Social stress induces neurovascular pathology promoting depression

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 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 down-regulation was sufficient to induce depression-like behaviors following subthreshold social stress while chronic antidepressant treatment rescued cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or AAV-shRNA-cldn5-injected mice caused infiltration of 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.

Early life stress sensitizes individuals to the psychological correlates of mild fluctuations in inflammation

“…ELS may also lead to greater permeability of the BBB (Kuvacheva et al, ), which allows more peripheral inflammatory cytokines and cells to access the CNS. Indeed, experimental animal models have shown that vulnerability to the behavioral effects of stress are linked to greater permeability in the BBB (Menard et al, ). Through these and other mechanisms, neuroinflammation during critical phases of development may alter functional circuits in the brain (Ganguly & Brenhouse, ) and have profound implications for several neurotransmitters, including glutamate, serotonin, and dopamine (Dooley et al, ; Miller, Haroon, Raison, & Felger, ).…”

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

“…In addition to autoimmune disorders, recruitment of peripheral monocytes into the brain parenchyma has been recently shown to be directly responsible for anxiety like phenotypes in mice following periods of psychological stress (Wohleb et al, 2018, Wohleb et al, 2013). Some debate exists over whether recruited peripheral monocytes infiltrate the brain parenchyma and directly interact with neurons or remain the perivascular space, where they generate depressive phenotypes via the production of inflammatory cytokines that diffuse across the brain parenchyma (Menard et al, 2017). When further investigating the indispensable components of monocyte infiltration into the brain using models of experimental autoimmune encephalitis (EAE) and stress-induced anxiety, it was established in both that the recruitment and activation of peripheral monocytes was dependent upon either a functional NLRP3 inflammasome or the activity of NLRP3 activated cytokines.…”

Neuroimmune nexus of depression and dementia: Shared mechanisms and therapeutic targets

“…Neutrophil extravasation into the brain along with neurotoxic extracellular traps has been observed in post-mortem brains of AD patients (Zenaro et al, 2015), while expression of myeloperoxidase, a marker of neutrophil activation, was up-regulated in the plasma of patients with both MDD and AD (Tzikas et al, 2014;Vaccarino et al, 2008). Moreover, dendritic or macrophage monocytes have been shown to infiltrate the extravascular brain regions in models of stress-induced depression and in a Tg3578 AD model, contributing to behavioural impairments and seizure susceptibility but also facilitating Aβ clearance (El Khoury et al, 2007;Koronyo-Hamaoui et al, 2009;Menard et al, 2017;Wohleb, McKim, Sheridan, & Godbout, 2015). While T lymphocyte and polymorphonuclear infiltration is better characterized in AD and MDD, further experimental testing using genetic models (Lys-M GFP + , Menard et al, 2017) can help to understand role and effects of monocyte trafficking in these disorders.…”

“…Moreover, dendritic or macrophage monocytes have been shown to infiltrate the extravascular brain regions in models of stress-induced depression and in a Tg3578 AD model, contributing to behavioural impairments and seizure susceptibility but also facilitating Aβ clearance (El Khoury et al, 2007;Koronyo-Hamaoui et al, 2009;Menard et al, 2017;Wohleb, McKim, Sheridan, & Godbout, 2015). While T lymphocyte and polymorphonuclear infiltration is better characterized in AD and MDD, further experimental testing using genetic models (Lys-M GFP + , Menard et al, 2017) can help to understand role and effects of monocyte trafficking in these disorders.…”