Probing Ethanol Dysregulation of Hypothalamic CRH neurons

Alcohol use disorder (AUD) affects approximately 14.1 million people in the United States. Despite the prevalence of this disorder, we lack a thorough understanding of its underlying neurobiological mechanisms. One of the major mechanisms believed to contribute to the development of AUD is the dysregulation of central stress systems (Brady & Sonne, 1999). Whereas acute alcohol elevates stress hormones, chronic alcohol intake results in diminished hypothalamic pituitary adrenal (HPA) axis function characterized by a reduced physiological response to stress (Stephens & Wand, 2012). Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVNCRH) are essential for initiating the HPA axis response. Moreover, PVNCRH neurons and HPA hormones show distinct adaptations to chronic stressors, excessive alcohol, and withdrawal from alcohol (Bryon Adinoff et al., 2003; Sivukhina et al., 2006). For example, AUD and abstinence both blunt hormonal HPA axis responses to stress, but basal cortisol production is hyperactive during acute withdrawal and hypoactive during protracted abstinence(B. Adinoff et al., 1998; Stephens & Wand, 2012). While much of the field has focused on the role of PVNCRH neurons in initiating the hormonal response to stress, recent studies have revealed these cells are also critical for stress-linked behaviors that are independent of stress hormone actions (Kim et al., 2019). These include active defensive behaviors (escape), social approach and perseverative, grooming behavior. These studies indicate that PVNCRH neurons orchestrate complex behaviors and highlight new opportunities to probe for how disruptions in local signaling and changes in afferent drive to PVNCRH neurons following alcohol consumption may affect behavior. In addition, preliminary studies from the Bains lab have found that PVNCRH neurons can track the valence of contexts over a scale of time that outlasts behavior. Changes in the activity of these neurons following alcohol exposure may contribute to aberrant patterns of behavior that drive chronic alcohol consumption. Here, we propose to use a multi-faceted approach integrating machine learning based behavioral analysis, cell type specific genetic manipulations, in vivo imaging and ex vivo slice physiology to begin to unravel the role of PVNCRH neurons in alcohol use disorders. We will test the central hypothesis that alcohol drinking leads to heightened activation of PVNCRH neurons driving persistent increases in stress behaviors and that PVNCRH neurons play a critical role in alcohol consumption.