Nutritionally responsive PMv DAT neurons are dynamically regulated during pubertal transition

Saenz de Miera, C.; Bellefontaine, N.; Silveira, M. A.; Fortin, C. N.; Zampieri, T. T.; Donato, J.; Williams, K. W.; Mendes de Silva, C.; Heikkinen, L.; Broberger, C.; Frazao, R.; Elias, C. F.

doi:10.1101/2025.02.03.636271

bioRxiv · 10.1101/2025.02.03.636271

Nutritionally responsive PMv DAT neurons are dynamically regulated during pubertal transition

Saenz de Miera, C.·Bellefontaine, N.·Silveira, M. A.·Fortin, C. N.·Zampieri, T. T.·Donato, J.·Williams, K. W.·Mendes de Silva, C.·Heikkinen, L.·Broberger, C.·Frazao, R.·Elias, C. F.

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Abstract

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 surrounded 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 neurons. Significance StatementWomen with excess or low energy stores (e.g., obesity or anorexia) have reproductive deficits, including altered puberty onset, disruption of reproductive cycles and decreased fertility. If able to conceive, they show higher risks of miscarriages and preterm birth. The hypothalamic circuitry controlling the interplay between metabolism and reproduction is poorly defined. Neurons in the ventral premammillary nucleus express the leptin receptor and play a key role in the metabolic control of reproduction. Those neurons are functionally and phenotypically heterogeneous. Here we show that a subset of leptin-sensitive neurons co-expresses the dopamine transporter (DAT), is dynamically regulated during pubertal transition and with nutrition and projects to brain sites relevant for sexual maturation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/636271v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@cb8223org.highwire.dtl.DTLVardef@ccf560org.highwire.dtl.DTLVardef@17e58org.highwire.dtl.DTLVardef@de021_HPS_FORMAT_FIGEXP M_FIG C_FIG The ventral premammillary nucleus of the hypothalamus plays an essential role in the metabolic control of reproduction. Puberty brings large changes to a subpopulation of PMvLepRb cells expressing the dopamine transporter (PMvDAT). DAT gene expression is higher in prepubertal than in adults and is regulated by leptin in prepubertal females. Dynamic projections from PMvDAT cells contact the kisspeptin and tyrosine hydroxylase (TH) populations in the AVPV/PeN during puberty, a critical time for the appearance of these cells in the AVPV/PeN.

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Saenz de Miera, C., Bellefontaine, N., Silveira, M. A., Fortin, C. N., Zampieri, T. T., Donato, J., Williams, K. W., Mendes de Silva, C., Heikkinen, L., Broberger, C., Frazao, R., Elias, C. F.. 2025-02-06. Nutritionally responsive PMv DAT neurons are dynamically regulated during pubertal transition. https://doi.org/10.1101/2025.02.03.636271

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