Daily and Estral Regulation of RFRP-3 Neurons in the Female Mice

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 amiderelated 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.

Age-dependent change of RFRP-3 neuron numbers and innervation in female mice

“…This loss of daily variation in the peptidergic input on RFRP-3 neurons may be partly responsible for the observed loss of the daily regulation of RFRP-3 neuronal activity. Indeed, both peptides may be involved in the daily regulation of RFRP-3 neurons, since previous studies have reported that VIP inhibits (Russo et al, 2015) and AVP activates (Angelopoulou et al, 2021) RFRP-3 neurons at specific time points.…”

Connecting the Dots: Potential Interactions Between Sex Hormones and the Circadian System During Memory Consolidation

“…Sex steroid hormones, likewise, negatively or positively feedback onto neurons in the hypothalamus to control LH and FSH release (for review see Wang and Moenter, 2020 ). Positive feedback is mediated by kisspeptin neurons in the rostral hypothalamus, whereas negative feedback is modulated by both kisspeptin neurons in the caudal hypothalamus and gonadotropin-inhibitory neurons ( Angelopoulou et al, 2021 ; Chassard et al, 2015 ; Gibson et al, 2008 ; Smith et al, 2005 ; Williams et al, 2011 ). Interestingly, both of these feedback loops, positive and negative, receive input from the SCN ( Vida et al, 2010 ), suggesting the clock is involved in regulating sex hormone concentrations.…”