Alterations in circulating extracellular vesicles underlie social stress‐induced behaviors in mice

Abstract

Chronic stress induces peripheral and intracerebral immune changes and inflammation, contributing to neuropathology and behavioral abnormalities relevant to psychiatric disorders such as depression.Although the pathological implication of many peripheral factors such as pro-inflammatory cytokines, hormones, and macrophages has been demonstrated, the roles of circulating extracellular vesicles (EVs) for chronic stress mechanisms remain poorly investigated. Here we report that chronic social defeat stress (CSDS)-induced social avoidance phenotype, assessed by a previously untested threechamber social approach test, can be distinguished by multiple pro-inflammatory cytokines and EVassociated molecular signatures in the blood. We found that the expression patterns of miRNAs distinguished the CSDS-susceptible mice from the CSDS-resilient mice. Social avoidance behavior scores were also estimated with good accuracy by the expression patterns of multiple EV-associated miRNAs. We also demonstrated that EVs enriched from the CSDS-susceptible mouse sera upregulated the production of pro-inflammatory cytokines in the LPS-stimulated microglia-like cell lines. Our results indicate the role of circulating EVs and associated miRNAs in CSDS susceptibility, which may be related to pro-inflammatory mechanisms underlying stress-induced neurobehavioral outcomes.

Stress induces major depressive disorder by a neutral sphingomyelinase 2-mediated accumulation of ceramide-enriched exosomes in the blood plasma

“…Our studies indicate a central role of phosphatidic acid as effector of exosomal ceramide in the blood plasma in the pathogenesis of MDD. However, exosomes have been shown to also contain miRNA molecules that can be altered under stress [ 46 ]. Furthermore, several miRNA molecules, for instance miR-34a, miR-106, miR-134, and miR-132, are deregulated in MDD and show brain enrichment in MDD [ 47 , 48 ].…”

Glutamine antagonist JHU083 improves psychosocial behavior and sleep deficits in EcoHIV-infected mice

“…SIT was performed to evaluate social avoidance, which belongs to social processes, a domain relevant to the psychopathology of depression ( Carcone and Ruocco, 2017 ). As we previously described ( Zhu et al, 2019 ; Sakamoto et al, 2021 ), mice were placed in a three-chamber apparatus (40 cm width × 20 cm height × 26 cm depth) containing a small, porous cage in the corner of each side chamber. Each trial consisted of 3 sessions: 1) The mouse was placed in the center chamber to habituate for 10 min, 2) the mouse was allowed to freely explore the empty side-chambers for an additional 10 min, and 3) a stranger mouse (stranger) of the same strain was placed in the plastic cage in one chamber, while a novel inanimate object (object) was placed in the opposing chamber's cage, and the test mouse was again allowed to explore all chambers freely for 10 min.…”

Extracellular Vesicles and the Stress System

“…Sakamoto et al [380] showed that plasma EVs from CSDS-susceptible mice with a social avoidance phenotype had a distinct miRNA profile, which distinguished them from CSDS-resilient mice. Among the differentially expressed miRNAs, miR-31-5p, miR-712-5p, miR-212-3p, miR-451a, miR-467b-3p, miR-193b-3p and miR-93-5p were associated with inflammation.…”