Neural Basis of Stress-Derailed Motherhood

项目总结 成为母亲往往与喜悦的独特感觉、宁静和个人成就感联系在一起。一个 然而，大量的孕妇和产后妇女无法达到这些阳性状态，因为 他们与高水平的生活压力作斗争。高度的怀孕压力会降低女性以后敏感地 对婴儿的照顾，在非常严重的情况下会导致对婴儿的忽视和虐待。此外，还提升了 怀孕期间的压力是最可靠和最强烈的预测母亲抑郁和 焦虑，在美国每年400万怀孕和新近分娩的妇女中，有10%-15%受到焦虑的困扰。 关于应激导致疾病的具体神经机制，人们缺乏了解。 母亲抑郁、焦虑，以及糟糕的婴儿照顾能力。如果没有这样的知识，几乎不可能 知道如何最好地干预或治疗处于最高风险的女性。这条基本路线的长期目标是 研究是为了更好地了解怀孕期间的压力是如何通过影响产后行为而脱轨的 应激信号神经肽、促肾上腺皮质激素释放因子(CRF)与 神经递质，5-羟色胺(5-HT)。该R21探索性/开发项目的目标是使用 作为母亲的实验室大鼠模型开始测试雌性生殖产生的假说 中脑中缝背核CRF受体的正常变化(即大多数前脑5- 这些变化会因怀孕压力而偏离轨道。我进一步假设规范性的 糖尿病视网膜病变中CRF受体的生殖变化保护母亲免受负面后果的影响 对他们的情感和照顾行为的压力。拟议的多方法研究采用了各种 回答我们问题的工具(qRT-PCR、受体放射自显影、双标记原位杂交、切片 电生理学、病毒载体介导的基因上调/下调、详细的行为分析)，并具有创新性 因为这是第一个研究有压力和无压力的女性生殖是如何影响CRF受体位置的-- 特别是在5-羟色胺能的背侧中缝，以及更广泛地提供关于 潜在的神经化学压力对女性大脑和行为的影响。这项重要的基础研究是 非常有意义，因为我们的结果有可能改进干预和治疗的策略 每年都有数以百万计的妇女及其婴儿受到妊娠压力的负面影响。

PROJECT SUMMARY Becoming a mother is often associated with a unique sense of joy, serenity, and personal fulfillment. A tremendous number of pregnant and postpartum women cannot reach these positive states, though, because they struggle with high levels of life stress. High pregnancy stress degrades women’s later ability to sensitively care for their infants, and in very severe cases contributes to infant neglect and abuse. In addition, elevated stress during pregnancy is one of the most reliable and strongest predictors of maternal depression and anxiety, which afflict 10-15% of the four million pregnant and recently parturient women in the U.S. each year. There is a dearth of knowledge about the specific neural mechanisms through which stress contributes to maternal depression, anxiety, and poor infant caregiving. Without such knowledge, it is virtually impossible to know how to best intervene or treat women who are at the highest risk. The long-term goal of this line of basic research is to better understand how stress during pregnancy derails postpartum behavior by affecting interactions between the stress-signaling neuropeptide, corticotropin releasing factor (CRF), and the neurotransmitter, serotonin (5-HT). The objective of this R21 exploratory/developmental project is to use a laboratory rat model of motherhood to begin testing the hypothesis that female reproduction generates normative changes in CRF receptors in the midbrain dorsal raphe nucleus (i.e., the source of most forebrain 5- HT), and that these changes are derailed by pregnancy stress. I further hypothesize that the normative changes across reproduction in CRF receptors in the DR protect mothers against the negative consequences of stress on their affective and caregiving behaviors. The proposed multi-method research employs a variety of tools to answer our questions (qRT-PCR, receptor autoradiography, dual-label in situ hybridization, slice electrophysiology, viral vector-mediated gene up/downregulation, detailed behavior analysis) and is innovative because it the first to study how stressed and unstressed female reproduction affect CRF receptors site- specifically in the serotonergic dorsal raphe, and more broadly to provide critical information about the neurochemistry underlying stress’ impact on the female brain and behavior. This important basic research is highly significant because our results have the potential to improve strategies for intervention and treatment of the millions of women and their infants negatively affected by pregnancy stress each year.