Psychosocial stressors are associated with an increased prevalence of mental health complications including anxiety and depression. While it is known that chronic stressors negatively affect health and influence quality of life, the mechanisms that underlie these neurobehavioral deficits are not well understood. In this proposal, we present novel data that repeated social defeat (RSD)-induced anxiety-like behavior is associated with the egress and trafficking of bone marrow (BM)-derived, glucocorticoid (GC)-insensitive myeloid cells to the brain. Moreover, RSD promotes the infiltration of CD11b+/Ly6Chigh/CCR2+ myeloid cells to specific brain regions associated with fear and threat appraisal. Our data also indicate that IL-1 receptor type-1 (IL-1R1) and ?-adrenergic receptor (?-ADR)-dependent pathways are critical in the development of behavioral and immunological alterations promoted by RSD. Additionally, that RSD promotes glucocorticoid (GC) insensitivity in peripheral myeloid cells. This is relevant because GC-insensitive cells are hyper-inflammatory following activation, that is, they express high levels of proinflammatory genes. Here evidence is also provided indicating that CD11b+ cells in the brain (resident microglia and infiltrating myeloid cells) are primed and less sensitive to GC. The goal of this 5 year project is to test the hypothesis that repeated social defeat stimulates trafficking of primed GC-insensitive, CD11b+/LyC6high/CCR2+ myeloid cells from the bone marrow to fear and threat appraisal regions in the brain to promote prolonged anxiety-like behavior. To address this hypothesis, three specific aims are proposed: 1). We will determine the degree to which RSD promotes the development of a permissive neurovascular unit to elicit brain region-dependent infiltration of CD11b+/Ly6Chigh/CCR2+ myeloid cells. We will focus on the role of ?-ADR and central IL-1R1 pathways in RSD-induced myeloid cell recruitment. Moreover, it is critical to compare and contrast the infiltrating myeloid cells with the resident microglial population after RSD. 2). The phenotype, GC sensitivity, and proliferative capacity of these cells following RSD will be determined. These experiments will also determine time- and brain region-dependent differences in these myeloid populations following RSD. While it is established that circulating myeloid cells will traffic to sites of tissue damage under inflammatory conditions in the CNS, the release and trafficking of this specific myeloid population to the brain is unique in a model of psychosocial stress where significant CNS trauma is absent. 3). The degree to which blockade of the chemokine receptor-2 (CCR2) prevents CD11b+/Ly6Chigh/CCR2+ myeloid cell infiltration and reverses prolonged anxiety-like behavior associated with RSD will be determined. Understanding how stress-associated promotion of myeloid cell trafficking contributes to neuroinflammation and the promotion of long-lasting anxiety-like behavior may lead to novel interventions that target myeloid cell trafficking and attenuate prolonged neurobehavioral complications associated with chronic stress.

Public Health Relevance

Psychosocial stressors are associated with an increased prevalence of mental health complications including anxiety and depression. While it is known that social stressors negatively affect health and quality of life, the mechanisms that underlie these neurobehavioral deficits are not well understood. The goal of this proposal is to understand how stress-associated promotion of myeloid cell trafficking to the brain contributes to neuroinflammation and the promotion of long-lasting anxiety-like behavior. Completion of this goal may lead to novel interventions to target myeloid cell trafficking to the central nervous system and attenuate prolonged neurobehavioral complications associated with chronic stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH097243-01A1
Application #
8503687
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Desmond, Nancy L
Project Start
2013-04-15
Project End
2018-01-31
Budget Start
2013-04-15
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$490,470
Indirect Cost
$162,157
Name
Ohio State University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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 :
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
McKim, Daniel B; Patterson, Jenna M; Wohleb, Eric S et al. (2016) Sympathetic Release of Splenic Monocytes Promotes Recurring Anxiety Following Repeated Social Defeat. Biol Psychiatry 79:803-813

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