Targeting the neural circuits controlling negative reinforcement to prevent alcohol seeking in males and females

ABSTRACT Alcohol use disorder (AUD) is characterized by high levels of alcohol intake followed by aversive negative affective states when individuals cease consumption. In certain individuals suffering from AUD, alcohol taking and seeking is, in many cases, thought to be motivated by negative reinforcement, where individuals continue consuming alcohol to avoid these negative internal states that are triggered by abstinence. While a large body of work has outlined the precise brain regions, cellular populations, and neural circuits that underlie these affective states and their effects on behavior in rodents and humans, to our knowledge, studies have not explicitly focused on the circuits controlling negative reinforcement itself – the action of avoiding aversive stimuli. Recent work from our group has shown that there are robust sex differences in negative reinforcement behavior at baseline. Moving forward, it will be critical to understand if there are sex differences in the circuits that control negative reinforcement and if alcohol-induced alterations in these circuits interact with biological sex to alter AUD. We focus on the role of medium spiny neurons (MSNs) in the nucleus accumbens (NAc) as our preliminary data show that manipulations of D1 receptor containing MSNs in the NAc causally mediate negative reinforcement. Additionally, previous work has shown that this cellular population can alter drinking and alcohol seeking and undergoes robust plasticity following alcohol consumption. Thus, D1 MSNs causally mediate negative reinforcement, are altered by alcohol consumption, and are capable of triggering alcohol seeking. We hypothesize that binge alcohol exposure enhances negative reinforcement by altering medium spiny neurons in the NAc on the circuit and molecular level, and that basal sex differences interact with alcohol- induced alterations in these systems. Using operant tasks where animals emit operant responses to avoid negative outcomes, we will 1. Use in vivo microendoscopy to outline the cell-type specific neural activity signatures that underlie negative reinforcement in males and females 2. Determine how these signatures are changed by alcohol exposure and abstinence in males and females and 3. Determine molecular effectors within these populations in both sexes using cell-type specific transcriptional profiling. Together, the Vanderbilt Alcohol Research and Education Center (VAREC) allows for an integration of research aimed at collaboratively answering how AUD-associated phenotypes emerge using precision neuroscience approaches.