Regulation and function of RFRP-3 neurons in the inhibition of mammalian reproduction

压力可以极大地抑制生育和生殖状态，但人们对这种情况在身体和大脑中是如何发生的知之甚少。事实上，尽管压力对生殖的负面影响已经得到了很好的认识，但在压力条件下汇聚在大脑中以抑制生殖的特定信号因素和神经机制仍然没有得到很好的了解。这项提议将使用新的小鼠模型和神经基因图谱来测试心理社会压力如何改变大脑中与控制生育有关的抑制性神经回路。这一提议将极大地扩展我们对应激源如何与大脑中控制生殖的特定部分进行“沟通”的知识。这些信息将极大地推动生殖神经内分泌学领域的发展。此外，鉴于应激抑制对许多动物生殖的共同主题，这项研究最终将对更好地了解多种脊椎动物的大脑和激素功能产生广泛影响。研究部分与一个全面的更广泛的影响计划相辅相成，其中包括培训和指导本科生和博士后学者，包括妇女和代表性不足的少数群体。该提案还包括一个旨在让少数族裔高中生参与科学研究的项目，以及一个新的大脑研究推广项目，以及与当地一所高中的实习合作，学生来自不同的种族和社会经济背景。压力可以抑制生育和生殖状况，但确切地说，这是如何发生的，人们很少了解。生殖是通过从大脑分泌促性腺激素释放激素(GnRH)来模拟的。高度保守的神经肽RFamide相关肽-3(RFRP-3)由RFRP基因编码，通过抑制GnRH的分泌负向调节生殖轴。然而，对RFRP-3神经元的表型、调节或功能必要性知之甚少。作为GnRH的抑制剂，RFRP-3准备将抑制应激信号传递到生殖轴，但这需要测试。这项建议将利用新的转基因RFRP-3小鼠模型(这是此类模型中的第一个)，结合尖端分子工具，从功能上测试RFRP-3神经元在调节应激对生殖状态的负面影响方面的参与和必要性，并识别在应激和非应激条件下激活的新的大脑基因。因此，这项研究将为RFRP-3神经元和其他脑回路在应激时生殖状态调节中的生理调节和功能作用提供新的见解，并将以以前的组织学和药理学方法所不可能的新方式经验性地探索RFRP-3的调节和功能。

Stress can drastically inhibit fertility and reproductive status, but how this happens in the body and brain is poorly understood. Indeed, although the negative effects of stress on reproduction are well appreciated, the specific signaling factors and neural mechanisms that converge in the brain to inhibit reproduction under stressful conditions remain poorly defined. This proposal will use novel mouse models and neural gene profiling to test how psychosocial stress alters inhibitory neural circuits in the brain in relation to controlling fertility. This proposal will substantially expand our knowledge of how stressors "communicate" with specific parts of the brain that control reproduction. This information will significantly advance the field of reproductive neuroendocrinology. Moreover, given the common theme of stress inhibition on reproduction in many animals, this research will ultimately have broad impact for better understanding brain and hormone functioning of multiple vertebrate species. The research component is complemented and integrated with a comprehensive broader impact plan which includes training and mentoring undergraduate students and post-doctoral scholars, including women and under-represented minorities. The proposal also includes a program aimed at engaging under-represented minority high school students in science research, as well as a new brain research outreach program and internship collaboration with a local high school with students from diverse ethnic and socioeconomic backgrounds.Stress can inhibit fertility and reproductive status, but exactly how this occurs mechanistically is poorly understood. Reproduction is simulated by gonadotropin-releasing hormone (GnRH) secretion from the brain. The highly-conserved neuropeptide RFamide-related peptide-3 (RFRP-3), encoded by the Rfrp gene, negatively regulates the reproductive axis by inhibiting GnRH secretion. However, very little is known about the phenotype, regulation, or functional necessity of RFRP-3 neurons. As an inhibitor of GnRH, RFRP-3 is poised to relay inhibitory stress signals to the reproductive axis, but this requires testing. This proposal will utilize new transgenic RFRP-3 mouse models (the first of their kind), coupled with cutting-edge molecular tools, to functionally test the involvement and necessity of RFRP-3 neurons in mediating the negative effects of stress on reproductive status, as well as identify novel brain genes that are activated under stressful and non-stressful conditions. This study will therefore provide fresh insight into the physiological regulation and functional roles of RFRP-3 neurons and other brain circuitry in the modulation of reproductive status during stress, and will empirically probe RFRP-3 regulation and function in new ways that have not been possible with former histological and pharmacological methods.