Stress-induced Dysregulation in Microglial HMGB1 Signaling

Substance use disorders (SUD), defined as the dependence to substances such as but not limited to alcohol, nicotine and illicit drugs, affect as high as 9% of Americans [1]. Mounting evidence suggests that the dysregulation of innate immune system plays a role in the pathophysiology of SUD [2-4]. Stress, a major risk factor for the development of addiction, has been shown to promote drug seeking and dependence relapse in several pre-clinical, population-based and epidemiology studies [5]. Stress-induced risk for SUD may be partially mediated by stress-induced dysregulation in innate immune pathways. High mobility group box protein 1 (HMGB1), an endogenous ligand for innate immune receptors, has been implicated in SUD and is significantly elevated in the brains of lifelong addicts [4].

HMGB1 upregulation and extracellular signaling is mediated by stress [6, 7]. Chronic stress has been shown to induce persistent dysregulation of HMGB1 expression and release in resident microglia [8], which may contribute to the pathogenesis of addiction. Here we propose to identify the long-lasting effects of stress on HMGB1-mediated signaling by identifying persistent stress-induced HMGB1 post-translational modifications in microglia. In addition, we aim to identify differences in the proteomic signature of resident microglia, the innate immune cells of the brain, in the presence and absence of microglial HMGB1 signaling to identify alterations in protein expression that may increase risk for the addiction.

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