About 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.
Is a feed-forward cascade plausible? In other words, is it possible that stress reduces neurogenesis, which leads to a hyperactive HPA response, which further reduces neurogenesis, thereby additionally increasing the stress response etc etc, eventually damaging the brain and leading to depression? As Lucassen et al point out, stress typically reduces neurogenesis by only ~30% which is much smaller than the 100% reduction seen in our transgenic mice. Could a 30% reduction be enough to initiate this vicious cycle? What if it was chronic? People have looked in the past and not observed HPA alterations after smaller (but also equally large) reductions in neurogenesis, so the answer might appear to be negative. But there are many important differences between studies, including when stress hormones were measured (e.g. baseline or after stress) as well as factors such as life history, genetic makeup, and stressor controllability, as is suggested in the commentary. Of course, in reality, chronic stress has multiple effects throughout the hippocampus (and brain) and so the development of depression is certainly due to additive effects (this is both their sentiment and mine). And so perhaps in the real world a more modest reduction in neurogenesis does have the potential to tip the scales towards depression, if it is coupled with other (which?) pathologies.
How could so few adult-born neurons regulate the HPA axis? Depending on my mood, my thoughts on this question fluctuate quite a bit. Half of the time I think “This is ridiculous” and the other half of the time I look at the evidence and think “Heck yeah. Maybe4.” (see our recent review for more detailed arguments on the heck yeah side of things). In our study we reduced neurogenesis for up to 12 weeks, preventing about 50,000 cells from being added or 10% of the total population. More important than sheer numbers, however, is the ever-increasing evidence that adult-born neurons are different from mature neurons – more plastic, more excitable, uniquely neuromodulated. Some of the most intriguing evidence comes from one of the authors themselves who has shown that even 4 month old neurons (but potentially older?) undergo extensive structural modification following learning whereas perinatal-born cells do not. We have estimated that ~40% of the total granule cell population is added in adulthood in the rat and so my point is that in the real world we have to consider that there are probably cumulative effects of adult neurogenesis over years, and even decades in humans. And so the population of adult-born cells, and its functionality, may not be so small in the end.
Do new neurons sense detect stress through glucocorticoids? One common assumption is that glucocorticoid receptors are necessary for inhibition of the HPA axis…but must that always be the case? By 1-2 weeks of age the majority of adult-born neurons do express MRs and GRs and therefore certainly could directly detect glucocorticoid levels and initiate a shutting down of the HPA axis. But perhaps new neurons process stressful information that is relayed through glutamatergic pathways. In this scenario new neurons might not be required for sensing glucocorticoids and initiating negative feedback. Instead, after being stressed, they could be required for biasing the animal away from the negative experience (akin to perceiving a change in context, similar Opendak & Gould‘s proposal for reconciling stress and memory hypotheses of new neuron function) which might reduce CNS drive on the HPA axis. This opens the door to the possibility that the HPA and behavioural roles of adult neurogenesis are somewhat dissociable, in which case a role for new neurons in the development of depression is not (only) through the feedforward cascade hypothesis but through direct effects on behaviour. This might also help explain the inconsistent links between stress hormones, hippocampal volume, and depression that plague the stress-depression literature.
So, we showed that adult-born neurons are required (in mice) for normal stress responses and emotional behaviour. Our final speculation was, well, just that – a leap towards the next big question. Maybe realistic, maybe not. Maybe a component of the real picture. In any case, the route has been mapped.
Lucassen PJ, Fitzsimons CP, Korosi A, Joels M, Belzung C, & Abrous DN (2012). Stressing new neurons into depression? Molecular psychiatry PMID: 22547116
Snyder JS, Soumier A, Brewer M, Pickel J, & Cameron HA (2011). Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature, 476 (7361), 458-61 PMID: 21814201
1You thought this footnote was going to be some comment on human depression vs. depressive-like behaviour in animal models but instead I just wanted to mention that, now that I’ve moved back to Canada, I feel compelled to use ‘behaviour’ instead of ‘behavior’ and it feels silly because the same people read this stuff no matter which country I’m in when I write it.
2Is there an emoticon for dusting the dirt off your hands, blowing smoke away from the tip of a revolver, or enjoying a refreshing beverage after chopping a bunch of wood or giving birth? Insert it here.
3One of the authors having actually commented on this blog (!), and who is 1st author on what looks to be a very interesting paper that is related to this whole discussion.
4I may be a pessimist. Realist? A guy with a healthy amount of skepticism?
5The photo? It’s a depression.