PD15-10 GABAergic and Kisspeptin Neurons Mediate Effects of Stress-induced Glucocorticoids on Reproduction in an Opposite Manner in Female Mice

Abstract S.A. Pereira: None. A.N. Fontes: None. L. Arvizu-Sanchez: None. C.G. Meireles: None. R.S. Carroll: None. U.B. Kaiser: None. V.M. Navarro: None. Background and Objectives: Glucocorticoid (GC) secretion induced by stress negatively impacts reproduction through effects at several levels of the hypothalamic-pituitary-gonadal (HPG) axis, including inhibition of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) release. Kisspeptin (Kiss1) neurons, are the GnRH and LH pulse generator and key regulators of reproduction and are proposed to play an important role in mediating the effects of GCs on HPG axis; however, the precise mechanisms are unknown. Kiss1 neurons are subject to regulation by several neural networks, in which GABAergic neurons appear to play a determinant role. Importantly, a large portion of GABAergic and Kiss1 neurons express glucocorticoid receptors (GR). We therefore hypothesized that GC signaling in GR-expressing GABAergic and/or GR-expressing Kiss1 neurons modulate the effects of stress and GCs on reproduction. Methods and Results: We generated mice lacking GR specifically in GABAergic or Kiss1 neurons using VgatCre or Kiss1Cre mice crossed with GRlox/lox mice to generate GABAGRKO or KISS1GRKO mice, respectively. Estrous cyclicity and ovarian morphology of GABAGRKO and KISS1GRKO mice and their littermate controls (GRlox/lox) were characterized under normal GC levels or during a 12-day restraint protocol (1-3h of restraint per day). Female GABAGRKO and KISS1GRKO mice displayed similar estrous cyclicity compared to control females. No differences were observed in the number of cycles within 30 days, in the time spent in each cycle stage (proestrus, estrus and diestrus) or in ovarian morphology of female GABAGRKO or KISS1GRKO mice compared to controls under normal GC levels. The restraint protocol resulted in fewer cycles in both control and GABAGRKO mice, but not in KISS1GRKO females. GABAGRKO females had fewer estrous cycles during restraint, spending less time in estrus and proestrus and more time in diestrus compared to restrained controls; in contrast KISS1GRKO had more estrous cycles during restraint, with no difference in time spent in the distinct phases of the estrous cycle compared to restrained controls. Conclusions: The absence of GR in GABAergic neurons results in greater suppression of estrous cycles during restraint in female GABAGRKO mice. In contrast, KISS1GRKO mice, lacking GR in Kiss1 neurons, were resistant to restraint-induced effects on estrous cyclicity. These findings suggest a role of GCs acting on GR in Kiss1 neurons to mediate the disruptive effects of stress on estrous cyclicity. In contrast, GC signaling in GABAergic neurons has a protective effect against restraint-induced disruption of estrous cyclicity. Sunday, June 2, 2024