Real-time activity of dynorphin-expressing neurons in mouse central amygdala during alcohol drinking

Abstract

AbstractAlcohol use disorder (AUD) is a prevalent chronic relapsing disease, affecting 30 million people (10.5%) in the United States alone that poses significant economic burden and health risks. Evidence from human and animal studies has identified crucial brain regions that are important for driving binge alcohol (ethanol) drinking and excessive drinking produced by the development of AUD. In preclinical models, the central amygdala (CeA) has emerged as a key mediator of binge alcohol consumption. A dynorphin-expressing subpopulation within the CeA (CeADyn) has been implicated in excessive alcohol drinking across both acute and chronic alcohol exposure models. Yet, how cellular activity of CeADynneurons is impacted by active alcohol drinking is not well-understood. Thus, it is pivotal to better understand specific brain mechanisms underlying the behavioral and physiological responses to alcohol that promote alcohol misuse. The goal of the current study was to probe the engagement of CeADynneurons in male and female mice during voluntary alcohol consumption using fiber photometry and to compare alcohol phenotypes with that of water and sucrose. Activity of the Cre-dependent calcium sensor, GCaMP7f, in the CeA of prodynorphin-Cre (Pdyn-Cre) mice was recorded and time-locked to bouts of licking during 2-hr, 20% alcohol drinking. To rigorously analyze this photometry data, multilevel modeling protocols were applied to better understand sex and temporal effects in these complex time series data. Analysis revealed a large increase in CeADynneuron calcium transients after bouts of licking for alcohol, and only modest increases during licking for water or 0.5% sucrose, indicating these neurons are uniquely engaged during alcohol consumption. Further testing revealed that differences in drinking behavior unique to alcohol (i.e. longer bout durations) do not fully explain signal differences between alcohol and other solutions nor is the alcohol response diminished across the 2-hr drinking session. These findings identified a unique functional signature for alcohol in a cell population that is known to control binge alcohol drinking.