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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
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Desmond, Nancy L
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Ohio State University
Schools of Dentistry
United States
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Weber, Michael D; McKim, Daniel B; Niraula, Anzela et al. (2018) The Influence of Microglial Elimination and Repopulation on Stress Sensitization Induced by Repeated Social Defeat. Biol Psychiatry :
Lisboa, Sabrina Francesca; Niraula, Anzela; Resstel, Leonardo Barbosa et al. (2018) Repeated social defeat-induced neuroinflammation, anxiety-like behavior and resistance to fear extinction were attenuated by the cannabinoid receptor agonist WIN55,212-2. Neuropsychopharmacology 43:1924-1933
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
Niraula, Anzela; Wang, Yufen; Godbout, Jonathan P et al. (2018) Corticosterone Production during Repeated Social Defeat Causes Monocyte Mobilization from the Bone Marrow, Glucocorticoid Resistance, and Neurovascular Adhesion Molecule Expression. J Neurosci 38:2328-2340
Niraula, Anzela; Witcher, Kristina G; Sheridan, John F et al. (2018) Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety. Biol Psychiatry :
Niraula, Anzela; Sheridan, John F; Godbout, Jonathan P (2017) Microglia Priming with Aging and Stress. Neuropsychopharmacology 42:318-333
Ramirez, Karol; Fornaguera-Trías, Jaime; Sheridan, John F (2017) Stress-Induced Microglia Activation and Monocyte Trafficking to the Brain Underlie the Development of Anxiety and Depression. Curr Top Behav Neurosci 31:155-172
Weber, Michael D; Godbout, Jonathan P; Sheridan, John F (2017) Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal. Neuropsychopharmacology 42:46-61
McKim, Daniel B; Niraula, Anzela; Tarr, Andrew J et al. (2016) Neuroinflammatory Dynamics Underlie Memory Impairments after Repeated Social Defeat. J Neurosci 36:2590-604

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