Hypothalamic control of reproductive aging

描述（由申请人提供）：生殖衰老的机制涉及下丘脑-垂体-性腺（HPG）轴三个水平的复杂相互作用，这一点越来越清楚。在大鼠和其他啮齿类动物中，生殖周期在中年时变得不规则，此后不久就不循环了，尽管卵巢仍有功能卵泡。这些观察结果支持下丘脑和/或垂体在向非周期性转变中的作用。我的实验室一直在研究GnRH神经元在生殖衰老中的作用，GnRH神经元是控制生殖功能的主要细胞。最近的证据表明，衰老过程中HPG功能受损的主要机制是由于GnRH细胞调节输入的年龄相关改变。在这里，我将研究中年过渡到无环性的神经内分泌机制，重点关注介导神经递质谷氨酸作用的NMDA受体（NMDAR）如何与GnRH细胞在视前区（POA）和中位突起（ME）的神经末梢相互作用，以及这些作用对生殖衰退的影响。我的模型是年轻的（有规律的发情周期）和中年的（有规律或不规则的周期，或无周期）Sprague-Dawley大鼠；因此，我的分析将把年龄（年轻vs.中年）和生殖状态（循环、不规则循环或无循环）作为独立变量考虑在内。提出了三个具体目标来检验我们的假设。目的1将研究POA中NMDARs的年龄相关变化对GnRH细胞和POA核的影响。目标2将检查ME中的类似关系。Aim 3将研究NMDARs和雌激素受体（er）如何在POA和ME的相同靶细胞（包括GnRH细胞）中表达，以及它们在生殖衰老过程中如何变化。总之，这些研究将把GnRH神经元、NMDARs和er联系起来，阐明这些系统如何协调作用，导致中年向非环性过渡，并提供对其机制的见解。我的三个具体目标构成了妇女围绝经期过渡模型的基础，这是一个与改善健康衰老相关的领域，并将为下丘脑在生殖衰老中的作用提供基础和功能见解。这些实验对绝经后激素替代疗法、确定治疗更年期症状的非激素方法以及潜在地延长生殖寿命具有临床意义，随着女性继续推迟生育年龄，这一点变得越来越重要。

DESCRIPTION (provided by applicant): It is becoming increasingly clear that the mechanisms for reproductive aging involve a complex interaction of the three levels of the hypothalamic-pituitary-gonadal (HPG) axis. In rats and other rodents, reproductive cycles become irregular at middle age and acyclicity ensues shortly thereafter, although the ovaries still contain functional follicles. These observations support the role of the hypothalamus and/or pituitary in the transition to acyclicity. My laboratory has been studying a role in reproductive senescence for GnRH neurons, the primary cells controlling reproductive function. Recent evidence suggests that a major mechanism for compromised HPG function during aging is due to age-related alterations in regulatory inputs to GnRH cells. Here, I will investigate the neuroendocrine mechanisms that underlie the transition to acyclicity at middle age, focusing on how the NMDA receptor (NMDAR), which mediates effects of the neurotransmitter glutamate, interacts with GnRH cells at their perikarya in the preoptic area (POA) and neuroterminals in the median eminence (ME), and the consequences of these effects on reproductive decline. My model is young (regular estrous cycles) and middle-aged (regular or irregular cycles, or acyclic) Sprague-Dawley rats; therefore, my analyses will take both age (young vs. middle-aged) and reproductive status (cyclic, irregularly cycling, or acyclic) into consideration as independent variables. Three Specific Aims are proposed to test our hypotheses. Aim 1 will investigate effects of age-related changes in NMDARs in POA, on GnRH cells specifically and in POA nuclei in general. Aim 2 will examine similar relationships in the ME. Aim 3 will study how NMDARs and estrogen receptors (ERs) may be expressed in the same target cells in POA and ME, including GnRH cells, and how these change during reproductive aging. Together, these studies will link GnRH neurons, NMDARs, and ERs, to elucidate how these systems act coordinately to result in the transition to acyclicity at middle age, and to provide insight into their mechanisms. My three Specific Aims form the basis for a model of the perimenopausal transition in women, an area relevant to improving healthy aging, and will provide fundamental and functional insights into the role of the hypothalamus in reproductive senescence. These experiments have clinical implications for postmenopausal hormone replacement therapy, for identifying non- hormonal approaches to treating menopausal symptoms, and for potentially expanding the reproductive lifespan, which is becoming more important as women continue to postpone childbearing until later in life.