Project Summary Alcohol (ethanol) dependence and relapse in abstinent alcoholics are major health problems throughout the world and neurochemical pathways that modulate these disorders are currently under investigation. However, the neurobiology underlying binge drinking, a dangerous pattern of behavior that proceeds and contributes to dependence, has received far less attention. Thus, it is of paramount importance to identify the neurocircuitry in the brain that modulates binge drinking as such knowledge will provide insight into the initial stages of alcohol use disorders (AUDs) and will shed new light on avenues for treating early-stage AUDs prior to the development of dependence. During the last funding period of this grant, our laboratory has provided converging evidence that corticotropin releasing factor (CRF) receptor signaling, via neurocircuitry providing cross-talk between brain regions that integrate emotions/stress responses with those that motivate reward-seeking behaviors, modulates binge-like ethanol drinking in mice. Furthermore, preliminary data described in this grant provide converging evidence that of a novel circuit linking stress and reward systems modulates binge-like ethanol intake in a sex- dependent manner, a highly significant discovery given our very limited understanding of the mechanisms that drive sex differences in ethanol intake and AUDs. A critical player in integrating reward-directed behaviors is the lateral hypothalamus (LH), and we provide preliminary evidence that blocking CRF type-1 receptors (CRF1R) in the LH, as well as chemogenetic silencing of a CRF+ pathway from the central amygdala (CeA) to the LH, reduce binge-like ethanol intake in male, but not female mice. The guiding hypothesis for the current grant is that CRF receptor signaling in the LH modulates binge-like ethanol drinking, which involves the CRF+ CeA → LH pathway, and that a history of binge-like ethanol drinking will promote plasticity within this CRF circuit linking stress and reward systems, all in a sex-dependent manner. We will use powerful and innovative chemogenetic, transgenic, electrophysiological, and histological approaches to test the hypothesis that LH-infusion of CRF1R antagonist and CRF type-2 receptor (CRF2R) agonist, and knockdown of CRF1R in the LH, will protect against binge-like ethanol drinking (Aim 1), chemogenetic inactivation or activation of CRF+ CeA neurons that project to the LH will blunt or increase binge-like ethanol intake, respectively (Aim 2), and a history of repeated binge-like drinking episodes will be associated with changes in CRF and CRF receptor levels and signaling in the CeA → LH neurocircuitry. Because our preliminary data provided converging evidence that CRF signaling in this pathway modulates binge-like ethanol drinking primarily in male mice, each aim is sufficiently powered to characterize sex differences. The aims of this grant will address a critical gap in the literature on the role of CRF ...