Project Summary/Abstract High risk, binge-level drinking accounts for most alcohol-related harm. Binge drinking often begins in adolescence when the brain is particularly vulnerable to alcohol insult, resulting in persistently atypical neurocognitive function. For example, we found that a history of adolescent binge drinking in adult people and adolescent intermittent ethanol (AIE) exposure in adult rats associates with less behavioral flexibility, which describes an individual’s ability to adjust their behavior to changing environmental circumstances. These behavioral effects are associated with altered resting-state functional connectivity among prefrontal and subcortical control circuits. Mechanistic links between adolescent alcohol exposure and reduced behavioral flexibility remain unclear, but several lines of evidence suggest a shift in the balance between excitation and inhibition [excitatory/inhibitory (E/I) balance], towards hyperexcitability in the prefrontal cortex (PFC) together with a weakening of top-down output from the PFC. Indeed, this proposal stems from our preliminary data in humans and rats that AIE and/or current binge drinking alters metrics of E/I balance measured via magnetic resonance spectroscopy (MRS) and EEG in humans and neurochemical and electrophysiological measures in rats. Thus, we will test the hypothesis that adolescent binge alcohol promotes a shift in the balance between excitatory and inhibitory (E/I) signaling within control circuits that has the net effect of reducing PFC output, which in turn mediates more habitual action selection and greater vulnerability to alcohol insult in adulthood. We further hypothesize that these AIE-induced E/I balance shifts are associated with altered functional connectivity (humans) and neurochemistry (rats) of control hubs, including the dorsolateral PFC (or analogous rodent prelimbic cortex) and anterior insula. To test this hypothesis, we will study rat and human subjects with or without a history of adolescent and/or current binge drinking (or binge exposure in rats) and assess behavioral flexibility in tasks that require adaptation to changes in response contingency. In human subjects, we will use MRS and EEG techniques to assess indices of E/I balance, and MRI to measure functional connectivity. In addition, we will measure whether changes in these measures mediate the effects of transcranial alternating current stimulation (tACS) of PFC on behavioral flexibility. In rats, we will use neurochemical and electrophysiological approaches to assess indices of E/I balance, and manipulate them via chemogenetic tools. This work may ultimately identify therapeutic targets differentiated by adolescent alcohol history and thus improve AUD treatment efficacy. Additionally, we propose a set of complementary studies that will extend this work and build on collaborations across the Alcohol Research Center. This explicitly translational approach allows the human and rodent findings to ...