Biology subjects

Elias, C. F.

Publications and source records attributed to Elias, C. F..

2 recordsLinked to original sources

bioRxiv2023

Glutamate neurotransmission from leptin receptor cells is required for typical puberty and reproductive function in female mice

The hypothalamic ventral premammillary nucleus (PMv) is a glutamatergic nucleus essential for the metabolic control of reproduction. However, conditional deletion of leptin receptor (LepRb) in vesicular glutamate transporter 2 (Vglut2) expressing neurons results in virtually no reproductive deficits. In this study, we determine the role of glutamatergic signaling from leptin responsive PMv neurons on puberty and fertility. We first assessed if stimulation of PMv neurons induces LH release in fed adult females. We used the stimulatory form of designer receptor exclusively activated by designer drugs (DREADDs) in LepRb-Cre mice. We collected blood sequentially before and for 1h after iv. clozapine-N-oxide injection. LH level increased in animals correctly targeted to the PMv, and LH level was correlated to the number of cFos immunoreactive neurons in the PMv. Next, females with deletion of Vglut2 in LepRb neurons (LepR{Delta}VGlut2) showed delayed age of puberty, disrupted estrous cycles, increased GnRH concentration in the axon terminals and disrupted LH responses, suggesting impaired GnRH release. To assess if glutamate is required for PMv actions in pubertal development, we generated a Cre-induced reexpression of endogenous LepRb (LepRloxTB) with concomitant deletion of Vglut2 (Vglut2-floxed) mice. Rescue of Lepr and deletion of Vglut2 in the PMv was obtained by stereotaxic injection of an adeno-associated virus vector expressing Cre recombinase. Control LepRloxTB mice with PMv LepRb rescue showed vaginal opening, follicle maturation and became pregnant, while LepRloxTB;Vglut2flox mice showed no pubertal development. Our results indicate that glutamatergic signaling from leptin sensitive neurons regulates the reproductive axis, and that leptin action on pubertal development via PMv neurons requires Vglut2. SIGNIFICANCE STATEMENTAge of puberty and reproductive function are strongly influenced by energy balance. Leptin is the primary metabolic hormone in reproductive control, but the neural circuitry involved is not fully understood. Previous studies have suggested that GABAergic but not glutamatergic neurotransmission is required for leptin action on reproduction. However, the PMv, a nucleus essential for the metabolic control of the reproductive function, densely expresses Lepr and is essentially glutamatergic. Here we show that remote activation of leptin-responsive neurons in the PMv induces LH secretion, while deletion of glutamatergic neurotransmission in LepR (or PMv) neurons disrupts pubertal development and impairs the reproductive function in female mice. Our findings indicate that glutamate in LepR, and specifically in PMv, neurons is required for reproductive maturation and function.

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↗