Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway

脑干-下丘脑神经通路对营养不良期间促性腺激素分泌的调节

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT The overall goal of this research is to understand how stress disrupts the ovarian cycle. Chronic undernutrition is a type of metabolic stress that impairs reproduction across species, and in women is implicated in the development of functional hypothalamic amenorrhea, an anovulatory disorder resulting from inadequate gonadotropin secretion. Although the tight coupling of energy balance to reproductive capacity is recognized in principle, the neuroendocrine loci and molecular mechanisms that mediate ovarian cycle dysfunction during undernutrition remain poorly understood. In females, ovulatory cyclicity is dependent on two populations of kisspeptin (Kiss1) neurons within the hypothalamus that coordinate gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) pulses and generation of the preovulatory GnRH/LH surge. Disruption of either arcuate Kiss1 (ARCKiss1) control of LH pulses or anteroventral periventricular Kiss1 (AVPVKiss1) control of the LH surge would be anticipated to impair ovarian cyclicity in females. Our preliminary studies demonstrate that chronic undernutrition rapidly disrupts ovarian cyclicity in female mice via impairment of both pulsatile LH secretion and the LH surge. We show that these inhibitory effects on the ovarian cycle are recapitulated by activation of brainstem A2NE neurons or via central administration of urocortin 2 (UCN2), a neuropeptide that specifically activates corticotropin-releasing hormone receptor 2 (CRHR2). Our observations that antagonism of CRHR2 or knockdown of CRHR2 in Kiss1 cells diminishes reproductive suppression in response to undernutrition or A2NE activation provide the foundation to test this neural pathway mediating the effects of undernutrition on reproductive neuroendocrine function. Currently it is not known how undernutrition disrupts the cycle or the neural processes controlling pulsatile or surge LH secretion. We propose to fill this gap by testing the overall hypothesis: Chronic undernutrition disrupts the ovarian cycle and fertility via activation of a NE – UCN2 – Kiss1 neural pathway that impairs two modes of LH secretion: LH pulses and the preovulatory LH surge. Aim1 will utilize a genetic knockout approach to investigate the role of CRHR2 within Kiss1 cells as a mediator of disrupted cycles, LH pulses, and the LH surge during chronic undernutrition. Aim 2.1 will utilize a chemogenic approach to test the sufficiency of this brainstem population to impair the ovarian cycle, inhibit AVPVKiss1 control of the LH surge, and disrupt ARCKiss1 control of LH pulses. Aim 2.2 will determine the necessity of A2NE signaling for disrupted ovarian cyclicity and impaired neural pathways underlying pulsatile and surge LH secretion. This project will employ powerful physiological, anatomical, molecular and transgenic tools to advance our knowledge of integrated stress responses and the regulation of gonadotropin secretion. Results from this proposal will provide enhanced understanding of the metabolic control of reproduction that may influence the management and treatment for anovulatory disorders resulting from negative energy balance. All necessary animal models and methods are in place to complete these studies.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
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KELLIE Breen Church其他文献

KELLIE Breen Church的其他文献

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{{ truncateString('KELLIE Breen Church', 18)}}的其他基金

FASEB SRC: The Mechanisms of Allostasis Conference: Stressed or Stressed Out
FASEB SRC:动态平衡机制会议:压力还是压力过大
  • 批准号:
    10537130
  • 财政年份:
    2022
  • 资助金额:
    $ 52.77万
  • 项目类别:
Transcriptomic and epigenomic basis for reproductive dysfunction during stress
应激期间生殖功能障碍的转录组和表观基因组基础
  • 批准号:
    10394958
  • 财政年份:
    2021
  • 资助金额:
    $ 52.77万
  • 项目类别:
Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
脑干-下丘脑神经通路对营养不良期间促性腺激素分泌的调节
  • 批准号:
    10684307
  • 财政年份:
    2021
  • 资助金额:
    $ 52.77万
  • 项目类别:
Transcriptomic and epigenomic basis for reproductive dysfunction during stress
应激期间生殖功能障碍的转录组和表观基因组基础
  • 批准号:
    10195913
  • 财政年份:
    2021
  • 资助金额:
    $ 52.77万
  • 项目类别:
Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
脑干-下丘脑神经通路对营养不良期间促性腺激素分泌的调节
  • 批准号:
    10488654
  • 财政年份:
    2021
  • 资助金额:
    $ 52.77万
  • 项目类别:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
糖皮质激素对生殖的神经内分泌调节
  • 批准号:
    9325553
  • 财政年份:
    2016
  • 资助金额:
    $ 52.77万
  • 项目类别:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
糖皮质激素对生殖的神经内分泌调节
  • 批准号:
    9895818
  • 财政年份:
    2016
  • 资助金额:
    $ 52.77万
  • 项目类别:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
糖皮质激素对生殖的神经内分泌调节
  • 批准号:
    9177432
  • 财政年份:
    2016
  • 资助金额:
    $ 52.77万
  • 项目类别:
The Role of Gonadotrope in Stress-Induced Reproductive Impairment
促性腺激素在压力引起的生殖损伤中的作用
  • 批准号:
    8810674
  • 财政年份:
    2010
  • 资助金额:
    $ 52.77万
  • 项目类别:
The Role of Gonadotrope in Stress-Induced Reproductive Impairment
促性腺激素在压力引起的生殖损伤中的作用
  • 批准号:
    7893551
  • 财政年份:
    2010
  • 资助金额:
    $ 52.77万
  • 项目类别:

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