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Frazao, R.

Publications and source records attributed to Frazao, R..

2 recordsLinked to original sources
bioRxiv2025

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 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.

neuroscience↗
bioRxiv2021

Reproductive neuronal circuitry in adaptive changes of energy balance

The crosstalk between metabolism and reproduction is essential for species survival. When dysfunctional, this interaction may decrease reproductive efficiency, but in physiological conditions of high energy demands, e.g., pregnancy and lactation, it is highly beneficial. Females display adaptive responses that assure offspring survival and health, including increased food intake and suppression of the reproductive function. Some of these physiological responses are modulated by leptin actions in neuronal pathways that are still unclear. The hypothalamic ventral premammillary nucleus (PMv) is a key integrative node of metabolic cues and reproductive status, comprised of either leptin-depolarized or -hyperpolarized neurons. Here, we show that the subset of leptin-hyperpolarized neurons coexpresses dopamine transporter (DAT) and prolactin receptor. DAT expression is higher in prepubertal conditions, when reproductive function is suppressed. These neurons innervate AgRP presynaptic terminals and may potentiate their inhibitory actions on reproduction. We further applied a mathematical model to reconcile our new findings with the current literature and to verify if those neurons are putative components of the metabolic control of reproduction. In our model, leptin-depolarized PMv neurons project to and directly stimulate kisspeptin and gonadotropin releasing hormone (GnRH) neurons. Leptin-hyperpolarized PMv DAT neurons are directly stimulated by prolactin and project to inhibitory control sites. During conditions of high prolactin levels, i.e., late pregnancy and lactation, this pathway may overcome the former, facilitating AgRP actions in the suppression of the reproductive function. Our model also predicts that overstimulation of this pathway may underlie earlier puberty and reproductive deficits observed in conditions of metabolic dysfunction. 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 undefined. Neurons in the ventral premammillary nucleus express leptin receptor and project to reproductive control sites. Those neurons are essentially glutamatergic, but functionally and phenotypically heterogeneous. They either depolarize or hyperpolarize in response to leptin. We show that leptin-hyperpolarized neurons coexpress dopamine transporter and prolactin receptor, and project to AgRP inhibitory output. Computational modeling was applied to build a neuronal network integrating metabolism and reproduction in typical and dysfunctional physiology.

neuroscience↗