A circuit-driven evaluation of the use of physical activity interventions to improve binge-like ethanol drinking

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Project Summary Physical activity (PA) is a cornerstone of human health and well-being; however, its implementation as a viable treatment and preventative option for alcohol use disorders (AUDs) remains understudied. This is underscored at the social level by the ~26% of adult U.S. citizens that report binge drinking and the mere 3% of citizens who manage to meet daily U.S. PA guidelines. The NIAAA recognizes the importance of understanding and promoting the use of PA for treating AUDs. The effects of voluntary PA on preclinical measures of excessive alcohol intake are mixed. We seek to better evaluate this relationship by addressing the role of voluntary PA in reducing binge-like ethanol drinking in a unique genetic risk model of drinking to intoxication, the High Drinking in the Dark (HDID-1) mouse line (Aim 1). Understanding and defining key stages of PA development and reinforcement may be important for determining its potential as an AUD treatment option. Chronic PA and alcohol use create neural remodeling across interconnected brain regions belonging to the mesocorticolimbic system. This neural network comprises of interoceptive brain regions – those responsible for the processing and translating the internal body state [such as the insula cortex (IC)] - aversion-related brain regions [such as the basolateral amygdala (BLA)] and brain regions important for reinforcement [i.e., the ventral tegmental area (VTA)]. Here, we plan to retrogradely trace the nucleus accumbens (NAc) - the central point of convergence for this system – and determine which neural inputs are engaged at 2- and 4-weeks of wheel-running. Prior wheel- running work has characterized cFos using slice-based immunohistochemistry, but only in male rodents. Considering stark sex differences in PA in humans and rodents, this application addresses a major gap in the literature. cFos immunoreactivity (IR) will be used in combination with a retrograde tracer (rAAV2-retro-GFP) to reliably characterize and trace the neural inputs to the NAc. We hypothesize that distinct aversion-related NAc projections (e.g. extended amygdala) will be engaged during acute wheel-running and that regions important for interoception and reinforcement (such as the IC and NAc) will be engaged following chronic PA. The IC relays relevant interoceptive information to limbic regions, such as the NAc, and influences motivated behaviors (like PA and alcohol use). Chemogenetically silencing the IC  NAc circuit has been shown to increase interoceptive effects of alcohol in rats. To determine the importance of the IC in the reinforcement of PA, we will test whether chemogenetically silencing or activating the IC  NAc circuit [using designer receptors exclusively activated by designer drugs (DREADDs)] will modulate voluntary PA at acute and chronic timepoints. We hypothesize that chemogenetically silencing the IC  NAc projection will increase acute PA (associated with aversion) and reduce chronic PA (associated with reward). In contrast, we hypothesize that chemogenetically activating the IC  NAc projection will decrease acute PA and increase chronic PA. To compliment prior alcohol work, we will to determine the importance of this circuit in PA.