Extended amygdala corticotropin-releasing factor circuits mediating sex-specific impacts of early life stress on alcohol sensitivity

Exposure to adverse childhood experiences (ACEs), such as abuse or neglect, is a powerful risk factor for the development of alcohol use disorder (AUD) in adulthood. Girls are more likely to experience multiple forms of childhood adversity, and as adults, the number of women engaging in alcohol binge drinking has rapidly increased in recent years, significantly narrowing the historical gap with men in rates of alcohol drinking and AUD diagnoses. Despite the abundant epidemiological evidence pointing to complex interactions between childhood adversity, sex, and alcohol use in adulthood, the neural mechanisms underlying sex differences in the effects of early life stress (ELS) on AUD susceptibility remain mostly unknown. Sensitivity to the motor effects of alcohol, which is known to be modulated by other forms of stress exposure, is a potentially highly relevant phenotype influencing AUD susceptibility. Mechanistically, the bed nucleus of the stria terminalis (BNST), a sexually dimorphic and neuropeptide-rich region in the extended amygdala, is a promising mediator of ELS-enhanced alcohol sensitivity. Specifically, activation of corticotropin- releasing factor (CRF) neurons in the BNST is associated with increased stress and other AUD-associated behaviors, including anxiety and alcohol binge drinking, suggesting they may also play a role in alcohol sensitivity. However, it remains unknown exactly how release of the CRF neuropeptide from BNST neurons relates to BNST neuronal activity and synaptic connectivity. Given the complexity of these distinct mechanisms regulating neuronal activation, neuronal connectivity patterns, and neuromodulator release, I will dissect the relative involvement of BNST-CRF neuronal activity, BNST-CRF structural connectivity, and BNST-CRF neuropeptide signaling in mediating ELS-enhanced alcohol sensitivity. With the goal of defining the mechanisms by which ELS-enhanced alcohol sensitivity contributes to AUD susceptibility, my aims will use a combination of behavioral, chemogenetic, viral tracing, and fiber photometry approaches. In the proposed studies, I will use an established, ethologically relevant model of ELS in mice to test the central hypothesis that ELS-enhanced alcohol sensitivity is mediated through increased BNST-CRF neuronal activity, circuit connectivity, and/or neuropeptide release in a sex-specific manner.