Social stress induces neurovascular pathology promoting depression, 2017, Russo et al

[Andy]

Abstract

Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood–brain barrier (BBB) permeability and infiltration of peripheral immune signals.

We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors.

These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression.

Paywalled at https://www.nature.com/articles/s41593-017-0010-3

New Scientist article on this, https://www.newscientist.com/articl...ss-makes-your-brain-vulnerable-to-depression/

 

[Invisible Woman]

Doesn't every human in the planet experience what they call social stress at some point?

Everyone at some point has parents or guardians or older siblings, teachers, bosses. Not all of these more powerful people will be kind, gentle and understanding.

If this is the case why are there not more cases of depression?

Perhaps I've misread it but the new scientist article seems to assume that increased IL-6 and depression are the whole story. Is it not possible that both could be symptomatic of some other, as yet unidentified, abnormality?

 

[Andy]

Doesn't every human in the planet experience what they call social stress at some point?

Everyone at some point has parents or guardians of older siblings, teachers, bosses. Not all of these more powerful people will be kind, gentle and understanding.

If this is the case why are there not more cases of depression?

But how would we quantify that? What is the exact amount of stress required? In the study itself, not all mice developed symptoms. To my mind, an equally valid question would be why are there not fewer cases of depression?

 

[Trish]

I've read the abstract and the NS article.

The question I want to ask is, how do they know it is the stress that causes the blood brain barrier (bbb) to be more leaky etc. Couldn't it equally be that there are a proportion of mice (and humans) who have a leakier bbb and are therefore more susceptible to these chemical and mood changes.

Since they can't tell if a mouse has a leaky bbb except by killing it, they can't know whether it was already leaky before the experiment started in those mice. In other words, does the stress cause the leakiness and hence the depression, or does the stress act on an already leaky bbb to trigger the depression.

Or have I missed something (quite likely).

 

[Indigophoton]

@Trish, I can't access the paper, but the NS article mentions two other groups of mice being included as part of the experiment,

Comparing blood, DNA and tissue samples from the stressed small mice, nine control mice and mice that were more relaxed in the presence of big bruisers suggests that there are three stages in the process of social stress leading to an altered mood.

If mice already had leaky BBB prior to the stress, then there should be mice with leaky BBBs in all three groups. Presumably, then, only the mice in the group that were put under stress had leaky BBBs on examination (or only to a significant extent/a significant number of mice).

Without being able to look at the whole paper, it's hard to know anything for sure, though.

 

[Jonathan Edwards]

Mouse 'models' like this are always self-fulfilling and tell us nothing about causation in human disease.