Optogenetic Activation of Arcuate Kisspeptin Neurons Generates a Luteinizing Hormone Surge-Like Secretion in an Estradiol-Dependent Manner.

Xian-Hua Lin,He-Feng Huang,Geffen Lass,Hui Wang,Ling-Si Kong,Kevin T O’Byrne,Xiao-Feng Li

doi:10.3389/fendo.2021.775233

Abstract

Traditionally, the anteroventral periventricular (AVPV) nucleus has been the brain area associated with luteinizing hormone (LH) surge secretion in rodents. However, the role of the other population of hypothalamic kisspeptin neurons, in the arcuate nucleus (ARC), has been less well characterized with respect to surge generation. Previous experiments have demonstrated ARC kisspeptin knockdown reduced the amplitude of LH surges, indicating that they have a role in surge amplification. The present study used an optogenetic approach to selectively stimulate ARC kisspeptin neurons and examine the effect on LH surges in mice with different hormonal administrations. LH level was monitored from 13:00 to 21:00 h, at 30-minute intervals. Intact Kiss-Cre female mice showed increased LH secretion during the stimulation period in addition to displaying a spontaneous LH surge around the time of lights off. In ovariectomized Kiss-Cre mice, optogenetic stimulation was followed by a surge-like secretion of LH immediately after the stimulation period. Ovariectomized Kiss-Cre mice with a low dose of 17β-estradiol (OVX+E) replacement displayed a surge-like increase in LH release during period of optic stimulation. No LH response to the optic stimulation was observed in OVX+E mice on the day of estradiol benzoate (EB) treatment (day 1). However, after administration of progesterone (day 2), all OVX+E+EB+P mice exhibited an LH surge during optic stimulation. A spontaneous LH surge also occurred in these mice at the expected time. Taken together, these results help to affirm the fact that ARC kisspeptin may have a novel amplificatory role in LH surge production, which is dependent on the gonadal steroid milieu.

Highlights

Normal reproductive function in mammals is controlled by the hypothalamic-pituitary-gonadal axis
anteroventral periventricular (AVPV) Kiss1 neurons have been noted to play a significant role in mediating positive estradiol feedback, leading to induction of the preovulatory luteinizing hormone (LH) surge [10], while neurons in the arcuate nucleus (ARC) are a major component of gonadotropin releasing hormone (GnRH) pulse generation
No response during optic stimulation was observed in wild type mice, but a spontaneous LH surge occurred at the usual time of day (n = 4, Figures 2E, F)

Summary

Introduction

Normal reproductive function in mammals is controlled by the hypothalamic-pituitary-gonadal axis. Unlike GnRH neurons, both ARC and AVPV kisspeptin neurons express estrogen receptor (ER)-a, acting as relay afferents for feedback Of these populations, AVPV Kiss neurons have been noted to play a significant role in mediating positive estradiol feedback, leading to induction of the preovulatory LH surge [10], while neurons in the ARC are a major component of GnRH pulse generation. AVPV Kiss neurons have been noted to play a significant role in mediating positive estradiol feedback, leading to induction of the preovulatory LH surge [10], while neurons in the ARC are a major component of GnRH pulse generation These ARC neurons co-express neurokinin B (NKB) and dynorphin A (Dyn) so are referred to as KNDy neurons [11,12,13]. With these results in mind, it is reasonable to propose ARC Kiss neurons may be involved in generating the pre-ovulatory GnRH/ LH surge under optimal hormonal conditions

Methods

Results

Conclusion