LAUSR

Abstract The energy sensing in reproduction is mainly modulated by the ventral premammillary nucleus (PMv) neurons in hypothalamus. They are sensitive to the adipocyte-derived hormone leptin; some of them are excitatory to leptin, and the others are inhibitory to leptin. Recently we have characterized PMv neurons expressing dopamine transporters (DAT) suppress female reproductive function, and this is inhibited by leptin. We hypothesize that 1) PMv DAT neurons depolarize AgRP neurons. Some PMv non-DAT neurons depolarize Kiss1 neurons, and this pathway is independent of GABAergic projection from AgRP to Kiss1 neurons. The other PMv non-DAT neurons innervate directly to GnRH neurons. The size of PMv DAT sub-population projecting to AgRP neurons is main determinant of suppressing GnRH bursting spikes. 2) The direct innervation from PMv non-DAT to GnRH neurons sustains GnRH pulsatility even with low level of kisspeptin secretion. To construct a minimal neuronal circuit for energy sensing, we developed a computational model of conductance-based electrophysiology; input signal to PMv by dopamine transporter and leptin, as well as estradiol to Kiss1 neurons, and the output response of bursting spike frequency by GnRH neurons. For excitatory PMv neurons, leptin-sensitive TRPC channels are incorporated. Leptin-dependent KATP as well as hypothesized dopamine-sensitive channels are applied for DAT neurons inhibited by leptin. Both subpopulation neurons release glutamate neurotransmitters. For Kiss1 neurons, we employed T-type calcium channels and hyperpolarization-activated rebounding channels with kisspeptin neuropeptide release. We have incorporated Kiss1 sub-populations in anteroventral periventricular (AVPV) with estradiol-positive feedback and those in the arcuate with estradiol-negative feedback. For AgRP neurons, leptin-dependent KATP channels are considered with GABAA release for projection to Kiss1 neurons. The computational neuronal circuitry model based on the regulation of PMv DAT neurons by viral DREADDs demonstrates that Kiss1 and AgRP neurons mediate for the suppression of GnRH neurons and regulation of female fertility. The direct relay from leptin-activated PMv to GnRH with restriction of kisspeptin secreted from Kiss1 shows a moderate contribution of this pathway to sexual maturation and fertility independent of steroidogenic feedback.