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.