Neuropeptide and Gonadal Steroid Action on Arcuate Kisspeptin Neurons: Implications for Central Regulation of Fertility.

[摘要] Pulsatile gonadotropin-releasing hormone (GnRH) release is essential to fertility and is modulated by gonadal steroids, most likely via steroid-sensitive afferents. Arcuate neurons coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons) are steroid-sensitive and have been postulated to both generate GnRH pulses and mediate steroid feedback on pulse frequency. KNDy neurons have been proposed to interact with one another via NKB and dynorphin to activate and inhibit the KNDy network, respectively, and thus alter kisspeptin output to GnRH neurons. To test the roles of NKB and dynorphin on KNDy neurons and the steroid sensitivity of these actions, targeted extracellular recordings were made of fluorescence-identified neurons from male mice that were either gonad-intact or castrate and otherwise untreated or treated in vivo with steroid receptor agonists. Senktide, an agonist for the high-affinity receptor for NKB (neurokinin-3 receptor, NK3R), increased action potential firing in KNDy neurons. Dynorphin reduced spontaneous KNDy neuron activity, but antagonism of kappa-opioid receptors (KOR) failed to induce firing in quiescent KNDy neurons. Senktide-induced activation was greater in KNDy neurons from castrate mice, whereas dynorphin-induced suppression was greater in those from intact mice. Similar to the intact condition, both estradiol and dihydrotestosterone suppressed NK3R agonist-induced KNDy neuron firing and enhanced the inhibition of firing rate caused by KOR activation. An estrogen receptor-alpha agonist but not an estrogen receptor-beta agonist mimicked the effects of estradiol on NK3R activation. These observations support stimulation and inhibition of KNDy neuron firing by NK3R and KOR activation, respectively. Modulation of these responses by gonadal steroids may be a mechanism mediating steroid negative feedback. Overall, the work presented here supports contribution of KNDy neurons to steroid-sensitive elements of a GnRH pulse generator.

[发布机构] University of Michigan

[效力级别] reproduction

[关键词] neuroendocrinology;reproduction;neuropeptides;gonadal steroid hormones;Physiology;Health Sciences;Molecular and Integrative Physiology