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Thursday
08.02.2018

A shield for the brain - mouse study reveals key role for a vascular protein in protecting the brain against stress-induced pro-inflammatory signals from the blood, preventing depression-like behavior

Like every year, speakers at our 3rdInternational Symposium on Resilience Research (taking place end of September 2017 in Mainz, Germany) showed lots of unpublished data, some of which have meanwhile made it into high-profile journals. One of those data sets, presented by Scott Russo from Mount Sinai, has recently come out in Nature Neuroscience (Menard et al.).

Like many studies on mouse resilience, the study used the Chronic Social Defeat Stress (...

Like every year, speakers at our 3rdInternational Symposium on Resilience Research (taking place end of September 2017 in Mainz, Germany) showed lots of unpublished data, some of which have meanwhile made it into high-profile journals. One of those data sets, presented by Scott Russo from Mount Sinai, has recently come out in Nature Neuroscience (Menard et al.).

Like many studies on mouse resilience, the study used the Chronic Social Defeat Stress (CSDS) paradigm, in which a mouse is exposed once a day over ten days to the attacks of a much heavier, aggressive “resident” mouse, whose cage it is forced to enter. CSDS induces long-lasting social aversion (reduced social interaction with other, non-aggressive mice) and anhedonia (e.g., reduced sucrose preference) in the intruder mouse, behavioral dysfunctions reminiscent of some of the symptoms of human depression. Hence, CSDS is considered by many an interesting depression model. However, CSDS does induce these dysfunctions in all intruder mice. Already in 2007, Krishan et al. could show in Cell that a substantial fraction of the intruders (the “resilient” ones) show social and reward-related behavior comparable to non-stressed control mice. This finding was probably a key moment for resilience research in rodent models and has since led to many important insights into the neurobiological underpinnings of resilience.

Many of those studies focussed on the brain, but there have also been intriguing findings about a role for the peripheral immune system in resilience (e.g., Hodes et al., in PNAS, 2014). Now, Menard et al. find that CSDS induces loss of expression of the protein claudin 5 (Cldn5) specifically in intruder mice susceptible to the detrimental behavioral long-term effects of CSDS – but not in the resilient mice. Cldn5 lives in tight junctions, the cellular structures that knit together the endothelial cells that line the blood vessels in the brain. Tight junctions are crucial components of the so-called Blood-Brain Barrier (BBB) that keeps molecules from the blood from freely entering the brain. Cldn5 reduction in the present study was mainly observed in blood vessels in the nucleus accumbens (a key region of the reward system, dysfunctions of which have been linked to depression) and was also accompanied by ultrastructural vessel abnormalities and permeability of the BBB in this brain area even for large blood proteins, in susceptible mice. Interestingly, post-mortem patient data indicated a similar loss of Cldn5 in depression.

When the authors knocked down Cldn5 in the accumbens, this exaggerated the effects of a milder variant of social stress into full-blown social aversion and anhedonia, and when Cldn5 expression was allowed to recover in these animals, this also rescued the behavioral deficits. Hence, Cldn5 expression might have a pro-resilience, protective function.

Enters the immune system. The authors (see Hodes et al.) had previously observed a drastic increase in blood levels of the pro-inflammatory cytokine IL-6 after CSDS in susceptible mice. They now extend this finding to IL-6 levels in the accumbens, and they provide evidence that stress-induced accumbal IL-6 is most likely derived from the blood, not produced locally. Downregulation of Cldn5 expression is apparently crucial for allowing the passage of IL-6 into the accumbens. Finally, they show that infusion of IL-6 into the accumbens before a mild variant of social stress is sufficient to induce marked social aversion.

Hence, inflammatory processes play a key pathogenic role in a mouse model of depression, in line with an increasing number of findings of inflammatory processes in depressed patients. For resilience research, the data indicate an important role for an intact Blood-Brain Barrier in protecting against detrimental influences of peripheral inflammatory processes. It will be interesting to see whether future research can identify methods to preserve or repair BBB integrity, which should have preventative effects in chronically stressed individuals.

From a broader perspective, the study is important because it finally provides a bridge between the immune system, whose role in stress-related pathology has aroused much interest in recent years (not least by the work of the Russo lab), and the brain in explaining the effects of chronic stress. This bridge seems to be the vasculature of the accumbens. What this also means is: if it turns out impossible to find ways to dampen peripheral inflammation of entry of cytokines into the accumbens, other ways of protecting or improving accumbal function might as well also help. In any way, the brain is back on center stage.

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Wednesday
24.01.2018

Stay tuned for resilient news and comments

Hear the latest news, get alerted about interesting papers, conferences, calls, grants or job openings, read comments and opinions, take part in discussions. 

This new blog is a service for the international resilience community by researchers of the DFG-funded Collaborative Research Center CRC 1193 “Neurobiology of Resilience“,  based in Mainz and Frankfurt; the International Resilience Alliance (www.intresa.org); the EU project DynaMORE; and the Deutsches Resilienz Zentrum in Mainz (www.drz.uni-mainz.de). We hope to develop this place into a true virtual home for all t...

Hear the latest news, get alerted about interesting papers, conferences, calls, grants or job openings, read comments and opinions, take part in discussions. 

This new blog is a service for the international resilience community by researchers of the DFG-funded Collaborative Research Center CRC 1193 “Neurobiology of Resilience“,  based in Mainz and Frankfurt; the International Resilience Alliance (www.intresa.org); the EU project DynaMORE; and the Deutsches Resilienz Zentrum in Mainz (www.drz.uni-mainz.de). We hope to develop this place into a true virtual home for all those interested in promoting this fascinating  and flourishing field of research.

New blog entries are announced via Twitter (ResilienceResearch@ResilienceRes, #resilience). Follow us and share!

And please comment and discuss with us. Or provide us with news and  information you feel might be interesting for everyone. Suggestions for blog entries  can be sent to rkalisch@uni-mainz.de and will be assessed by the editorial team.

Greetings from the team. And hope to see you again here.

Raffael Kalisch, Beat Lutz, Michèle Wessa, Oliver Tüscher, Klaus Lieb, Marianne B Müller

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