Estrogen‐mediated signaling mechanisms regulate voluntary running behavior in rats

Abstract

Despite the myriad social and health benefits of exercise, humans display heterogeneous levels of participation. Significant progress has been made in identifying molecular events, systems, and mechanisms that support exercise’s beneficial effects, but it is not clear yet what regulates exercise behavior itself or serves to maintain prolonged chronic exercise behavior.The human heterogeneity in voluntary exercise can be recapitulated in a rodent model of wheel running, a behavior with high rewarding properties. While rats given continuous access to running wheels all began with low running activity, a 3‐week training program dramatically increased running activity and uncovered a wide range of individual differences in running behavior. In addition, we have identified intriguing sex differences in this model. Compared to age‐matched males, female rats exhibited significantly higher levels of average daily running. When assessing individual female rats’ running behavior, we also observed a repetitive peak‐valley pattern of running activity, with peaks coinciding with the proestrus stage (highest estrogen level) in the rat estrous cycle. Bilateral ovariectomy (OVX) not only lowered their overall running activity, but also completely eliminated cyclical variations. Furthermore, low dose estrogen replacement via osmotic mini‐pumps in an OVX background restored running activity to pre‐OVX levels, and acute estradiol injections were able to replicate running peaks. Collectively, those results suggest estrogen exerts strong regulation of female running activity. By taking individual and sex differences into consideration in the experimental design, we anticipate our subsequent biochemical assays will identify signaling molecules and pathways involved in running activity that is driven by a surge of estradiol.