Decoding microglia responses to psychosocial stress reveals blood-brain barrier breakdown that may drive stress susceptibility
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ABSTRACT:
PROVIDER: PRJNA421967 | ENA |
REPOSITORIES: ENA
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Project description:An animal’s ability to cope with or succumb to deleterious effects of chronic psychological stress may be rooted in the brain’s immune responses manifested in microglial activity. Mice subjected to chronic social defeat (CSD) were categorized as susceptible (CSD-S) or resilient (CSD-R) based on behavioral phenotyping, and their microglial RNAs were isolated and analyzed by global gene expression microarrays. Microglia transcriptome from CSD-S mice was enriched for pathways that describe phases of CNS healing to sterile injury including, inflammation, oxidative stress, debris clearance, and wound resolution. Histochemical experiments confirmed the array predictions: CSD-S microglia showed elevated phagocytosis and oxidative stress, and the brains of CSD-S but not CSD-R or HC mice showed vascular leakage of intravenously injected fluorescent tracers. The results suggest that the inflammatory profile of CSD-S microglia may be precipitated by leakage of blood-born substances into brain parenchyma. We hypothesize that these CNS-centric responses contribute to the stress-susceptible behavioral phenotype.
2018-07-31 | GSE107941 | GEO
Project description:An animal's ability to cope with or succumb to deleterious effects of chronic psychological stress may be rooted in the brain's immune responses manifested in microglial activity. Mice subjected to chronic social defeat (CSD) were categorized as susceptible (CSD-S) or resilient (CSD-R) based on behavioral phenotyping, and their microglia were isolated and analyzed by microarray. Microglia transcriptomes from CSD-S mice were enriched for pathways associated with inflammation, phagocytosis, oxidative stress, and extracellular matrix remodeling. Histochemical experiments confirmed the array predictions: CSD-S microglia showed elevated phagocytosis and oxidative stress, and the brains of CSD-S but not CSD-R or non-stressed control mice showed vascular leakage of intravenously injected fluorescent tracers. The results suggest that the inflammatory profile of CSD-S microglia may be precipitated by extracellular matrix degradation, oxidative stress, microbleeds, and entry and phagocytosis of blood-borne substances into brain parenchyma. We hypothesize that these CNS-centric responses contribute to the stress-susceptible behavioral phenotype.
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Project description:Psychosocial stress has profound effects on the body, including the peripheral immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3,4,5, the underlying mechanisms are not well understood. Here we show that a myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is elevated in serum from MDD subjects as well as in stress susceptible (SUS) mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), thereby altering social behavior. Using a combination of mass cytometry and single-cell RNA-sequencing, we performed high-dimensional phenotyping of immune cells in circulation and brain and demonstrate that peripheral monocytes are strongly affected by stress. Both peripheral and brain infiltrating monocytes of SUS mice show increased expression of Mmp8 following CSDS. We further show that peripheral MMP8 directly infiltrates the NAc parenchyma to control ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behavior and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a novel mechanism by which peripheral immune factors can affect central nervous system function and behavior in the context of stress. Targeting specific peripheral immune cell-derived proteins, such as matrix metalloproteinases, could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.
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