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 a (ERa) 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 ERa in LepR neurons in sexual behavior, I used Cre-loxP system
to generate mice with deletions of ERa specifically in LepR neurons (ERa¿LepR mice). I found that male and
female ERa¿LepR mice demonstrated remarkable dysfunctional sexual behaviors and profound reproductive
deficits. Furthermore, restoration of MPA ERa via stereotaxic injection of adeno-associated virus (AAV)-DIO-
GFP-ERa into the MPA significantly improved sexual behavior in ERa¿LepR 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 ERa+/LepR+ neurons in the MPA in sexual behavior in
both sexes. The objectives of this proposal are to 1) determine whether ERa in LepR neurons is required to
mediate the nutrition-induced rescue of male sexual behavior, and 2) determine whether ERa+/LepR+ neurons
in the MPA regulate sexual behavior in both sexes. These studies will identify neurobiological mechanism that
ERa 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.