Program Director/Principal Investigator (Sheridan, JF & Godbout JP): PROJECT SUMMARY/ABSTRACT: Dynamic inflammatory signaling in the brain may have a causative role in anxiety. We report that repeated social defeat (RSD) in mice induces sympathetic-mediated release of primed monocytes from the bone marrow that are actively recruited to the brain. Collectively, we show that RSD promotes prolonged anxiety-like behavior that depends on activation of microglia and recruitment of inflammatory monocytes to threat appraisal regions of the brain. This application demonstrates that microglial recruitment of IL-1? producing monocytes to neurovascular endothelium is necessary for the potentiation of anxiety-like behavior in response to social stress. Despite this knowledge, three key mechanistic questions remain to be answered, which will allow for the development of novel interventions for treatment of neuropsychiatric complications associated with stress: 1) How does RSD activate microglia in threat appraisal regions? 2) How are inflammatory monocytes selectivity recruited to neurovascular endothelium in threat appraisal regions? 3) What are the key factors produced by neurovascular endothelia cells that potentiate neuroinflammation and anxiety? We show that microglial activation in response to RSD depends on neuronal activation within threat appraisal regions. Moreover, preliminary evidence suggests that this is mediated by activation of the purinergic receptor, P2RX7, on microglia. Novel data presented here show that monocyte recruitment and the development of anxiety-like behavior after RSD requires microglial activation. Furthermore, cell-specific transcriptional profiling indicates that microglia recruit monocytes to the brain via chemokine ligand (CCL2) secretion. These recruited monocytes produce IL-1??and promote anxiety-like behavior by endothelial IL-1 Receptor-1 activation. Notably, this IL-1R1 activation is associated with increased neurovascular expression of COX2, the enzyme that synthesizes neuroactive prostaglandins. Thus, the goal of this project is to test the hypothesis that recruitment and subsequent interaction of inflammatory monocytes with neurovascular endothelial cells is critical for the augmentation of neuroinflammation and potentiation of anxiety-like behavior following RSD. To address this hypothesis, three specific aims are proposed.
In Aim -1, we will ascertain the extent to which RSD-induced microglial activation is dependent on stimulation of the P2RX7 purinergic receptor.
In Aim -2, we will determine the degree to which microglial production of CCL2 is required for monocyte recruitment to threat appraisal regions and the induction of anxiety-like behavior after RSD.
In Aim -3, we will assess the role of endothelial COX2 following RSD and determine other key factors produced by IL-1R1-stimulated endothelial cells that facilitate anxiety-like behavior after RSD. Understanding how microglial recruitment of IL-1? producing monocytes to threat appraisal regions potentiates neuroinflammation and anxiety-like behavior will lead to new interventions for neuropsychiatric complications associated with stress. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
Sheridan, JF & Godbout JP): PROJECT NARRATIVE: In humans, psychological stress is associated with an increased prevalence of mental health complications including anxiety and depression. While stress significantly influences health and quality of life, the mechanisms involved are not well understood. Here we show that repeated social defeat (RSD) in a pre- clinical mouse model causes prolonged anxiety-like behavior that depends on activation of neurons in threat appraisal regions, microglial activation, and recruitment of inflammatory monocytes to the brain. Therefore, we hypothesize that the dynamic interaction of inflammatory monocytes with neurovascular endothelium causes augmentation of neuroinflammation and the enhancement of anxiety-like behavior in response to RSD. Understanding how microglia recruitment of cytokine producing monocytes to threat appraisal regions contributes to neuroinflammation and anxiety-like behavior will lead to novel cellular based interventions for neuropsychiatric complications associated with stress. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page