PROJECT SUMMARY Alcohol-related blackout has traditionally been considered a warning sign of the development of an Alcohol Use Disorder (AUD). However, not all individuals who binge drink experience blackouts, and blackouts are not uncommon among individuals considered social drinkers. While pharmacological and behavioral factors contribute to blackout risk, they are not fully predictive. Recent work in the field has begun to consider individual variability in blackout susceptibility, and the literature indicates that some individuals have a genetic predisposition to experiencing blackouts. Preliminary work in our lab has indicated that having a history of certain non-REM parasomnias classified as Disorders of Arousal (DoA) may increase one’s risk of experiencing blackouts. Disorders of arousal, a diagnostic category that includes sleepwalking, are defined by inappropriate motor arousal during slow-wave sleep. These arousal events are preceded by decreases in functional connectivity between the motor cortex and prefrontal and subcortical targets, which allow for wake- like activity in the motor cortex to occur simultaneously with slow-wave sleep elsewhere. Importantly, atypical connectivity patterns persist into waking life in these individuals. As preliminary EEG work in our lab has demonstrated abnormal patterns of resting-state EEG activity in individuals with a history of blackout, we hypothesize that susceptibility to blackout and susceptibility to disordered arousal during sleep may be mediated by similar baseline patterns of neural connectivity. Given the role of GABAergic interneurons in modulating cortical functional connectivity, we hypothesize that individual variability in the efficiency of GABAergic inhibition of the motor cortex directly contributes to blackout susceptibility. Preliminary work from our lab has also indicated that self-reported feelings of stimulation in response to alcohol and self-reported resilience to the motor effects of drinking (e.g., stumbling) are correlated with number of blackouts experienced. We propose a model in which some individuals express a neurobiological phenotype defined by reduced efficiency of GABAergic inhibition of the motor cortex, which results in unstable functional connectivity at sober baseline and a relative resilience of the motor cortex to GABA-A mediated suppression of activity by alcohol. When paired with steep elevations in blood alcohol concentration, we hypothesize that this phenotype contributes to functional dissociation of the motor cortex and allows for motor activity past the point at which long-term memory storage is impaired and behavior is disinhibited (i.e., the blackout state). The purpose of this project is to investigate the role of GABAergic modulation of the motor cortex in blackout susceptibility using non-invasive neurophysiological metrics to examine circuitry in individuals with a history of blackout and binge- drinking controls. Identifying the neurobiological...