Nutritionally Responsive PMv DAT Neurons Are Dynamically Regulated During Pubertal Transition.

Pubertal development is tightly regulated by energy balance. The crosstalk between metabolism and reproduction is orchestrated by complex neural networks, and leptin action in the hypothalamus plays a critical role. The ventral premammillary nucleus (PMv) leptin receptor (LepRb) neurons act as an essential relay for leptin action on reproduction. Here, we show that mouse PMv cells expressing the dopamine transporter (DAT) gene, Slc6a3 (PMvDAT), form a novel subpopulation of LepRb neurons. Virtually, all PMvDAT neurons expressed Lepr mRNA and responded to acute leptin treatment. Electrophysiological recordings from DATCRE; tdTomato mice showed that PMvDAT cells in prepubertal females have a hyperpolarized resting membrane potential compared to diestrous females. Slc6a3 mRNA expression in the PMv was higher in prepubertal than in adult females. In prepubertal females, Slc6a3 mRNA expression was higher in overnourished females from small size litters than in controls. Prepubertal Lepob females showed decreased PMv Slc6a3 mRNA expression that recovered to control levels after 3 days of leptin injections. Using a tracer adenoassociated virus in the PMv of adult DATCre; Kiss1hrGFP females, we observed PMvDAT projections in the anteroventral periventricular and periventricular nucleus (AVPV/PeN), surrounding Kiss1hrGFP neurons, a population critical for sexual maturation and positive estrogen feedback in females. The DATCRE; tdTomato projections to the AVPV were denser in adult than in prepubertal females. In adults, they are in close apposition to tyrosine hydroxylase neurons. Overall, these findings suggest that the DAT expressing PMvLepRb subpopulation play a role in leptin regulation of sexual maturation via actions on AVPV kisspeptin/tyrosine hydroxylase neuron.