Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats

Many animals synchronise their reproductive activity with the seasons to optimise the survival of their offspring. This synchronisation involves switching on and off their gonadotrophic axis. Ever since their discovery as key regulators of gonadotrophin-releasing hormone (GnRH) neurones, the hypothalamic RF-amide peptides kisspeptin and RFamide-related peptide (RFRP) have been a major focus of research on the seasonal regulation of the gonadotrophic axis. In the present study, we investigated the regulation of both neuropeptides in the Djungarian hamster, a major animal model for the study of seasonal reproduction. During the long-day breeding period, kisspeptin neurones in the anteroventral periventricular area are solely controlled by a positive sex steroid feedback and, in the arcuate nucleus, they are subject to a very strong negative sex steroid feedback associated with a minor photoperiodic effect. During short-day sexual quiescence, the disappearance of this hormonal feedback leads to high levels of kisspeptin in arcuate neurones. Notably, chronic central administration of kisspeptin is able to over-ride the photoperiodic inhibition of the gonadotrophic axis and reactivate the reproductive function. Therefore, our data suggest that kisspeptin secretion by arcuate neurones during sexual quiescence is inhibited by mechanisms upstream of kisspeptin neurones. RFRP expression is solely controlled by photoperiod, being strongly reduced in short days independently of the sex steroid feedback. Thus, kisspeptin and RFRP display contrasting patterns of expression and regulation. Upstream mechanisms controlling these neurones should be the focus of further studies on the roles of these RFamide neuropeptides in the seasonal control of reproduction.

supporting

confidence: 91%

Differential response patterns of kisspeptin and RFamide‐related peptide to photoperiod and sex steroid feedback in the Djungarian hamster (Phodopus sungorus)

Rasri-Klosen

Simonneaux

Klosen

2017

“…In support of this possibility, ablation of ARC kisspeptin neurones leads to atypical LH surge amplitude. 56,57 The present findings are also in agreement with a recent study demonstrating RFRP-3 suppression of ARC kisspeptin expression in free-cycling Syrian hamsters maintained in long photoperiods. 23 This same previous study found that hamsters injected with RFRP-3 in the afternoon, but not in the morning, exhibit suppression of LH concentrations when in proestrus.…”

Section: Discussionsupporting

confidence: 93%

“…Our results show that the expression of ARC Kiss1 mRNA co‐varies with circulating LH levels, with RFRP‐3 acting to reduce both Kiss1 mRNA expression and circulating concentrations of LH in the afternoon but not in the morning, consistent with this pathway of control. In support of this possibility, ablation of ARC kisspeptin neurones leads to atypical LH surge amplitude . The present findings are also in agreement with a recent study demonstrating RFRP‐3 suppression of ARC kisspeptin expression in free‐cycling Syrian hamsters maintained in long photoperiods .…”

Section: Discussionsupporting

confidence: 93%

Time‐of‐day‐dependent sensitivity of the reproductive axis to RFamide‐related peptide‐3 inhibition in female Syrian hamsters

Gotlieb

Baker

Moeller

et al. 2019

In spontaneously ovulating rodent species, the timing of the luteinising hormone (LH) surge is controlled by the master circadian pacemaker in the suprachiasmatic nucleus (SCN). The SCN initiates the LH surge via the coordinated control of two opposing neuropeptidergic systems that lie upstream of the gonadotrophin‐releasing hormone (GnRH) neuronal system: the stimulatory peptide, kisspeptin, and the inhibitory peptide, RFamide‐related peptide‐3 (RFRP‐3; the mammalian orthologue of avian gonadotrophin‐inhibitory hormone [GnIH]). We have previously shown that the GnRH system exhibits time‐dependent sensitivity to kisspeptin stimulation, further contributing to the precise timing of the LH surge. To examine whether this time‐dependent sensitivity of the GnRH system is unique to kisspeptin or a more common mechanism of regulatory control, we explored daily changes in the response of the GnRH system to RFRP‐3 inhibition. Female Syrian hamsters were ovariectomised to eliminate oestradiol (E2)‐negative‐feedback and RFRP‐3 or saline was centrally administered in the morning or late afternoon. LH concentrations and Lhβ mRNA expression did not differ between morning RFRP‐3‐and saline‐treated groups, although they were markedly suppressed by RFRP‐3 administration in the afternoon. However, RFRP‐3 inhibition of circulating LH at the time of the surge does not appear to act via the GnRH system because no differences in medial preoptic area Gnrh or RFRP‐3 receptor Gpr147 mRNA expression were observed. Rather, RFRP‐3 suppressed arcuate nucleus Kiss1 mRNA expression and potentially impacted pituitary gonadotrophs directly. Taken together, these findings reveal time‐dependent responsiveness of the reproductive axis to RFRP‐3 inhibition, possibly via variation in the sensitivity of arcuate nucleus kisspeptin neurones to this neuropeptide.

“…One intriguing speculation is that SCN inputs to ARN KISS neurones may modulate the LH surge. Although there is little evidence for the ARN to be involved in the timing of the LH surge, recent studies have suggested that the ARN KISS neurones may be involved in regulating the amplitude of the LH surge, potentially through direct projections to preoptic area kisspeptin neurones …”

Section: Discussionmentioning

confidence: 99%

“…35 Hence, it is possible that there is no direct or substantial circadian modulation of the different ARN KISS neurone sub-populations. involved in regulating the amplitude of the LH surge, 39,40 potentially through direct projections to preoptic area kisspeptin neurones. 41 In summary, these studies reveal marked sex-and subregionspecific effects of two neuropeptides on ARN KISS neurones.…”

Section: Discussionmentioning

confidence: 99%

Sex‐ and sub region‐dependent modulation of arcuate kisspeptin neurones by vasopressin and vasoactive intestinal peptide

Schafer

Kane

Colledge

et al. 2018

A population of kisspeptin neurones located in the hypothalamic arcuate nucleus (ARN) very likely represent the gonadotrophin‐releasing hormone pulse generator responsible for driving pulsatile luteinising hormone secretion in mammals. As such, it has become important to understand the neural inputs that modulate the activity of ARN kisspeptin (ARNKISS) neurones. Using a transgenic GCaMP6 mouse model allowing the intracellular calcium levels ([Ca2+]i) of individual ARNKISS neurones to be assessed simultaneously, we examined whether the circadian neuropeptides vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP) modulated the activity of ARNKISS neurones directly. To validate this methodology, we initially evaluated the effects of neurokinin B (NKB) on [Ca2+]i in kisspeptin neurones residing within the rostral, middle and caudal ARN subregions of adult male and female mice. All experiments were undertaken in the presence of tetrodotoxin and ionotropic amino acid antagonists. NKB was found to evoke an abrupt increase in [Ca2+]i in 95%‐100% of kisspeptin neurones throughout the ARN of both sexes. By contrast, both VIP and AVP were found to primarily activate kisspeptin neurones located in the caudal ARN of female mice. Although 58% and 59% of caudal ARN kisspeptin neurones responded to AVP and VIP, respectively, in female mice, only 0%‐8% of kisspeptin neurones located in other ARN subregions responded in females and 0%‐12% of cells in any subregion in males (P < 0.05). These observations demonstrate unexpected sex differences and marked heterogeneity in functional neuropeptide receptor expression amongst ARNKISS neurones organised on a rostro‐caudal basis. The functional significance of this unexpected influence of VIP and AVP on ARNKISS neurones remains to be established.