Sex and Time of Day Alter the Interactions Between Hypothalamic Glia and the Neural Circuits Controlling Reproduction.

An upstream network, including glia and arcuate nucleus (ARC) kisspeptin neurons, controls hormone secretion from preoptic area (POA) gonadotropin-releasing hormone (GnRH) neurons, which form the final common pathway for the central control of fertility. In males, chemogenetic activation of Gq-mediated signaling in POA glia activated GnRH neurons and downstream luteinizing hormone (LH) release, while chemogenetic activation of ARC glia had no effect on ARC kisspeptin neurons. We characterized sex differences and time-of-day effects in these critical circuits to understand their effects on reproduction. Chemogenetic activation of glial fibrillary acidic protein (GFAP)-expressing cells increased intracellular calcium concentrations regardless of sex, brain region, or time of day. Activation of POA glia or treatment with the gliotransmitter analog dimethyl prostaglandin E2 (dmPGE2) increased GnRH neuron firing rate, and these responses were dependent upon sex and time of day. In contrast, ARC kisspeptin neuron firing rate was unresponsive to ARC glia activation or dmPGE2 regardless of sex or time of day. POA glial activation increased LH levels in males and females but the response in males was more rapid. ARC glia activation had no effect on LH in females and the response in males was delayed compared to POA glia activation. A similar LH response persisted after ARC kisspeptin neuron ablation, suggesting it is not mediated by those neurons. GnRH neurons, rather than arcuate kisspeptin neurons, are thus the main target of glial regulation of reproductive neuroendocrine output and this regulation is dependent on sex and time of day.