Novel circuit mechanism of alcohol dependence vulnerability following early-life adversity

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SUMMARY Childhood adversity increases the vulnerability to develop an alcohol use disorder later in life, and variations in genes involved in corticotropin-releasing factor (CRF) signaling modulate this risk. However, the CRF-dependent mechanism(s) mediating the facilitation of alcohol abuse by early life stress is unknown. We recently discovered that CRF neurons located in the parasubthalamic nucleus (PSTN) may play a critical role in this mechanism because (1) they control voluntary ethanol drinking, and (2) they are enduringly altered by early life stress. Notably, these neurons send excitatory projections to the central nucleus of the amygdala (CeA), where CRF signaling is known to promote ethanol intake escalation in dependent animals. Accordingly, the present project will test the hypothesis that dysregulated CRF transmission from the PSTN to the CeA may facilitate the transition to alcohol dependence following early life stress. This project will leverage a novel mouse model of the interaction between early life stress and excessive ethanol intake by limiting bedding and nesting (LBN) materials during early postnatal development, a naturalistic model of simulated poverty, and exposing adult mice to voluntary ethanol drinking sessions alternated with chronic intermittent ethanol vapor inhalation (CIE). We established that LBN rearing accelerates ethanol intake escalation in male mice exposed to CIE and elicits negative affect during withdrawal. In Aim 1, we will determine the influence of sex on these phenotypes and test the hypothesis that, in vulnerable mice, LBN and CIE exert synergistic effects on the activity of PSTN→CeA CRF neurons. In Aim 2, we will attempt to reverse the enduring consequences of LBN on CIE-induced motivational and affective phenotypes by inhibiting PSTN→CeA CRF neurons using chemogenetics. Our approach capitalizes on the complementary expertise of two experienced collaborating researchers and leverages state- of-the-art methodology for the manipulation of neuronal activity in vivo. Our discoveries will pave the way for the identification of molecular mechanisms underlying the life-long pathological consequences of early life stress, which may ultimately enable the development of personalized therapeutic strategies for individuals who experienced childhood adversity and suffer from an alcohol use disorder.