Neurophysiological Genetics of Binge Drinking

University Of New Mexico Health Scis Ctr, Albuquerque NM

Investigators

Abstract

Decreased functional corticostriatal connectivity is a hallmark of Alcohol Use Disorder, yet we know very little about the trajectory of its development following repeated excessive alcohol drinking experiences. Our long- term goal is to identify molecularly defined functional circuits that can be targeted to reverse or prevent this alcohol-induced corticostriatal aberration to reduce excessive drinking. Our objective is to leverage monosynaptic circuit labeling and optogenetic tagging/manipulation, together with in vivo and ex vivo electrophysiological approaches and single-nucleus RNA sequencing, to uncover the functional and molecular causes and consequences of repeated excessive alcohol consumption on a key glutamatergic circuit originating in the Prelimbic cortex (PRL) and terminating in the Nucleus accumbens core (NACC), dubbed here PRL→NACC. Our central hypothesis is that repeated excessive alcohol consumption decreases the function of PRL→NACC projections and their local NACC targets via the recruitment of alcohol-sensitive gene co- expression networks, leading to deficits in information flow within and between these brain regions that increase the salience of alcohol and alcohol-associated cues and drive increases in alcohol drinking intensity. Our rationale for the use of multiple electrophysiological readouts, functional manipulations, and molecular endpoints to investigate the causes and consequences increases in drinking intensity is their combination allows a comprehensive picture of how alcohol influences neural function to be traced from the gene level, through the neural systems level, and ultimately back to behavior. In Aim 1, we will use high-density silicon electrode recordings in freely behaving mice in the home cage as well as complementary ex vivo electrophysiological assessments at key time points to test the hypothesis that alterations in baseline, cue- induced and acute alcohol exposure-induced PRL→NACC function drives increases in alcohol drinking intensity. In Aim 2, we will use optogenetic manipulations to determine the causal role of monosynaptic PRL→NACC projection neurons to the development and maintenance of HID/AFL to test the hypothesis that inhibition/facilitation of this circuit will cause decrease and increases in drinking intensity, respectively. In Aim 3, we will characterize the transcriptional signature of PRL→NACC neurons, determine the genes they recruit as a function of HID/AFL, and identify and characterize the PRL GABAA interneuron subpopulation most impacted by HID/AFL. This work will test the hypothesis that HID/AFL-induced functional plasticity of PRL→NACC projection neurons involves recruitment of genes into these neuronal populations. The research proposed is innovative because it will systematically characterize, for the first time, the functional and molecular mechanisms of PRL→NACC projection neurons to HID/AFL. The proposed research is significant because it will elucidate novel neurophysiological and neurogenetic mechanisms that contribute to HID/AFL that can be targeted to prevent and treat AUDs.