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Post by Former NIMH Director Thomas Insel: Immune to Stress?

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Some of us seem to cope better with life’s hard knocks than others. One might assume that the secrets to understanding these individual differences in resilience must be sought in the brain. Maybe not.

Just a couple of weeks ago, NIMH’s Miles Herkenham and colleagues reported discovery of a counterintuitive route to stress resilience that works in mice – at least initially – via the peripheral immune system.1 The researchers wanted to know whether cells of the adaptive immune system might retain the memory of a psychological stress when transplanted into another animal. Based on previous results, it seemed unlikely that immune cells from an animal in a depression-like state might confer resilience to an unstressed animal.

The researchers transplanted white blood cells (lymphocytes) from mice that had developed depression-like behaviors into mice of an experimental strain lacking lymphocytes – so that the foreign cells would readily integrate into their bodies. The treated naïve mice were markedly more sociable, less anxious and their brains showed increased birth of new cells and fewer inflammatory cells than control animals, following social stress. Control cells had no effect.

Could it be that just as immune cells acquire the ability to fend off infectious agents to maintain homeostasis, they might similarly adapt to challenges to homeostasis in systems affecting brain and behavior? After all, it’s well known that the brain and the immune system are talking to each other. And other recent studies have demonstrated some remarkable effects of transfusing blood from one mouse to another, including rejuvenating effects in older mice receiving blood from juveniles.2

But the mechanisms are not clear. Using the same social defeat mouse model in the innate immune system, Scott Russo recently reported  that preexisting individual differences in mice’s blood levels of a key immune/inflammatory system messenger chemical predicted – and conferred risk for – vulnerability to depression-like behaviors.3 Levels of interleukin-6 (IL-6) were abnormally high in mice that avoided social situations after repeated encounters with a dominant animal. When the researchers gave previously resilient mice immune systems from vulnerable mice – through bone marrow transplants – they too developed the depression-like behaviors following social stress. By contrast, bone marrow transplants of stem cells that create white blood cells lacking IL-6 reduced the behaviors. So did inoculating vulnerable mice with IL-6-blocking antibodies.

It’s still unclear how these two sets of provocative mouse findings jibe with each other. Seeming discrepancies might be traceable to diverging effects of the adaptive immune system versus the innate immune system. Using the same mouse model, John Sheridan has demonstrated effects more consistent with Russo’s pegged to the innate immune system.4 Yet both new studies suggest that individual differences in the immune system may affect susceptibility to stress. If these findings in mice extrapolate to humans, could our emotional responses to stress also be amenable to interventions via the peripheral immune system? Strategies for leveraging the brain through other peripheral channels, such as the blood-brain barrier, may also prove fruitful.

Not only do we need to take off our brain-centric blinders in our search to understand resilience, but in light of the recent counterintuitive report, we also have to qualify simplistic notions that stress-triggered increases in immune/inflammatory responses are necessarily a bad thing.


1 Lymphocytes from Chronically Stressed Mice Confer Antidepressant-Like Effects to Naive Mice . Brachman RA, Lehmann, ML, Maric D, Herkenham, M. Journal of Neuroscience, January 28, 2015, Volume 35, Number 4.

2 Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.  Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-CorayT. Nat Med. 2014 Jun;20(6):659-63. doi: 10.1038/nm.3569. Epub 2014 May 4. PMID:24793238

3 Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress.  Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, Rebusi N, Heshmati M, Aleyasin H, Warren BL, Lebonté B, Horn S, Lapidus KA, Stelzhammer V, Wong EH, Bahn S, Krishnan V, Bolaños-Guzman CA, Murrough JW, Merad M, Russo SJ. Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):16136-41. doi: 10.1073/pnas.1415191111. Epub 2014 Oct 20.PMID: 25331895

4 Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. Wohleb ES, Powell ND, Godbout JP, Sheridan JF.J Neurosci. 2013 Aug 21;33(34):13820-33. doi: 10.1523/JNEUROSCI.1671-13.2013. PMID:23966702