Neurobiological Mechanisms of Mating-Induced Stress-Buffering and Anxiolysis

Mating is a socially rewarding experience that yields protective benefits to health, confers resistance to stress, and lowers anxiety-related behaviors in a number of mammalian species, including humans and rodents. These beneficial effects may stem from hormonal and neurobiological changes that not only promote and maintain sexual function but also alleviate stress and anxiety. However, the brain sites and biological mechanisms regulating such effects are poorly understood. Sexual activity increases serum testosterone levels and stimulates gamma-aminobutyric acid (GABA) containing cells, both of which can reduce anxiety and attenuate stress responses of the paraventricular nucleus (PVN) and hypothalamic-pituitary-adrenal (HPA) axis. One brain region that potentially mediates these effects is the medial preoptic area (MPOA) of the hypothalamus, a critical site for male sexual behavior, anti-sympathetic function, and testosterone- and GABA-mediated suppression of the PVN. This dissertation investigates whether steroid sensitive cells in the MPOA and PVN afferents are involved in mating-induced anxiolysis and stress reduction. Here, I report that repeated mating lowers anxiety-like behaviors and corticotrophin-releasing hormone (CRH) expression in the PVN. Sexually experienced males also exhibit lower levels of stress-reactive serum corticosterone and less stress-induced c-Fos immunoreactivity (ir) in hypophysiotrophic neurons that contain CRH, compared to sexually naïve males subjected to stress. Together, this suggests that sexual experience buffers behavioral, physiological, and neuronal responses to stress. Additionally, unilateral intra-MPOA administration of an androgen receptor (AR) antagonist prior to each mating session blocked the suppressive effects of mating on stress-induced c-Fos reactivity in ipsilateral PVN, demonstrating a critical role for ARs in mating-induced stress attenuation. Further, sexually experienced males displayed higher AR expression in the MPOA, as evident from immunohistochemical analysis and western immunoblots. Moreover, dual immunolabeling revealed that AR-ir preoptic cells co-localize with GABA, indicating a potential inhibitory role for androgen-mediated actions in the MPOA. Lastly, to better understand how activity in the MPOA affects functioning in the PVN, a circuit level of analysis was employed. Here, the retrograde neuronal tracer, Fluorgold (FG) was microinfused into the PVN and afferents to the PVN from the MPOA were examined. Retrograde tracing confirmed that PVN afferents emanate from the MPOA. Further, retrograde tracing combined with immunolabeling revealed that a dense population of AR-ir cells in the MPOA express FG, and thus project to the PVN. In addition, a subpopulation of mating-induced c-Fos-ir cells were also co-labeled with FG, indicating that mating stimulates PVN afferents from the MPOA. Collectively, these data demonstrate that repeated mating suppresses stress-responses of the PVN, in part by AR-mediated actions in the MPOA. Further, repeated mating results in higher AR density in the MPOA and the majority of AR-containing preoptic cells project to the PVN. In addition, since AR-containing cells in the MPOA are GABAergic, this may be one means by which repeated mating enhances the inhibitory effects of androgens in the MPOA, perhaps in androgen-sensitive projections to the PVN. These data demonstrate that repeated mating imparts neurobiological and physiological alterations in stress responses systems and an androgen-mediated mechanism in the MPOA regulates mating-induced stress buffering in the PVN.