PURPOSE: Genes had selectively evolved to enhance the motivation for physical movement in human during the Paleolithic era. To prepare for a potential forthcoming food deficiency, high physical activity was essential for survival in the environment where hunting wild animals and gathering plants. In modern society, however, developing technology and engineering has made human life easier to accomplish tasks with not much movement and effort, resulting in a profound deficiency in physical activity (i.e., physical inactivity).METHODS: In this review, the authors summarized previous studies searched by the PubMed, Google Scholar, and Science Direct databases.RESULTS: Reduced physical activity is significantly associated with the high prevalence of various diseases including metabolic syndrome, obesity, sarcopenia, and cancer. Unfortunately, in women, menopause negatively impacts their body and physiology mainly due to the loss of estrogens, which also contributes to behavioral changes such as a significant reduction of physical activity levels during menopausal transition. In this review, the author focused to describe the underlying brain mechanism by which menopause results in reduced levels of physical activity through estrogens, estrogen receptors, and dopamine signaling in the nucleus accumbens, the main controller for exercise motivation.CONCLUSIONS: Estrogen receptor, specifically ERα, and dopamine receptors are the main controllers for voluntary physical activity. Furthermore, high running motivation is associated with enhanced dopamine activity. More studies are needed to verify whether enhanced dopamine activity can protect against menopause-associated reduction in physical activity.