Successful reproductive function depends on the proper activation of the gonadotropic axis and the development of adequate sexual behavior. While the hypothalamic mechanisms regulating gonadotropin release have been extensively studied, those regulating sexual behavior and specifically those connecting behavior and fertility have remained elusive. The amygdala has been documented to integrate sexual cues, e.g. pheromones, to elicit sexual behavior and lesion studies have indicated its relevance for proper GnRH release in both sexes. Interestingly, the hypothalamic neuropeptide, kisspeptin (Kiss1), critical for reproductive function, has also been identified in the amygdala. Our preliminary data documents that the activation of Kiss1 neurons in the medial amygdala (MeAKiss1 neurons) stimulates LH release. Therefore, our overarching aim is to characterize in detail the role of MeAKiss1 neurons in males and females in the control of gonadotropin release and sexual behavior through a combination of functional, pharmacological and genetic studies that will include: 1) optogenetic and chemogenetic manipulation of cre- expressing neurons in Kiss1-cre mice; 2) ablation of MeAKiss1 neurons using cre-dependent, apoptosis inducing, Casp3 viruses; and 3) track tracing of projections from MeAKiss1 neurons to hypothalamic neurons using fiber markers (mCherry), mono-synaptic track tracers and calcium photometry circuit mapping. Moreover, we will characterize the interaction between these two functions (i.e. gonadotropin release and sexual behavior) by assessing the activation of Kiss1 and GnRH neurons during mating, and the activation of hypothalamic nuclei involved in sexual behavior during the LH surge in females. Overall, the successful completion of this project will significantly extend our understanding of the role of the medial amygdala in the integration of sexual behavior and gonadotropin release, which is fundamental to synchronize mating and ovulation for successful reproduction. The expected findings will offer new platforms for the treatment of reproductive disorders of central origin such as hypogonadism or low sex drive.
The central control of reproductive function has focused mainly on the hypothalamic neurons that control GnRH release, however, the amygdala, located outside of the hypothalamus has been documented to participate in the control of reproduction through yet unknown mechanisms. Our preliminary data suggests that Kiss1 neurons in this brain region play a critical role in reproduction. We will test this hypothesis through a series of genetic, optogenetic and pharmacological studies aimed to target these neurons in both sexes to determine their role in gonadotropin release and sexual behavior.
