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

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. Here, we will better evaluate this relationship by testing 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. Both 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 following binge-like drinking and PA. Prior wheel-running (WR) work has characterized cFos using slice-based immunohistochemistry, but only in male rodents. Considering stark sex differences in humans and rodent PA levels, 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 reinforcement and interoceptive-related NAc projections (e.g. IC, and extended amygdala) will be disrupted/disengaged following binge-drinking and that WR will act to potentiate neural circuit communication and modularity. The IC relays relevant interoceptive information to limbic regions, such as the NAc, and influences motivated behaviors (like PA and alcohol use). Optogenetically stimulating the IC Æ NAc projection reduces aversion resistant drinking in male rats. To evaluate the role of the IC Æ NAc projection in binge-like drinking and PA, this R00 will test whether chemogenetically silencing or activating the IC Æ NAc circuit [using designer receptors exclusively activated by designer drugs (DREADDs)] will modulate these important behaviors. We hypothesize that chemogenetically silencing the IC Æ NAc projection will decrease binge-like ethanol drinking in sedentary mice and prevent a recently characterized decrease in binge-like intake following PA. In contrast, we hypothesize that chemogenetically activating the IC Æ NAc projection will decrease ethanol intake (in sedentary mice) and further attenuate ethanol intake in wheel-running mice. Taken together, the goals of this proposal are 1) to determine the efficacy of voluntary physical activity (PA) to reduce binge-like ethanol drinking in a genetic risk model for harmful drinking and 2) to identify mesocorticolimbic circuits important for binge-like drinking and PA and 3) test a neural mechanism central to PA as an adjunctive treatment option for AUDs.