Deciphering the interactions of stress, corticosteroids, and Kiss1 neurons in reproduction and vasomotor symptoms in aging females

项目总结 血管运动症状(VMS)，也称为潮热，是感觉到的高潮的常见扰动 更年期妇女由于雌二醇水平耗尽而经历的体温。 这些VMS会导致大量出汗和外周血管扩张，从而对患者的生活质量产生不利影响 更年期妇女，与随后的心血管疾病和痴呆症的风险相关。最近，神经元 产生神经肽Kispeptin(由Kiss1基因编码)、神经激肽B(NKB，由Tac2编码)、 和强啡肽(dyn，由Pdyn编码)，被称为下丘脑弓状核中的KNDy神经元 的小鼠已被确定为潮热的媒介，通过一条共同的途径也控制着脉搏 GnRH分泌和下丘脑-垂体-性腺轴(HPG)的活动。基于这一双重角色 KNDy神经元，我们假设负面影响生殖功能的因素，如压力和 高皮质醇血症，通过KNDy神经元起作用，也会影响体温调节(即VMS)和睡眠 更年期的病人。为此，使用更年期和VMS的小鼠模型，我们的目标是：1)确定 这些效应通过直接调节Kiss1或间接调节Tac2或Pdyn而发生； 确定这些影响是否发生在KNDy神经元本身和/或通过KNDy上游的神经元 神经元--具体地说，是通过GABA能神经元。此外，考虑到绝经量下降与 性激素不仅与VMS有关，而且还与睡眠模式紊乱有关，我们的目的是探讨 应激、皮质类固醇和KNDy神经元在缺乏性类固醇的情况下睡眠中断。成功者 这一提议的完成将对压力在以下方面的作用和影响提供重要的新的机械论见解 在睡眠核心的帮助下，KNDy神经元、HPG轴、VMS和相关的睡眠障碍。 这些见解对于开发新的、更安全和更有效的工具以缓解 压力和潮热对女性的影响，如本分数申请的项目1和项目2所研究的， 从而改善妇女的生殖健康老龄化结果。

PROJECT SUMMARY Vasomotor symptoms (VMS), also known as hot flashes, are common perturbations of perceived high temperature that women experience during menopause as a consequence of the depletion of estradiol levels. These VMS entail profuse sweating and peripheral vasodilation that can adversely affect quality of life in menopausal women, relevant to subsequent risk of cardiovascular disease and dementia. Recently, neurons producing the neuropeptides kisspeptin (encoded by the Kiss1 gene), neurokinin B (NKB, encoded by Tac2), and dynorphin (Dyn, encoded by Pdyn) and referred to as KNDy neurons in the hypothalamic arcuate nucleus of mice have been identified as mediators of hot flashes through a common pathway that also controls pulsatile GnRH secretion and the activity of the hypothalamic-pituitary-gonadal (HPG) axis. Based on this dual role of KNDy neurons, we hypothesize that factors that negatively impact reproductive function, such as stress and hypercortisolemia, act through KNDy neurons and will also affect thermoregulation (i.e., VMS) and sleep in menopausal patients. To this end, using mouse models of menopause and VMS, we aim to: 1) determine if these effects occur through direct regulation of Kiss1 or indirectly through regulation of Tac2 or Pdyn; and 2) determine if these effects occur on the KNDy neurons themselves and/or via neurons upstream of KNDy neurons—specifically, via GABAergic neurons. In addition, given the association of the menopausal decline of sex steroids with not only VMS but also disruption of sleep patterns, we aim to explore the relationships of stress, corticosteroids and KNDy neurons in the absence of sex steroids with sleep disruption. The successful completion of this proposal will offer important new mechanistic insights into the roles and effects of stress on KNDy neurons, the HPG axis, VMS, and associated sleep disturbances with the assistance of the Sleep Core. These insights will be critical to inform the development of new, safer and more effective tools to mitigate the effects of stress and of hot flashes in women, as studied in Project 1 and Project 2 of this SCORE application, and thereby improve reproductive health aging outcomes in women.