Sex-dependent shifts in behavioral profiles and cortical signaling following adolescent binge drinking

PROJECT SUMMARY / ABSTRACT Along with the structural development of the prefrontal cortex (PFC) during adolescence, innervation of the PFC by several local neurotransmitter systems also develops, including the gamma-aminobutyric acid (GABA) system. Somatostatin (SST)-expressing GABA cells undergo significant developmental changes throughout adolescence, including in structure and function (Du et al., 2018) – importantly, SST neurons are a cell population known to be vulnerable to alcohol in adulthood (Dao et al., 2020, Dao et al. 2021). However, little is known about how developmental alcohol exposure may influence this key GABAergic and peptidergic population in the PFC – which could, in turn, lead to catastrophic, irreversible changes in PFC signaling and functional connectivity. Additionally, sex differences in the development of the PFC SST system may render it uniquely vulnerable to adolescent alcohol consumption. The objectives of this application are to characterize changes in behavior, overall cortical adaptations in SST neuron function and peptide signaling, and functional connectivity following developmentally relevant periods of adolescent binge alcohol consumption. Using the drinking-in-the-dark (DID) model of voluntary binge alcohol consumption, we will assess how adolescent-specific exposure to alcohol alters sex-specific long-term behavioral phenotypes, somatostatin peptidergic circuits, and overall brain systems, thereby linking a localized cell- type specific change with behavior and brain dynamics on a network scale. Using complementary approaches, we will systematically and comprehensively test the hypothesis that adolescent alcohol changes behavioral profiles, SST neuron and peptide function, and functional connectivity of the PFC. We will use a multidisciplinary approach spanning slice electrophysiology, in vivo signaling, quantification of cycling sex hormones, and resting-state functional connectivity to systematically characterize this system. Additionally, we will identify risk factors for later alcohol-induced behavioral changes using non-invasive imaging throughout drinking. These high-impact experiments have significant public health implications. By understanding the role of an understudied population of cortical peptidergic neurons, new treatment targets may be informed. Additionally, the rapid timescale of animal developmental models allows for a faster and more in-depth characterization of the effects of adolescent binge drinking compared to human studies, which span decades. This work is likely to significantly inform prevention and intervention efforts related to adolescent binge drinking.