Decade in review #1: the neurogenesis-depression hypothesis

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. Searching “neurogenesis” and “depression” in Pubmed I can find papers by Daszuta, McEwen, and Duman discussing reduced adult neurogenesis as a potential factor in depression and mood disorders just before the decade, in 1999. But the study that really got the field going was the finding that antidepressants can increase neurogenesis, by Malberg et al., in 2000. And so, with the turn of the last decade, depression officially replaced epilepsy as the most popular disorder that is potentially related to neurogenesis (the neurogenesis-epilepsy hypothesis was killed in dramatic fashion briefly wounded in 1999*). Within the next few years it was clear that every type of chemical antidepressant increased neurogenesis, as did electroconvulsive shock, as did environmental influences such as running and social housing, which are known to have antidepressant effects. Furthermore, factors that precipitate depression, such as chronic stress, potently downregulate neurogenesis. But while these findings are all consistent with the possibility that neurogenesis plays a role in depression, antidepressants / ECS / exercise / stress also have many other effects on the brain that could explain their effects on mood. So more experiments were needed.

In 2003, Santarelli et al. delivered findings everybody was waiting for: without neurogenesis, antidepressants don’t work. Thinking about this study I am inspired to write a post on the “Top drool-producing papers in the field of adult neurogenesis.” Undoubtedly, this would be near the top, as it seemed to provide the killer evidence needed to link neurogenesis to depression. Moreover, merely reducing neurogenesis was not sufficient to induce anxiogenic or depressive behavior, it just blocked the benefits of antidepressants. This finding was welcome (to me) because it suggested neurogenesis is involved in regulating depressive behavior, but it is not the only factor, consistent with other studies that had failed to find neurogenesis-depression links. The remainder of the decade was rounded out with studies that, while partially confirming a role for neurogenesis in anxiety/depressive behavior, also illustrated the complexity of the situation. For example, neurogenesis does not mediate the effects of antidepressants in some strains of mice, and may mediate antidepressant effects in distinct behavior tests in different species (e.g. forced swim test in rats but not mice). Also confirming but complicating are the findings from Abrous’ group showing (with a transgenic model of reduced neurogenesis as opposed to irradiation in the previously mentioned studies) that merely reducing neurogenesis can be anxiogenic.

So we started the decade with a mere proposal that neurogenesis was relevant for depression/anxiety/mood disorders. We ended with hundreds of correlative studies and several studies spanning several groups showing that relatively specific reductions in adult neurogenesis can lead to depressive behavior if the conditions are right. What will 2010-2020 unveil? How about: 1) One hundred more studies of depressive behavior in neurogenesis-deficient animals, 2) the first test of the neurogenesis-depression hypothesis in humans, and 3) a switch to autism as the most popular disorder that is potentially related to adult neurogenesis.

*Lots of recent and interesting research points to a role for neurogenesis in the pathogenesis (also here) and also recovery from seizures

Malberg JE, Eisch AJ, Nestler EJ, & Duman RS (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience, 20 (24), 9104-10 PMID: 11124987

Santarelli, L. (2003). Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants Science, 301 (5634), 805-809 DOI: 10.1126/science.1083328