Chronic stress in mice leads to the ‘learned helplessness‘ model of depression in mice. Also, from studies in humans as well as other animals we know that chronic stress is a risk factor and cause for depression and this is mediated by the interactive effects of two stress related systems: “the neural substrate for the organism’s stress response comprises two anatomically distinct but functionally integrated circuits, the corticotropin-releasing hormone CRH system and the locus coeruleus–norepinephrine LC-NE system.”
The relation between cortisol level/ activity in the CRH/LE-NE system and stress related maladaptation is not simple , but the relationship is complex.
There are many theories of depression. A finding that has gained ground in recent years is the enhanced neurogenesis due to administration of anti-depressants and how the action of anti-depressants may be due to their enhancing neurogenesis effects.
However this new study in PNAS, conducted on mice, casts doubt that the relation between stress/depression and neurogenesis is simple. It seems the relation is as complex as that between stress/depression and the cortisol levels.
I would first like to briefly summarize the findings of the study:
- chronic stress paradigm used was that of social defeat (cohabitation with a socially dominant conspecific). 10 days of this social defeat were administered. this typically leads to social avoidance behaviors and these behaviors are correlated with other depressive phenotypes.
- after 10 days when social avoidance (time interacting with a potential friendly con-specific) was measured it was found that about half the mice exhibited social avoidance and were sensitive to the stress; the rest of the half were ‘resilient’ and did not differ from control mice (not exposed to chronic social defeat) in their social avoidance.
- all mice, both resilient and sensitive , showed decreased proliferation in subgranular zone (SGZ) for new cells immediately after stress exposure. This effect disappeared / normalised after 24 hrs.
- Cell survival for cells created before stress exposure was not affected by stress exposure.
- cell survival for neurons created 1 day after stress exposure was enhanced selectively for those mice that were susceptible or sensitive to stress, but was not enhanced for the resilient mice or the mice taken as a whole.
- when the mice were irradiated, before stress exposure, to prevent neurogenesis, then the social avoidance behavior, even in susceptible mice disappeared. It is thus evident that social avoidance is mediated by increased neurogenesis post-stress exposure in the susceptibel mice.
Overall, the results I believe are clearly in favor of conceptualizing the susceptible mice as ‘orchid’ mice – having enhanced tendency for neurogenisis following positive/negative events of interests. they are biologically sensitive to context and exhibit neurogenesis reactivity similar to stress reactivity shown by orchid children. Given a positive life experience the increased neurogenesis post-event helps in having happy memories and cognition s and better functioning; preponderance of negative life vents in contrast lead to more negative and longlasting cognitions and memories leading to reduced functioning. Of course the dandelion mice are resilient and not that much affected by chronic stress. However, they would also not be able to make best use of environment in good conditions.
The only hiccup I see in the whole scheme of things is the effect of anti-depressants on neurogenesis and my earlier theorizing that cells may die under repetitive stress and reduced or absent neurogenisis would be a prime factor in depression. However, the relation between neurogenesis and stress will be , I am sure, complex and needs to be settled empirically, rather than theoretically. However one thing is clear, neurogenesis has a rpime role to play in depression , mediated perhaps by, chronic stress exposure and genetic diatheisis (orchid-dandelion effect).
I am excited and would love to hear of more papers that are addressing this new trend in depression – neurogenesis research keeping in mind the biological sensitivity to context thing too.
Lagace, D., Donovan, M., DeCarolis, N., Farnbauch, L., Malhotra, S., Berton, O., Nestler, E., Krishnan, V., & Eisch, A. (2010). Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance Proceedings of the National Academy of Sciences, 107 (9), 4436-4441 DOI: 10.1073/pnas.0910072107