excitatory synaptic connections, then young neurons are initially useless and only become physiologically and behaviorally meaningful when they have matured to a point where they can relay and process information. It is therefore critical that the developmental timecourse of new neurons be mapped out, so we know when new neurons become functionally relevant, or whether they might even have different functions at different ages.

Below are what I hope to be comprehensive visual collages of all published timecourse experiments, where a certain property of new neurons is examined at multiple (≥ 3) different ages. They are grouped by studies of: 1) cell survival, 2) marker expression, 3) functionality, and 4) miscellaneous studies that do not quite fit into the first 3 categories. I’ve ordered the data roughly chronologically and have included the first author’s name and publication year so you can read deeper, if needed. Indeed, if you know these studies already, a brief look at the graphs will bring back the take home message. However, since the data is stripped of text, if the studies are unfamiliar, you’ll have to go to the original source to figure out what the heck they mean (use Pubmed to at least obtain abstracts for the original studies if I didn’t provide a direct link).

Personally, I like timecourse studies for the same reason I like to have all my music albums or books visible at the same time: at a single glance they provide a lot of information – each individual stage of maturation can be interpreted within a bigger picture. The result of these many hours of work will either be a) that the purpose of adult neurogenesis will become immediately clear, or b) that we’ll all have some fancy collages to pin on our bulletin boards and look intelligent.

The survival timecourse

addition of new neurons

New neurons are born and then many die. The survival timecourse answers the questions: How many new neurons are born? Where are they born and where do they end up, anatomically? How many of them survive and can their survival be altered? Survival timecourses are typically performed by injecting animals with a mitotic marker that will label new neurons as they’re being born, e.g. ³H-thymidine (old school), BrdU (tried and true – example), or a GFP-expressing retrovirus (new school). At a later date one can then detect these birthdated new neurons and count them, see where they’re located etc.

Continue reading Everything you always wanted to know about neurogenesis timecourses (but were afraid to ask)