EFFECTS OF COMMON LIFE STRESSES ON FERTILITY

该项目更新的总体目标是确定共同生活压力（即， 节食、适度运动和心理压力）损害生殖轴的活动和生育能力。 雌性食蟹猴和女性一样，一年中有28天的月经周期， 个体对应激反应的差异，应激敏感的动物迅速发展为应激诱导的 生殖功能障碍，中等压力弹性动物发展压力诱导的生殖功能障碍 功能障碍后，持续的压力暴露，和高压力弹性的动物保持正常 在整个压力暴露期间的月经周期。有趣的是，所有的猴子都表现出明显的 压力下的生育能力这些研究中使用的压力是根据女性记录的压力模式进行的 下丘脑性闭经，他们通常会经历增加的心理社会压力， 轻度代谢应激（由节食和运动引起）。猴子暴露在温和的 心理社会压力（将猴子转移到新的房间）+适度饮食（卡路里减少20%） 摄入量）+适度运动（每周5天，以中等速度跑步1小时）。我们确定了几 与压力敏感性相关的稳定特征：卵泡期雌二醇分泌较低，黄体期 孕激素分泌期，心率加快，焦虑行为增加，大脑活动降低 5-羟色胺系统，并增加下丘脑GABA能神经元的基因表达。我们的研究结果 这表明，共同的生活压力有更显着的影响，循环水平的生殖 激素和生育能力比以前认识到的，特别是在压力敏感的个人。具体 本更新的目的是：（1）确定是否通过慢性治疗增加脑5-羟色胺水平 5-羟色胺再摄取抑制剂（SSRI;一种常见的抗焦虑药物）将提高压力恢复能力，（2） 确定压力敏感个体与压力弹性个体的神经回路的进一步差异，以及（3） 确定压力暴露是否在卵巢水平对卵母细胞活力产生负面影响， 胚胎发育和卵巢细胞类固醇生成能力。建议的研究将进一步促进我们的 了解常见的生活压力如何影响生殖功能，长期目标是 开发新的治疗方法，使压力敏感的人更具压力弹性。

The overall goal of this project renewal is to determine the mechanisms by which common life stresses (i.e., dieting, moderate exercise and psychological stress) impair activity of the reproductive axis and fertility. Female cynomolgus monkeys, which like women have 28-day menstrual cycles throughout the year, show individual differences in responsiveness to stress, with stress-sensitive animals rapidly developing stressinduced reproductive dysfunction, medium stress-resilient animals developing stress-induced reproductive dysfunction after sustained stress exposure, and highly stress-resilient animals maintaining normal menstrual cyclicity throughout stress exposure. Interestingly, all monkeys show a significant impairment of fertility with stress exposure. The stress used for these studies is patterned after that documented in women with Hypothalamic Amenorrhea, who generally experience increased psychosocial stress combined with a mild metabolic stress (resulting from dieting and exercise). Monkeys are exposed to a combination of mild psychosocial stress (moving monkeys to a new housing room) + a moderate diet (20% decrease in calorie intake) + moderate exercise (running at a moderate pace for 1 hour, 5 days a week). We identified several stable characteristics associated with stress-sensitivity: lower follicular phase estradiol secretion, lower luteal phase progesterone secretion, higher heart rate, increased anxious behavior, lower activity of the brain serotonin system, and increased gene expression in hypothalamic GABAergic neurons. Our findings suggest that common life stresses have a more significant impact on both circulating levels of reproductive hormones and fertility than previously appreciated, particularly in stress-sensitive individuals. The specific aims of this renewal are: (1) to determine whether increasing brain serotonin levels by chronic treatment with a serotonin reuptake inhibitor (SSRI; a common anti-anxiety medication) will improve stress resilience, (2) identify further differences in neural circuits in stress-sensitive versus stress-resilient individuals, and (3) determine whether stress exposure has a negative impact at the level of the ovary on oocyte viability, early embryo development and ovarian cell steroidogenic capacity. The proposed studies will further our understanding of how common life stresses impact reproductive function, with the long-term goal of developing new treatments to make stress-sensitive individuals more stress resilient.