Abstract

Female reproductive success relies on proper integration of circadian- and ovarian- signals to the hypothalamic-pituitary-gonadal axis in order to synchronize the preovulatory LH surge at the end of the ovarian follicular stage with the onset of the main active period. In this study, we used a combination of neuroanatomical and electrophysiological approaches to assess whether the hypothalamic neurons expressing Arg-Phe amide-related peptide (RFRP-3), a gonadotropin inhibitory peptide, exhibit daily and estrous stage dependent variations in female mice. Furthermore, we investigated whether arginine vasopressin (AVP), a circadian peptide produced by the suprachiamatic nucleus regulates RFRP-3 neurons. The number of c-Fos–positive RFRP-3 immunoreactive neurons is significantly reduced at the day-to-night transition with no difference between diestrus and proestrus. Contrastingly, RFRP neuron firing rate is higher in proestrus as compared to diestrus, independently of the time of the day. AVP immunoreactive fibers contact RFRP neurons with the highest density observed during the late afternoon of diestrus and proestrus. Application of AVP increases RFRP neurons firing in the afternoon (ZT6-10) of diestrus, but not at the same time point of proestrus, indicating that AVP signaling on RFRP neurons may depend on circulating ovarian steroids. Together, these studies show that RFRP neurons integrate both daily and estrogenic signals, which downstream may help to properly time the preovulatory LH surge.

Highlights

  • Mammalian reproductive competence is controlled centrally by neuroendocrine mechanisms operating along the hypothalamic- pituitary- gonadal (HPG) axis

  • The percentage of c-Fos-positive RFRP-3 neurons was significantly reduced at the day-to-night transition (ZT12-ZT16), around the time of the luteinizing hormone (LH) surge, on the day of proestrus, and at the same period on the day of diestrus (Two-way ANOVA, daytime, F (5, 48) = 39.56, p < 0.0001; estrous stage, F (1, 48) = 1.413, p = 0.2403; Figure 1C, Figure 1D)

  • We investigated in female mice whether RFRP-3 neurons, reported to regulate gonadotropin-releasing hormone (GnRH) neuronal activity and LH secretion [12], act as an interface for suprachiasmatic nucleus (SCN)-derived arginine vasopressin (AVP) fibers and E2 feedback, in order to convey daily and estral cues to the HPG axis

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Summary

Introduction

Mammalian reproductive competence is controlled centrally by neuroendocrine mechanisms operating along the hypothalamic- pituitary- gonadal (HPG) axis. The HPG axis is submitted to a complex regulation leading to a time-controlled ovulation triggered by an acute and transient luteinizing hormone (LH) release from the pituitary gland. This LH surge is driven by a former gonadotropin-releasing hormone (GnRH) surge which depends on high circulating estrogen (E2) secreted by mature ovarian follicles [1, 2]. Kp and RFRP-3 neurons lie upstream of the GnRH neurons and are thought to be the converging site where daily and ovarian signals are conveyed to the HPG axis, establishing the gated time window during which the preovulatory GnRH/ LH surge occurs [12]

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