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RFamide-Related Peptide Neurons Modulate Reproductive Function and Stress Responses.

ABSTRACT: RF-amide related peptide 3 (RFRP-3) is a neuropeptide thought to inhibit central regulation of fertility. We investigated whether alterations in RFRP neuronal activity led to changes in puberty onset, fertility, and stress responses, including stress and glucocorticoid-induced suppression of pulsatile luteinizing hormone secretion. We first validated a novel RFRP-Cre mouse line, which we then used in combination with Cre-dependent neuronal ablation and DREADD technology to selectively ablate, stimulate, and inhibit RFRP neurons to interrogate their physiological roles in the regulation of fertility and stress responses. Chronic RFRP neuronal activation delayed male puberty onset and female reproductive cycle progression, but RFRP-activated and ablated mice exhibited apparently normal fertility. When subjected to either restraint- or glucocorticoid-induced stress paradigms. However, we observed a critical sex-specific role for RFRP neurons in mediating acute and chronic stress-induced reproductive suppression. Female mice exhibiting RFRP neuron ablation or silencing did not exhibit the stress-induced suppression in pulsatile luteinizing hormone secretion observed in control mice. Furthermore, RFRP neuronal activation markedly stimulated glucocorticoid secretion, demonstrating a feedback loop whereby stressful stimuli activate RFRP neurons, which in turn further activate the stress axis. These data provide evidence for a neuronal link between the stress and reproductive axes.

SUBMITTER: Mamgain A

PROVIDER: S-EPMC7821868 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To conserve scarce energetic resources during winter, seasonal breeders inhibit reproduction and other nonessential behavioral and physiological processes. Reproductive cessation is initiated in response to declining day lengths, a stimulus represented centrally as a long-duration melatonin signal. The melatonin signal is not decoded by the reproductive axis directly, but by an unidentified neurochemical system upstream of gonadotropin-releasing hormone (GnRH). The dorsomedial nucleus of the hypothalamus (DMH) has been implicated in seasonal changes in reproductive function in Syrian hamsters (Mesocricetus auratus), although the specific-cell phenotype decoding photoperiodic information remains unknown. RFamide-related peptide (RFRP; the mammalian homolog of the gonadotropin-inhibitory hormone (GnIH) gene identified in birds) has emerged as a potent inhibitory regulator of the reproductive axis and, significantly, its expression is localized to cell bodies of the DMH in rodents. In the present study, the authors explored the relationship between RFRP expression, photoperiod exposure, and reproductive condition/hormonal status. In male hamsters that respond to short days with reproductive inhibition, RFRP-ir and mRNA expression are markedly reduced relative to long-day animals. Replacement of testosterone in short-day animals did not affect this response, suggesting that alterations in RFRP expression are not a result of changing sex steroid concentrations. A subset of the hamster population that ignores day length cues and remains reproductively competent in short days (nonresponders) exhibits RFRP-ir expression comparable to long-day hamsters. Analysis of cell body and fiber density suggests a potential interplay between peptide production and release rate in differentially regulating the reproductive axis during early and late stages of reproductive regression. Together, the present findings indicate that photoperiod-induced suppression of reproduction is associated with changes in RFRP and mRNA expression, providing opportunity for further exploration on the role that RFRP plays in this process.

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RFamide-Related Peptide Neurons Modulate Reproductive Function and Stress Responses.

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