Behavioral and neural network characterizations of the reinforcement of voluntary physical activity in heterogenous mice
Authors: Grigsby Kolter , Usmani Zaynah , Ozburn Angela 
Published: May 2023

Maintaining healthy and consistent levels of physical activity (PA) is a cost-effective means of reducing the onset of >40-chronic diseases; however, these benefits go largely unrealized by the ~97% of adult Americans who fail to meet activity guidelines. Our prior work suggests that acute activity engages aversion-related brain regions, which may act as a barrier to PA adherence. Chronic PA is reinforcing and creates neural remodeling a across a network of brain regions belonging to the mesocorticolimbic system - comprising of stress and aversion-related brain regions [such as the basolateral amygdala (BLA)] and important reinforcement brain regions [i.e., the ventral tegmental area (VTA)]. A primary focus of this study is to determine how neural inputs to the nucleus accumbens (NAc) -the central point of convergence for this system– are engaged during acute and chronic PA. Objectives: Here we tested whether sex differences in the reinforcing value of wheel-running exist in a genetically diverse population of mice, the Heterogeneous Stock/Northport (HS/Npt). Moreover, we sought to identify the neural circuits engaged during acute and chronic voluntary wheel-running in these mice. Hypothesis: Given established findings that female rodents run more than males, we hypothesized that female HS/Npt mice would find wheel-running less aversive than males. We further hypothesized that 1-week of voluntary wheel-running would increase cFos expression (compared to mice with 1-week of wheel-lock) in brain regions associated with stress and aversion, whereas 4-weeks of wheel-running would increase neural engagement in brain regions associated with reinforcement, including the NAc, insular cortex, VTA and the medial preoptic area (a sexually dimorphic brain region critical for the estrogenic control of wheel-running in female rodents). Methods: As a proxy for their hedonic state, mice were provided a two-bottle choice saccharin preference test following acute or chronic PA. To better define the mesocorticolimbic system, we used an established retrograde tracer (rAAV-retro) to label the neural inputs to the NAc, which helped to identify important brain region involvement at two distinct stages of PA reinforcement. Results: There were no differences in running distance between female and male mice at 1- or 4-weeks and no differences in saccharin preference at 1-week. In contrast, male HS/Npt showed lower saccharin preference compared to females at 4-weeks of voluntary wheel running, suggesting a potential sex difference in the reinforcement value of chronic PA. Whole brain cFOS imaging is currently underway. Conclusions: It appears that chronic voluntary activity may confer lower hedonic states in male mice. Moreover, an improved understanding of how neural circuits across the mesocorticolimbic system are engaged during crtical stages of PA (in males and females) may prove important for determining neural and behavioral barriers to exercise adherence in humans. American College of Sports Medicine This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.