Psychological stressors, including social stressors, profoundly influence immunity and behavior. In humans, chronic stress is associated with an increased prevalence of mental health complications, including anxiety and depression. While it is well known that these stress-associated conditions significantly affect health and influence quality of life, the mechanisms involved are not completely understood. In this proposal, we present novel data that indicate that anxiety-like behavior caused by exposure to social disruption (SDR), a model of social stress, is associated with the egress and trafficking of bone marrow (BM)-derived, glucocorticoid (GC)-insensitive myeloid progenitor cells (MPCs). Moreover, following SDR we show that these bone marrow-derived MPCs (CD11b+/Ly6Chigh/CCR2+) traffic to specific brain regions. Previous reports indicate that MPC populations, including dendritic cells (CD11c+/CD11b+) and macrophages (CD11b+) collected from the spleens of mice exposed to SDR were insensitive to the anti- inflammatory regulation provided by GCs. This is relevant because GC-insensitive MPCs are associated with hyper-inflammatory immune responses. Along with changes in BM-derived myeloid populations, social threat increases the reactivity of resident microglia in the brain. For example, microglia collected from SDR mice showed a primed phenotype with increased surface expression of several inflammatory markers, including CD86, TLR4, and CD14 (J. Neuroscience 2011, in press). Corresponding with their primed phenotype, microglia from mice exposed to SDR produced higher levels of inflammatory cytokines following mitogen stimulation. Therefore, the overarching goal of this project is to test the hypothesis that social threat activates catecholaminergic pathways that increase the activation of resident microglia and increase the infiltration of MPCs to prolong anxiety-like behavior. To address this hypothesis we propose three specific aims using a mouse model of social threat that results in the activation of neurocircuitry associated with threat appraisal and fear/anxiety-like responses. In the first aim we will elucidate the neuroendocrine pathways that contribute to the development and egress of GC-insensitive MPCs from the bone marrow after social threat. In the second aim we will elucidate the mechanism by which social threat facilitates the recruitment of MPCs to specific brain regions. In the third aim, we will determine how social threat-induced activation of microglia and MPC recruitment contributes to prolonged anxiety-like behavior.
These aims are relevant to understanding how stress-associated activation of innate immune cells contributes to anxiety-like behavior and may lead to interventions that diminish neuroinflammation and prolonged neurobehavioral complications.

Public Health Relevance

In humans, chronic stress is associated with an increased prevalence of mental health disorders including anxiety and depression. While it is well known that stress-associated conditions significantly influence health and the quality of life, the mechanisms involved are not completely understood. We propose that stress- induced anxiety-like behavior is exacerbated by inflammatory changes in the brain mediated by the infiltration of bone marrow-derived myeloid progenitor cells (MPCs) into the brain parenchyma. The trafficking of MPCs is regionally specific, and occurs in response to neuronal activation. In this proposal, a murine model of social threat will be used to test the hypothesis that social stress promotes the activation of catecholamine circuits that stimulate bone marrow-derived MPCs to traffic to the brain and produce cytokines that cause prolonged anxiety-like behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH093473-02
Application #
8411588
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Desmond, Nancy L
Project Start
2012-01-15
Project End
2016-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2013
Total Cost
$366,000
Indirect Cost
$126,000
Name
Ohio State University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Wohleb, Eric S; McKim, Daniel B; Shea, Daniel T et al. (2014) Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. Biol Psychiatry 75:970-81
Wohleb, Eric S; Patterson, Jenna M; Sharma, Vikram et al. (2014) Knockdown of interleukin-1 receptor type-1 on endothelial cells attenuated stress-induced neuroinflammation and prevented anxiety-like behavior. J Neurosci 34:2583-91
Powell, Nicole D; Sloan, Erica K; Bailey, Michael T et al. (2013) Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via *-adrenergic induction of myelopoiesis. Proc Natl Acad Sci U S A 110:16574-9
Wohleb, Eric S; Powell, Nicole D; Godbout, Jonathan P et al. (2013) Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J Neurosci 33:13820-33