Spleen Monocyte Progenitors Promote Recurring Anxiety

Ohio State University, Columbus OH

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Abstract

? DESCRIPTION (provided by applicant): Chronic psychosocial stress contributes to the development and exacerbation of anxiety disorders. Additionally, stress-induced immune activation is implicated in the development of these negative mental health outcomes. Here, I propose a novel immune mechanism that may mediate the development of chronic recurring anxiety following psychosocial stress. I show that repeated social defeat (RSD) in mice promoted the production of monocytes in the spleen. RSD caused bone marrow derived hematopoietic stem progenitor cells (HSPCs) to accumulate in the spleen that resulted in significant generation of splenic monocytes for at least 24 days. In response to acute stress many 24 days after RSD, splenic monocytes trafficked to the brain and promoted the recurrence of prolonged anxiety-like behavior. Acute stress did not alter these parameters in naïve mice. Thus, RSD promoted stress-sensitization that persisted for at least 24 days. Hypothesis: Splenic monocyte generation mediates the recurrence of anxiety following acute stress 24 days after RSD. Three specific aims are proposed to address this hypothesis. The first aim proposes to more fully character the kinetics and phenotypes of splenic monocyte generation following RSD. The second aim addresses the role of neuroendocrine activation during RSD in splenic monocyte generation and the recurrence of anxiety 24 days later. The third aim proposes to directly address the role of splenic HSPCs in the maintenance of stress-sensitization. Overall, this proposal shows novel data that psychosocial stress causes monocyte generation within the spleen that may contribute to stress-sensitization many days after the cessation of the stressor. Three specific aims outline numerous novel approaches to address the role of splenic monocyte generation in stress-sensitization.