Immunological adaptations to psychosocial stress may promote the pathophysiology of chronic inflammatory diseases. In humans, social stress activates neuronal and neuroendocrine pathways that result in significant physiological, immunological, and behavioral consequences associated with the development and recurrence of mental health complications, including anxiety. Repeated social defeat (RSD) is a murine stressor that replicates many aspects of the human stress response, including increased circulating cytokines, monocyte trafficking, and prolonged anxiety-like behavior. In both humans and rodents, the brain interprets physiological stress within fear and threat appraisal circuitry. My lab has shown that RSD induces activation of microglia within discrete stress-responsive brain regions, such as the prefrontal cortex. This is relevant because stress- induced recruitment of circulating monocytes to these brain regions promotes the development of anxiety-like behavior. Emerging evidence suggests that microglia propagate neuroinflammatory signaling that modulates neuronal and endocrine responses to stress. For example, microglia are the primary source of pro- inflammatory cytokines, including interleukin (IL)-1?. Unfortunately, the mechanisms that underlie stress- induced monocyte recruitment and subsequent neurobehavioral deficits are not completely understood. Monocyte recruitment to the brain after RSD likely involves dynamic interactions among cell types that comprise the neurovascular unit, including endothelial cells and microglia. In support of this, RSD induces the expression of key adhesion molecules on vascular endothelial cells within the same brain regions where previous findings of microglial activation and monocyte trafficking occurred. Additionally, I show novel data that inhibition of microglial activation with minocycline attenuates RSD-induced neuroinflammatory gene expression, monocyte trafficking to the brain, and development of anxiety-like behavior. Therefore, it is plausible that stress-induced microglial activation and brain cytokine signaling enhance neuroendocrine outflow that may further reinforce stress-related behaviors. Here, I will use a murine model of stress to test the hypothesis: microglia-derived IL-1? signaling activates vascular endothelial cells after RSD, which facilitate region-specific monocyte recruitment to the brain via neurovascular adhesion molecule expression to promote anxiety-like behavior. I propose three specific aims to address this hypothesis.
The first aim defines the role of microglia in activating brain region-specific vascular endothelium after RSD.
The second aim characterizes the degree of endothelial activation by microglia-derived IL-1? signaling after RSD.
The third aim determines if adhesion molecule blockade prevents RSD-induced neuroinflammation and anxiety. Overall, this proposal will advance our knowledge on the role of reactive brain endothelium in modulating stress-induced immunological and behavioral changes, and may lead to the development of novel therapies to treat inflammation and anxiety.

Public Health Relevance

Psychosocial stress is associated with increased inflammatory conditions, earlier mortality, and higher prevalence of mental health complications, including anxiety. I propose that psychosocial stress promotes formation of reactive endothelium, which facilitates monocyte recruitment into stress-responsive brain regions, leading to the development of anxiety. Understanding the role of reactive brain endothelium can help delineate the mechanisms by which psychosocial stress induces prolonged anxiety and lead to novel interventions to alleviate inflammation caused by stress. !

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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NIDR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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Ohio State University
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Schools of Dentistry/Oral Hygn
United States
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Sawicki, Caroline M; Kim, January K; Weber, Michael D et al. (2018) Ropivacaine and Bupivacaine prevent increased pain sensitivity without altering neuroimmune activation following repeated social defeat stress. Brain Behav Immun 69:113-123
McKim, D B; Weber, M D; Niraula, A et al. (2018) Microglial recruitment of IL-1?-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry 23:1421-1431