Nutrition Regulates Sexual Function

PROJECT SUMMARY Dysfunctional sexual behavior, characterized by disturbances in sexual desire, preference, arousal, and orgasm, is a common, burdensome, and costly health condition. Overweight/obesity puts individuals at higher risks of dysfunctional sexual behavior; in contrast, underweight/extremely leanness also impairs sexual behavior. However, how nutritional regimens affect sexual behavior, and the underlying molecular and neural mechanisms are unclear. Using C57Bl6j wild type mice, I found that leptin rescued the detrimental effects of nutrition deprivation on sexual behavior in male mice. In addition, weight loss rescued sexual behavior in obese male mice. These findings highlighted the bidirectional regulation of nutrition on sexual behavior and interestingly, the nutrition-induced rescue in sexual behavior was only seen in males. Estrogen and leptin are both reported to signal nutritional status to modulate multiple physiological processes including metabolism and sexual behavior. I showed that estrogen receptor α (ERα) and the long-form leptin receptor (LepR) co-localized in several brain regions, including the medial preoptic area (MPA), the periaqueductal gray (PAG) and the arcuate nucleus of hypothalamus (ARH). To examine the role of ERα in LepR neurons in sexual behavior, I used Cre-loxP system to generate mice with deletions of ERα specifically in LepR neurons (ERαΔLepR mice). I found that male and female ERαΔLepR mice demonstrated remarkable dysfunctional sexual behaviors and profound reproductive deficits. Furthermore, restoration of MPA ERα via stereotaxic injection of adeno-associated virus (AAV)-DIO- GFP-ERα into the MPA significantly improved sexual behavior in ERαΔLepR mice in both sexes, without significantly ameliorating the fertility deficits. This interesting segregation between sexual behavior and fertility stimulated our interest in further investigating the role of ERα+/LepR+ neurons in the MPA in sexual behavior in both sexes. The objectives of this proposal are to 1) determine whether ERα in LepR neurons is required to mediate the nutrition-induced rescue of male sexual behavior, and 2) determine whether ERα+/LepR+ neurons in the MPA regulate sexual behavior in both sexes. These studies will identify neurobiological mechanism that ERα and leptin signaling interact to coordinate nutrition and sexual behavior. Results are expected to advance our understanding about the central regulation of sexual behavior. In addition, the proposed experiments take advantage of my research skills in mouse sexual behavior (acquired during my graduate studies) and the strength in nutrition, neural circuitry and mouse genetics (available in my postdoctoral mentor’s group) and will provide me with a unique training opportunity to acquire new neuroscience skills, including intersectional genetics and optogenetics. These will no doubt help me move toward my career goal of becoming an independent research scientist at an academic institution.