Norepinephrine in Stress-Induced Amenorrhea of Macaques

描述（由申请人提供）：本项目的总体目标是确定脑干去甲肾上腺素系统是否在共同生活压力（即，节食、适度运动和心理压力）损害生殖轴的活动。我们利用了一种功能性下丘脑闭经（FHA;一种临床病症，占女性不孕症的30%）的猴模型，其中猴暴露于心理压力（搬到新房间）和中度代谢压力（卡路里摄入量减少20%，每周5天，每天适度跑步1小时）。与女性一样，一些雌性猴子对压力敏感（SS），当暴露于这种常见生活压力的组合时，月经周期会立即受损，而其他雌性猴子则具有中等压力弹性（MSR），在停经前排卵一次，而其他雌性猴子则具有高压力弹性（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促性腺激素能功能和对GnRH神经元活性具有抑制作用的神经系统的上调，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分泌的调节和生殖系统的稳态中起着关键作用。此外，5-羟色胺抑制脑干蓝斑核（LC）的NE神经元。这意味着SS动物中血清素的减少可能导致LC中NE神经元的慢性过度激活，并且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的焦虑表现。因此，在目前的建议，我们将测试的假设，NE系统在LC的活性升高，也是部分负责的压力敏感的猴子的生殖轴的抑制。目的1将进行试点研究，以确定在SS和HSR猴NE系统的生理功能，并确定是否抗焦虑药物，reboxelide，将防止应激诱导的生殖功能障碍。目的2：研究应激状态下，SS、MSR和HSR猴LC NE神经元中关键基因和蛋白的表达，以及应激相关传入神经纤维密度的变化。 公共卫生相关性：我们已经开发出一种范式，区分压力敏感和压力适应性猕猴。这项资助的目的是确定脑干去甲肾上腺素能系统在存在和不存在压力的情况下具有不同敏感性的个体中的功能，并确定选择性去甲肾上腺素摄取抑制剂是否可以预防压力引起的生殖功能障碍。该结果可能为功能性下丘脑性闭经提供一种新的治疗方法。

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.