Abstract/Project Summary Disorders of androgens imbalance are highly prevalent in both sexes. Hyperandrogenic females experience reproductive dysfunction, whereas low androgens disrupt sexual behavior, decrease libido and fertility, and induce fatigue, depression, and bone loss in both sexes. Studies using mouse genetics (e.g., androgen receptor knockout) replicate male reproductive dysfunctions caused by low androgens or AR insensitivity. In females, AR insensitivity results in subfertility, with disrupted uterine morphology, fewer corpora lutea, abnormal estrous cycles and accelerated reproductive senescence. AR is highly expressed in multiple brain sites, but the role of specific neuronal circuitry or individual subpopulations has not been demonstrated, and the causes and mechanisms underlying disorders of androgen imbalance mediated by brain AR remain unknown. This is particularly important in androgens abuse and for gender dysphoric/gender incongruent individuals which seek gender-affirming hormone treatment. The consequences and potential effects of supraphysiologic androgens on brain function are largely unknown. Our main goal in this application is to determine the role of direct androgen actions in highly interconnected brain sites that express low or virtually no aromatase, i.e., neuronal circuitry not susceptible to estrogen actions following site-specific conversion of testosterone to estradiol. The circuit is comprised of the posterior nucleus of the amygdala (PA) and the ventral premammillary nucleus (PMv). The PA relays conspecific olfactory signals and is highly relevant for human’s physical and sexual health. Functional neuroimaging studies, neurological insults or brain lesions have shown that the PA has a critical role in sexual drive, hyper- or hyposexuality, and sexual disorders (e.g., paraphilias) in a sex specific mode. The PA densely projects to the PMv which has a fundamental role in the modulation of the neuroendocrine reproductive axis. Our goal is to determine the role of AR in specific brain nuclei of male and female mice focused on the integration of environmental signals, sexual behavior, and neuroendocrine control. We hypothesize that AR in PA neurons is necessary for sex recognition, and sexual arousal, and that PA inputs to PMv AR neurons connect sexual arousal to neuroendocrine (gonadotropins) and behavioral responses. We will employ Cre-loxP and FlpO-Frt approaches to conditionally delete Ar in these neuronal populations, viral vectors, TeTox and DREADDs technology to remotely silence or activate AR expressing neurons, different steroids milieu, and molecular mapping of chemically defined AR neurons in two independent aims. Our findings will open new opportunities for a better understanding of the mechanisms associated with the pathophysiology of altered levels of androgens mediated by neuronal AR. Unraveling the role of AR in defined neuronal circuitry is an essential step toward the prevention of adverse health consequences caused by hyper- or hypoandrogenism in a sex-specific manner.

Project Narrative High levels of androgens in women is associated with disrupted neuroendocrine function and infertility, whereas low androgens decrease sexual behavior and fertility, and induce fatigue, depression, and bone loss in both sexes. High density of androgen receptors is observed in the brain, but their function in specific neuronal populations is unknown. We will use genetic mouse models and molecular tools to determine the role of androgens receptor in chemically defined subsets of neurons and the underlying mechanisms associated with reproductive deficits caused by altered androgens signaling in the brain.