EAGER: Estrogen Receptors and Neural Stress Circuitry

应激性事件会导致身体功能和行为的短期和长期变化，从而抑制那些对即刻生存不重要的东西，促进那些对即刻生存至关重要的东西。压力应对是一种重要的适应机制，使有机体能够迅速适应威胁生存的具有挑战性的环境。应激影响生物体的各种器官，特别是大脑，影响与动态平衡、认知、免疫功能、生殖和战斗或逃跑行为反应相关的过程。有趣的是，人们观察到了应激反应的性别差异，女性通常比男性对应激源表现出更高的反应性。此外，研究还表明，雌激素促进应激反应，而雄激素则抑制应激反应。对于这个项目来说，重要的是来自PI实验室的最新发现，即雌激素对压力和焦虑的影响是由大脑中表达的雌激素受体β蛋白(ER-β)介导的。工作假设是，ER-β在不同大脑区域的激活对于调节应激反应至关重要，然后影响整个身体的应激循环。这个急切的项目将创造一个独特的模型，在这个模型中，可以在特定的细胞类型和/或在选定的时间在大脑的目标区域操纵ER-β蛋白，同时仍然允许这种关键信号蛋白在其他组织中表达。这个模型系统将被用来研究ER-β在产生性别差异的应激反应中的作用，不仅在大脑中，而且还将在一般生理和行为水平上更好地了解压力如何影响有机体。这些发现不仅将影响对压力的神经内分泌调节的理解，还将影响发育生物学、生殖生物学、认知神经科学和性别差异进化的领域。该项目将使用全面的方法和独特的模型系统，在将分子技术与生理学相结合的混合领域为学生和研究员提供培训经验。目标是让受训人员参与科学研究的所有方面，包括分子生物学和基因组学方面的先进技术方法、数据解释和分析、研究伦理、在国家会议上介绍数据以及发表他们的研究结果。

Stressful events cause short- and long-term changes in body functions and behavior to suppress those that are not critical for immediate survival and promote those that are. Stress coping is an important adaptive mechanism in allowing the organism to quickly adapt to challenging circumstances that threaten survival. Stress influences various organs of organisms, including especially the brain, to affect processes related to homeostasis, cognition, immune function, reproduction, and fight-or-flight behavioral responses. Interestingly, sex differences in stress reactivity have been observed, with females usually exhibiting higher reactivity to a stressor than males. Furthermore, it has also been demonstrated that estrogens enhance stress reactivity while androgens inhibit it. Important to this project are recent findings from the PI's laboratory that estrogen effects on stress and anxiety are mediated by the protein estrogen receptor beta (ER-beta) expressed in the brain. The working hypothesis is that activation of ER-beta within distinct brain regions is critical for modulation of stress-reactivity, which then impacts the stress circuitry throughout the body. This EAGER project will create a unique model in which the protein ER-beta can be manipulated in a specific cell type and/or at a chosen time in targeted regions of the brain while still allowing the expression of this key signaling protein in other tissues. This model system will be utilized to study the role of ER-beta in producing sex differences in stress reactivity not only in the brain, but also to better understand how stress affects the organism at the general physiological and behavioral levels. The findings will impact not only understanding of the neuroendocrine regulation of stress, but also the areas of developmental biology, reproductive biology, cognitive neuroscience, and the evolution of sex differences. The project will provide training experience for students and fellows in a hybrid area that integrates molecular techniques with physiology using a comprehensive approach and unique model systems. The goal is to involve the trainees in all aspects of scientific research including advanced technical approaches in molecular biology and genomics, data interpretation and analysis, research ethics, presentation of data at national meetings, and publication of their findings.