Norepinephrine in Stress-Induced Amenorrhea of Macaques

描述（由申请人提供）：该项目的总体目标是确定脑干去甲肾上腺素系统是否在日常生活压力（即节食、适度运动和心理压力）损害生殖轴活动的机制中发挥作用。我们使用了功能性下丘脑闭经（FHA，临床上占女性不育的30%）的猴子模型，在这个模型中，猴子暴露于心理压力（搬到一个新的房间）和适度的代谢压力（卡路里摄入量减少20%，每周5天，每天适度跑步一小时）。与女性一样，一些雌性猴子对压力敏感（SS），当暴露于这种常见的生活压力组合时，月经周期会立即受损，而其他雌性猴子具有中等压力弹性（MSR），在闭经前排卵一次，其他雌性猴子具有高度压力弹性（HSR），并在压力期间排卵。我们有大量证据表明，SS雌性具有较低的CNS血清素能功能和抑制GnRH神经元活动的神经系统的上调，从而使它们对应激诱导的生殖轴抑制更敏感。然而，去甲肾上腺素（NE）在应激反应、LH分泌调节和生殖系统稳态中起着关键作用。此外，血清素抑制脑干蓝斑核（LC）的NE神经元。这意味着SS动物血清素的减少可能导致LC中NE神经元的慢性过度激活，而这些神经元的过度激活与焦虑症有关。因此，值得注意的是，SS猴子也表现出更高水平的行为激动，这是一种非人类灵长类动物焦虑的表现。因此，在当前的提案中，我们将测试LC中NE系统活性升高也部分负责应激敏感猴子生殖轴抑制的假设。目的1将进行初步研究，以确定SS和HSR猴子的NE系统的生理功能，并确定抗焦虑药物瑞波西汀是否能预防应激性生殖功能障碍。目的2将测定应激和无应激情况下SS、MSR和HSR猴子LC中关键基因和蛋白的表达，并检测LC中应激相关传入神经的纤维密度。

DESCRIPTION (provided by applicant): The overall goal of this project is to determine whether the brain stem norepinephrine system plays a role in the mechanisms by which common life stresses (i.e., dieting, moderate exercise and psychological stress) impair activity of the reproductive axis. We have utilized a monkey model of Functional Hypothalamic Amenorrhea (FHA; a clinical condition which accounts for as much as 30% of female infertility), in which monkeys are exposed to psychological stress (moving to a new room) and moderate metabolic stress (a 20% decrease in calorie intake and moderate running for an hour a day, 5 days a week). As occurs in women, some female monkeys are stress-sensitive (SS), and have an immediate impairment of menstrual cycles when exposed to this combination of common life stresses, whereas other female monkeys are medium stress resilient (MSR) ovulate once before amenorrhea and others are highly stress-resilient (HSR) and ovulate during stress. We have substantial evidence that SS females have lower CNS serotonergic function and an up- regulation of neural systems that are inhibitory to GnRH neuronal activity, thereby making them more sensitive to stress-induced suppression of the reproductive axis. However, norepinephrine (NE) plays a pivotal role in the stress response, in the regulation of LH secretion and in the homeostasis of the reproductive system. Moreover, serotonin inhibits the NE neurons of the locus coeruleus (LC) nucleus in the brain stem. This means that the reduction in serotonin in the SS animals may lead to chronic over-activation of NE neurons in the LC, and over-activation of these neurons has been implicated in anxiety disorders. Thus, it is noteworthy that SS monkeys also exhibit higher levels of behavioral agitation, a nonhuman primate manifestation of anxiety. Therefore, in the current proposal we will test the hypothesis that elevated activity of the NE system in the LC is also in part responsible for the suppression of the reproductive axis in stress-sensitive monkeys. Aim 1 will conduct pilot studies to determine the physiological function of the NE system in SS and HSR monkeys and to determine if the antianxiety medication, reboxetine, will prevent stress-induced reproductive dysfunction. Aim 2 will determine the expression of pivotal genes and proteins in the NE neurons of the LC and examine the fiber density of stress-related afferent innervation of the LC in SS, MSR and HSR monkeys in the presence and absence of stress. PUBLIC HEALTH RELEVANCE: We have developed a paradigm that discriminates stress-sensitive from stress-resilient macaques. The goal of this grant is to determine the function of the brain stem noradrenergic system in individuals with different sensitivities in the presence and absence of stress, and to determine if a selective norepinephrine uptake inhibitor can prevent stress-induced reproductive dysfunction. The outcome may suggest a novel treatment for Functional Hypothalamic Amenorrhea.