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The neuroimmunology of social-stress-induced sensitization

Abstract

Myriad clinical findings provide links between chronic stressors, inflammation, and mood disorders. Furthermore, traumatic or chronic exposure to psychological stressors may promote stress sensitization, in which individuals have long-term complications, including increased vulnerability to subsequent stressors. Post-traumatic stress disorder (PTSD) is a clinically relevant example of stress sensitization. PTSD alters neuronal circuitry and mood; however, the mechanisms underlying long-term stress sensitization within this disorder are unclear. Rodent models of chronic social defeat recapitulate several key physiological, immunological, and behavioral responses associated with psychological stress in humans. Repeated social defeat (RSD) uniquely promotes the convergence of neuronal, central inflammatory (microglial), and peripheral immune (monocyte) pathways, leading to prolonged anxiety, social withdrawal, and cognitive impairment. Moreover, RSD promotes stress sensitization, in which mice are highly sensitive to subthreshold stress exposure and recurrence of anxiety weeks after the cessation of stress. Therefore, the purpose of this Review is to discuss the influence of social-defeat stress on the immune system that may underlie stress sensitization within three key cellular compartments: neurons, microglia, and monocytes. Delineating the mechanisms of stress sensitization is critical in understanding and treating conditions such as PTSD.

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Fig. 1: Social defeat stress activates the hypothalamic pituitary adrenal axis and sympathetic nervous system to promote the release of monocytes into circulation.
Fig. 2: Repeated social defeat induces neuronal activation that coordinates peripheral and central immune responses that influence behavior and cognition.
Fig. 3: Overview of repeated social defeat and stress sensitization of central and peripheral immune compartments.
Fig. 4: Microglia are primed and more reactive to peripheral immune challenges after repeated social defeat.

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Acknowledgements

This research was supported by NIMH grants R01-MH-119670 and R56-MH116670 (to J. P. G. and J. F. S.). C. M. S. was supported by both NIDCR Training Grant T32-DE014320 and F30-DE026075.

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Biltz, R.G., Sawicki, C.M., Sheridan, J.F. et al. The neuroimmunology of social-stress-induced sensitization. Nat Immunol 23, 1527–1535 (2022). https://doi.org/10.1038/s41590-022-01321-z

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