Hypothalamic control of reproductive aging

描述（由申请人提供）：越来越清楚的是，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。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，此后不久无周期性增强，尽管卵巢仍含有功能性卵泡。这些观察结果支持了下丘脑和/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，在衰老过程中受损的HPG功能的一个主要机制是由于年龄相关的GnRH细胞的调节输入的变化。在这里，我将调查的神经内分泌机制，在中年的过渡到非周期性，重点是如何的NMDA受体（NMDAR），介导的神经递质谷氨酸的影响，与GnRH细胞在其核周视前区（POA）和正中隆起（ME）的神经末梢相互作用，以及这些影响生殖下降的后果。我的模型是年轻（规律的发情周期）和中年（规律或不规律的周期，或无周期）Sprague-Dawley大鼠;因此，我的分析将年龄（年轻与中年）和生殖状态（周期，不规律的周期，或无周期）作为自变量考虑。提出了三个具体目标来检验我们的假设。目的1将探讨年龄相关的影响，在NMDAR的POA，具体的GnRH细胞和POA核一般。目标2将研究ME中的类似关系。目标3将研究NMDAR和雌激素受体（ER）如何在POA和ME中的相同靶细胞（包括GnRH细胞）中表达，以及这些在生殖衰老过程中如何变化。总之，这些研究将连接GnRH神经元，NMDAR和ER，以阐明这些系统如何协调作用，导致中年时向非周期性过渡，并深入了解其机制。我的三个具体目标形成了女性围绝经期过渡模型的基础，这是一个与改善健康老龄化相关的领域，并将为下丘脑在生殖衰老中的作用提供基本和功能性的见解。这些实验对绝经后激素替代疗法、确定治疗绝经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直到晚年，生殖寿命变得越来越重要。

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.