Analysis of cerebrovascular dysfunction caused by chronic social defeat in mice, 2020, Lehmann et al.

[Hoopoe]

NIH blog Psychological stress damages brain’s blood vessels by Brandon Levy

Millions of Americans suffered from depression and anxiety even before COVID-19 began upending their lives. To make matters worse, the stresses of living through a pandemic might not only worsen mental health but could also wreak havoc on the brain itself. New IRP research has found that psychological stress damages blood vessels in the brains of mice and dramatically alters the behavior of genes in certain blood vessel cells.1

https://irp.nih.gov/blog/post/2020/07/psychological-stress-damages-brain-s-blood-vessels

 

[Trish]

This is the research paper cited.

Analysis of cerebrovascular dysfunction caused by chronic social defeat in mice
by Lehmann et al.

Abstract
Psychological stress and affective disorders are clinically associated with hypertension and vascular disease, but the biological links between the conditions have not been fully explored.

To examine this relationship, we used chronic social defeat (CSD) stress, which produces anxiety-like and depressive-like behavioral declines in susceptible mice. In such mice, CSD also produces cerebrovascular microbleeds in scattered locations. Here, we showed further evidence of vascular pathology and blood-brain barrier breakdown by visualizing plasma immunoglobulins and erythrocytes within the parenchyma and perivascular spaces of CSD brains. To further characterize the impact of stress on the cerebrovasculature, brain endothelial cells (bECs) were isolated, and global gene expression profiles were generated.

Bioinformatic analysis of CSD-induced transcriptional changes in bECs showed enrichment in pathways that delineate the vascular response to injury. These pathways followed a temporal sequence of inflammation, oxidative stress, growth factor signaling, and wound healing (i.e., platelet aggregation, hemostasis, fibrinogen deposition, and angiogenesis). Immunohistochemical staining for markers of fibrinogen deposition and angiogenesis confirmed the existence of the markers at the sites of vascular disruptions.

Recovery after CSD cessation was marked by recruitment of leukocytes perhaps participating in vascular repair. The data suggest that co-morbidity of affective disorders and vascular diseases may be attributed in part to a common link in altered endothelial cell function.

My paragraph breaks added.

 

[rvallee]

Anyone else find it remarkable that those mice can answer psychometric questionnaires? I mean, this is truly amazing. How is this not a major discovery? Those mice are incredible!

Because that's the only way depression and anxiety are "diagnosed" in humans. Since, you know, there is no test or reliable signs and symptoms. Unless, of course, those are simply invalid and based entirely on superficial features of the kind that would not differentiate between sleep, locked-in syndrome and coma.

A human bully can inflict physical trauma on another human. Is it hypothesized that in mice this is impossible? That the microbleeds are not the result of blunt force. I really doubt the mouse bullying takes the form of mental anguish or insulting their mama.

Imagine if physics worked this way. All you need to "prove" you have a perpetual heat machine is to ask a bunch of people to confirm that it "feels" warm. QED. What more can anyone expect? We'd basically still at horses and buggies but it would be super easy to publish major breakthroughs.

 

[Hoopoe]

Yes it's in mice but it would be great if they could make some progress on the biology of depression and anxiety.

 

[Hutan]

Yes, it's interesting.
Nice to see the paper is free access.

Endothelial dysfunction could be caused by a whole range of things, perhaps even high blood pressure caused by chronic stress.

But, to @rvallee's point,

2.2. Chronic social defeat (CSD)
CSD was used to model the effects of chronic psychosocial stress in mice. As in our previous studies (Lehmann et al., 2013a, Lehmann et al., 2018), an experimental C57BL/6N mouse was housed for 1, 7, or 14 days in the home cage of an aggressive, territorial male CD-1 mouse with a perforated transparent acrylic partition separating the mice. Mice were randomly assigned to each treatment group. The partition was removed for 5 min each day to allow agonistic encounters between the mice. Home cage (HC) mice were housed 2 per cage with a perforated partition permanently separating the mice.

Mice were exposed to 'agonistic encounters' from aggressive mice - so we can't rule out the possibility that physical harm caused physiological changes.

 

[Hutan]

Sixteen h after the last defeat session, whole brain minus cerebellum, brainstem, and meninges were dissected from phenotyped HC and CSD mice perfused with 0.9% saline. CSD mice were selected that had SI and LD scores indicative of stress-susceptibility (Lehmann et al., 2018).

This sounds loose. So, they didn't examine all of the mice exposed to 'chronic social defeat', only those ones that seemed rather unsociable and preferring the dark (versus light areas). So, potentially, they have selected mice that aren't feeling great for reasons other than being anxious and stressed, perhaps because they have an injury inflicted by an 'agonistic encounter'.

 

[Forbin]

I would have guessed that mice experience chronic social defeat due to their terrible pick-up lines...

 

[Woolie]

Yes it's in mice but it would be great if they could make some progress on the biology of depression and anxiety.

You know, honestly, I think they should just leave those mice alone. Many of the "rodent models" of psychopathology are really questionable, and I don't think they have a lot to say about actual human conditions like depression and anxiety. I don't think we should be subjecting creatures to such suffering without very good justification.

For one, there is the problem of inferring psychological states from rodent behaviours. Believe it or not, there's a rodent model of schizophrenia, and one of autism! How on earth can we infer such complex conditions, just based on behaviours like how close a mouse likes to get to other mice. Or whatever. As for depression and anxiety, it would help if we first had a reasonable formulation of what we meant by those in humans, before we go about torturing mice (I think the current diagnostic categories are loose to the point of being useless).

For another, there is the problem that they do these really extreme interventions, that involve great physical and well as psychological harm, and then attribute all the outcomes to psychology (for example "maternal deprivation" studies involve leaving the pups without food or water for a critical period of their infant lives, that's bound to mess up your brain development).

A third issue I have is that the hypotheses are trite and essentially always posed in the same direction - can we show that this that, or the other terrible "stress" or "trauma" will have some sort of measurable effects on health? Its a body of work that has no place for equipoise (everyone is a believer; nobody is interested in demonstrating that these things don't cause such outcomes). Of what practical value is this relentless search for yet another demonstration of a terrible health outcome from some sort of stress? Do we really need health psychology to tell us that its not a good idea to deprive babies of food and water for an extended period when really young? Or can we just use our humanity for that? Ditto for psychological stress. We should want to ease the suffering of people in situations where they feel disempowered, helpless and afraid. We don't need health psychology to tell us that. But not eliminate stress altogether. Life is full of demands, pressures, distress, pain and suffering, and isn't that part of the journey?

 

[Mithriel]

Basic biological processes can be elucidated from mice experiments and it is perfectly possible that chronic stress causes physical damage to the body and it would have been good to get an answer from a properly conducted test.

But you can only talk about the biology of stress if you place all your animals in the same stressful situation then look at all of them to see what damage they have. Then you can say that 50% of stressed animals have damaged blood vessels or whatever. You can't pick out some mice and expect it to tell you anything useful.

Animal experiments should only be used in a very limited way when nothing else would do, not carelessly in work designed to prove a hypothesis.