Norepinephrine in Stress-Induced Amenorrhea of Macaques

描述(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常见生活压力(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。我们使用了一个功能性下丘脑闭经(FHA；一种临床情况，占女性不孕症的30%)的猴子模型，在该模型中，猴子面临心理压力(搬到新房间)和中等代谢压力(卡路里摄入量减少20%，一周5天每天适度跑步一小时)。与女性一样，一些雌性猴子对应激敏感(SS)，当暴露在这种常见生活压力的组合中时，会立即损害月经周期，而其他雌性猴子在闭经前排卵一次，而其他雌性猴子则高度应激弹性(HSR)并在应激期间排卵。我们有大量证据表明，SS女性具有较低的CNS 5-羟色胺能功能和对GnRH神经元活动有抑制的神经系统上调，从而使她们对应激诱导的生殖轴抑制更加敏感。然而，去甲肾上腺素(NE)在应激反应、调节黄体生成素分泌和生殖系统的动态平衡中起着关键作用。此外，5-羟色胺还抑制脑干蓝斑(LC)核的去甲肾上腺素神经元。这意味着SS动物体内5-羟色胺的减少可能导致LC中NE神经元的慢性过度激活，而这些神经元的过度激活可能与焦虑障碍有关。因此，值得注意的是，SS猴子也表现出更高水平的行为激动，这是一种非人类的灵长类焦虑表现。因此，在目前的提案中，我们将检验LC中NE系统活性升高也是应激敏感猴子生殖轴受到抑制的部分原因的假设。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可以防止应激导致的生殖功能障碍。目的2测定SS、MSR和HSR猴LC区NE神经元中关键基因和蛋白的表达，以及在有无应激的情况下，SS、MSR和HSR猴LC区应激相关传入神经的纤维密度。 与公共健康相关：我们开发了一种区分压力敏感型和压力恢复型猕猴的范式。这项资助的目的是确定在有和没有压力时不同敏感度的人的脑干去甲肾上腺素系统的功能，并确定选择性去甲肾上腺素摄取抑制剂是否可以防止压力导致的生殖功能障碍。这一结果可能为功能性下丘脑闭经提供了一种新的治疗方法。

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.