FRI274 Dopamine Transporter-Expressing Leptin-Sensitive Neurons In The Ventral Premammillary Nucleus Innervate Kiss1 Neurons

Abstract

Abstract Disclosure: C. Sáenz de Miera: None. L. Heikkinen: None. C. Broberger: None. C.F. Elias: None. Pubertal development is tightly regulated by energy balance, and easily disrupted in states of excess or negative energy reserves. This crosstalk between metabolism and reproduction is orchestrated by complex neural networks coordinated by circulating hormones, notably, leptin action in the hypothalamus plays a critical role. The ventral premammillary nucleus (PMv) is rich in leptin receptor (LepRb) neurons, and acts as an essential relay for leptin action on reproduction. Here, we describe a novel subpopulation of leptin sensitive neurons within the PMv that express dopamine transporter (DATPMv). We observed that in both prepubertal and adult females in diestrous, virtually all DATPMv neurons express LepRb mRNA and respond to acute leptin treatment with phosphorylation of the intracellular marker signal transducer and activator of transcription 3 (pSTAT3). Electrophyisological recordings from DAT-CRE;R26tdTomato (DAT-tdTom) mice show that DATPMv cells in adult females have a higher resting membrane potential than those in prepubertal females. DAT mRNA expression in the PMv is higher in prepubertal than in adult females. However, DAT mRNA expression was similar in adult females in diestrous, ovariectomized (OVX), and OVX treated with estradiol, indicating that the age difference observed is not due to the increase in estradiol during pubertal maturation. To trace DATPMv projections, we injected an adenoassociated virus expressing Cre-dependent channelrhodopsin (ChR2-mCherry) in the PMv of adult female DAT-Cre;Kiss1-hrGFP mice, which express GFP driven by kiss1 regulatory elements. ChR2-mCherry projections were observed in the anteroventral periventricular nucleus (AVPV) surrounding Kiss1-hrGFP neurons, a population critical for sexual maturation and positive estrogen feedback in females. No projections were observed near arcuate nucleus Kiss1-hrGFP neurons, in the medial preoptic area (MPOA) or near GnRH neurons. This contrasts with previous observations of dense projections from the overall PMv LepRb population to the MPOA, surrounding GnRH cell bodies suggesting the DATPMv subpopulation has different target areas than the non-DAT LepRb neurons. Using DAT-tdTOM females we observed that overall tdTom projections to the AVPV are denser in adult diestrous than in prepubertal females. Overall, these findings suggest that the DAT expressing LepR subpopulation in the PMv play a role in leptin regulation of sexual maturation via actions on AVPV kisspeptin neurons. Presentation: Friday, June 16, 2023