The present proposal explores a novel conceptualization of glucocorticoid (GC) action in the stress response during a fight/flight emergency. This is that stress-induced GCs function to alert the organism's CNS innate immune system to potential """"""""danger"""""""" signals that include 1) exogenous pathogens and/or pathogen associated molecular patterns (PAMPs), &2) endogenous danger signals or alarmins, which can be released in response to a wide array of stimuli including sterile injury. Here, GCs """"""""prime"""""""" or """"""""sensitize"""""""" the CNS innate immune/inflammatory response to subsequent stimulation, such as occurs upon exposure to infectious agents or injury. The idea is that stress-induced GCs can function as an endocrine """"""""warning signal"""""""" to the CNS innate immune system to induce a preparatory response (microglial sensitization) to subsequent proinflammatory stimuli. Neuroinflammatory processes are a focus here given the emerging roles of CNS pro-inflammatory cytokines in the etiology of psychiatric disorders in which stress &GCs are key etiologic factors. The primary objectives are: 1) to explore how stress sensitizes microglia to pro-inflammatory challenges &2) examine whether GCs mediate stress-induced sensitization of microglia. The general hypotheses to be tested are that A) stress sensitizes microglia to pro-inflammatory stimuli by upregulating pattern recognition receptors (PRRs) on microglia. The PRRs Toll-Like receptor (TLR) 2 and/or 4 transduce the pro-inflammatory cytokine effects of endogenous danger signals. We propose that stress """"""""primes"""""""" microglia by upregulating TLR 2 and/or 4 on microglia for a period of days post-stress. Subsequently, upregulated TLRs expressed by microglia sense endogenous danger signals released upon exposure to a pro- inflammatory stimulus. B) TLR mediation requires that the later pro-inflammatory stimulus increase an endogenous molecule in the brain that acts at the TLRs. High Mobility Group Box1 (HMGB1), an alarmin released in response to danger, is an endogenous protein in the CNS that acts at TLRs &we suggest that HMGB1 is increased by a pro-inflammatory stimulus &then acts at the stress-upregulated TLRs, thereby inducing a potentiated pro-inflammatory cytokine response. C) GCs mediate the stress-induced sensitization of microglia (i.e. upregulation of TLR 2/4). Clinically, stress and neuroinflammatory processes are emerging as important factors in the etiology of psychiatric disorders. Also, an extensive body of evidence implicates GCs in the etiology of such disorders. The proposed work may provide valuable insight into how stress/GCs regulate neuroinflammatory processes in psychiatric disorders. Thus, the present research may lead to a reconceptualization of stress/GCs as neuroinflammatory predisposing factors in the etiology of psychiatric disorders (i.e. major depression, PTSD).

Public Health Relevance

Stress is a key factor in the development of mental health disorders and has been found to increase brain inflammation. Likewise, inflammation in the brain is also considered a key factor in the development of mental health disorders such as major depression. The present research studies how stress predisposes people to mental health disorder by focusing on how stress increases brain inflammation.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Desmond, Nancy L
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University of Colorado at Boulder
Schools of Arts and Sciences
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Frank, Matthew G; Adhikary, Sweta; Sobesky, Julia L et al. (2016) The danger-associated molecular pattern HMGB1 mediates the neuroinflammatory effects of methamphetamine. Brain Behav Immun 51:99-108
Frank, Matthew G; Weber, Michael D; Fonken, Laura K et al. (2016) The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: A role for the NLRP3 inflammasome. Brain Behav Immun 55:215-224
Frank, Matthew G; Weber, Michael D; Watkins, Linda R et al. (2016) Stress-induced neuroinflammatory priming: A liability factor in the etiology of psychiatric disorders. Neurobiol Stress 4:62-70
Fonken, Laura K; Weber, Michael D; Daut, Rachel A et al. (2016) Stress-induced neuroinflammatory priming is time of day dependent. Psychoneuroendocrinology 66:82-90
Fonken, Laura K; Frank, Matthew G; Kitt, Meagan M et al. (2015) Microglia inflammatory responses are controlled by an intrinsic circadian clock. Brain Behav Immun 45:171-9
Frank, Matthew G; Watkins, Linda R; Maier, Steven F (2015) The permissive role of glucocorticoids in neuroinflammatory priming: mechanisms and insights. Curr Opin Endocrinol Diabetes Obes 22:300-5
Weber, Michael D; Frank, Matthew G; Tracey, Kevin J et al. (2015) Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: a priming stimulus of microglia and the NLRP3 inflammasome. J Neurosci 35:316-24
Frank, Matthew G; Weber, Michael D; Watkins, Linda R et al. (2015) Stress sounds the alarmin: The role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming. Brain Behav Immun 48:1-7
Frank, Matthew G; Hershman, Sarah A; Weber, Michael D et al. (2014) Chronic exposure to exogenous glucocorticoids primes microglia to pro-inflammatory stimuli and induces NLRP3 mRNA in the hippocampus. Psychoneuroendocrinology 40:191-200
Weber, Michael D; Frank, Matthew G; Sobesky, Julia L et al. (2013) Blocking toll-like receptor 2 and 4 signaling during a stressor prevents stress-induced priming of neuroinflammatory responses to a subsequent immune challenge. Brain Behav Immun 32:112-21

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