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Social Stress, Inflammation & Depression
from Jules: we are dealing wit an epidemic in HIV, its called Aging & HIV. with over 50% now older than 50 years old & an expected 50% over 60 soon, along with severe comorbidities & polypharmacy & disability in significant members of aging HIV+ - yet, there remains no concerted effort by federal US officials to even discuss the problem in an organized way never mind strategizing solutions. Severe depression along with isolation mobility limitations smong older aging HIV+ is one of the serious problems. Increasingly doctors are putting all these people on anti depression medications, but that is not the answer. Is that ok, to just put these patients on anti-depressants. The aging HIV problem will get worse, morbidity & mortality will worsen suite ideation & substance abuse will worsen, housing & long term care issues will worsen. It is time for federal officials and other stakeholders to begin discussing this problem, which by the way impacts both marginalized patient populations as well as others, but as usual marginalized patient populations are impacted worse, have less services often and capacity to navigate the healthcare system.
Social stress induces neurovascular pathology promoting depression
Nature Neuroscience Nov 13 2017
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.
Main
Major depressive disorder (MDD) is the leading cause of worldwide disability and the most prevalent mood disorder1,2. The prevalence of MDD is two- to threefold higher in patients with cardiovascular disease and, conversely, MDD is associated with an ∼80% increased risk of cardiovascular morbidity and mortality1,3,4,5. Chronic inflammation and sustained increases in circulating pro-inflammatory cytokines have been associated with atherosclerotic plaque formation, progression and rupture, likely contributing to the pathogenesis of cardiovascular disease and heart failure6. Concomitantly, clinical studies report higher levels of circulating pro-inflammatory cytokines in patients with MDD, a pattern that has been replicated in preclinical animal models of depression1,7,8,9,10. Individual differences in the peripheral immune system and modulation of cytokine release, notably IL-6, are associated with susceptibility versus resilience to chronic social stress11. Chronic stress mobilizes the innate immune system and stimulates enhanced proliferation and release of inflammatory monocytes and neutrophils into the bloodstream12,13.
It has been hypothesized that peripheral myeloid cells or pro-inflammatory cytokines can diffuse into the brain of stressed individuals as a result of stress-induced neurovascular damage and increased BBB permeability7,14,15,16,17,18,19. Indeed, a clinical study reported an altered cerebrospinal fluid to serum ratio of peripheral markers in depressed patients, suggesting that BBB integrity is compromised20. However, the possible link between BBB permeability, stress vulnerability and depression is still controversial21. The BBB is formed by endothelial cells sealed by tight junction proteins, pericytes and astrocytes, and serves to prevent potentially harmful signals in the blood from entering the brain. Here we evaluate the effect of chronic social defeat stress (CSDS), a mouse model of depression, on BBB-related gene expression and define a role for the tight junction protein claudin 5 (Cldn5) in the establishment of depression-like behaviors and MDD. Cldn5 is a major cell adhesion molecule in endothelial cells22, and loss of Cldn5 has been shown to promote loosening of the BBB and increased permeability23. Our study thus characterizes and functionally interrogates the neurovascular pathology associated with social stress vulnerability.
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发表于 2017-12-10 16:12
