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Social stress induces neurovascular pathology promoting depression
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Nature Neuroscience 20, 1752-1760 (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. Cldn5downregulation 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.
Discussion
Overall, our findings suggest that chronic social stress alters BBB integrity through downregulation of the tight junction protein Cldn5 in the NAc, which, combined with stress-induced recruitment of peripheral immune signals, results in increased BBB permeability, passage of blood circulating proteins such as IL-6, and the development of depression-like behaviors (Supplementary Fig. 11). Our findings complement decades of correlative clinical evidence suggesting that the immune system and elevations in circulating pro-inflammatory cytokines, particularly IL-6, are involved in the establishment of MDD1,7,11,38,39. We previously reported higher serum IL-6 in patients with untreated MDD and treatment-resistant MDD when compared to healthy controls11,40. Though a potential link between BBB leakiness and depression was first proposed over 50 years ago41, the development of new tools, such as valid rodent models of depression and high-resolution imaging, have made it feasible to address this question. Our work highlights an important function of the BBB-related tight junction protein Cldn5 as a regulator of stress-induced depression-like behaviors. While size-selective loosening of the BBB to small molecules (<800 Da) was previously described in Cldn5-deficient mice23, we show here that chronic social stress can also loosen the BBB by downregulating Cldn5, allowing larger molecules to infiltrate the NAc parenchyma in SS mice.
Though we found increased passage of proteins of up to ~69 kDa, we did not detect infiltration of peripheral Ccr2+ monocytes as in a previous report14. This may be related to differences in social stress models or to our use of a bitransgenic mouse that allows simultaneous tracking of monocytes and microglia without generating chimeric mice through bone marrow transplantation. We nevertheless confirm a recent report showing that monocytes are recruited to vessels and ventricular space within the brain34. From these vascular sites, monocytes can release pro-inflammatory cytokines, such as IL-6, that can then penetrate the brain parenchyma to act locally on neurons and glia. To our knowledge, this is the first study to provide direct evidence that chronic stress is sufficient to allow infiltration of circulating cytokines in the absence of local mechanical trauma or a brain tumor42,43. Greater understanding of the mechanisms by which chronic stress activates the immune system and undermines BBB integrity may promote the design of more effective antidepressant strategies, either by augmenting current treatment protocols or by informing the discovery of new therapeutics that enhance neurovascular health in stress-related brain regions. A major impediment to this goal is the lack of therapeutic agents that can enhance Cldn5 expression to repair endothelial damage as, so far, no such compound exists.
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