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

Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Published Date: Jul 15, 2025

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 (PMv), form a novel subpopulation of LepRb neurons. Virtually, all PMv neurons expressed Lepr mRNA and responded to acute leptin treatment. Electrophysiological recordings from DAT; tdTomato mice showed that PMv 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 Lep 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 DAT; Kiss1 females, we observed PMv projections in the anteroventral periventricular and periventricular nucleus (AVPV/PeN), surrounding Kiss1 neurons, a population critical for sexual maturation and positive estrogen feedback in females. The DAT; 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 PMv subpopulation play a role in leptin regulation of sexual maturation via actions on AVPV kisspeptin/tyrosine hydroxylase neuron.

Authors

  • Cristina Sáenz de Miera
    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
  • Nicole Bellefontaine
    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
  • Marina A Silveira
    Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, Texas, USA.
  • Chelsea N Fortin
    Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA.
  • Thais T Zampieri
    Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
  • Jose Donato
    Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
  • Kevin W Williams
    Center for Hypothalamic Research, Department of Internal Medicine, Peter O'donnell Jr. Brain Institute, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
  • Cristiano Mendes-da-Silva
    Department of Biosciences, Federal University of Sao Paulo, Santos, Brazil.
  • Laura Heikkinen
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
  • Christian Broberger
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
  • Renata Frazao
    Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
  • Carol F Elias
    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.

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