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

RFRP-3神经元在抑制哺乳动物生殖中的调节和功能

• 批准号: 1457226
• 负责人: Alexander Kauffman
• 金额: $ 76.09万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1457226&HistoricalAwards=false
• 关键词: Regulation; function; RFRP; neurons; inhibition

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.

压力可以极大地抑制生育能力和生殖状态，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，虽然压力对生殖的负面影响是很好的理解，特定的信号因素和神经机制，在大脑中收敛，以抑制在压力条件下的生殖仍然定义不清。该提案将使用新的小鼠模型和神经基因分析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。这一提议将大大扩展我们对压力源如何与控制生殖的大脑特定部位“交流”的知识。这些信息将大大推进生殖神经内分泌学领域。此外，考虑到许多动物的生殖压力抑制的共同主题，这项研究最终将对更好地了解多种脊椎动物物种的大脑和激素功能产生广泛的影响。研究部分得到了一个全面的、更广泛的影响计划的补充和整合，该计划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民族。该提案还包括一项旨在让代表性不足的少数族裔高中生参与科学研究的计划，以及一项新的大脑研究外展计划，以及与当地一所高中与来自不同种族和社会经济背景的学生进行实习合作。压力可以抑制生育能力和生殖状况，但这种情况到底是如何发生的机制尚不清楚。生殖是由大脑分泌促性腺激素释放激素（GnRH）来模拟的。由Rfrp基因编码的高度保守的神经肽RFamide相关肽-3（RFRP-3）通过抑制GnRH分泌来负调节生殖轴。然而，关于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准备将抑制性应激信号传递到生殖轴，但这需要测试。该提案将利用新的转基因RFRP-3小鼠模型（此类动物中的第一个），再加上尖端的分子工具，功能性地测试RFRP-3神经元在介导压力对生殖状态的负面影响中的参与和必要性，以及识别在压力和非压力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期间调节生殖状态中的生理调节和功能作用提供新的见解，并将以新的方式经验性地探索RFRP-3的调节和功能，这些方式是以前不可能的组织学和药理学方法。

项目成果

Acute Psychosocial Stress Inhibits LH Pulsatility and Kiss1 Neuronal Activation in Female Mice

急性心理社会压力抑制雌性小鼠 LH 搏动和 Kiss1 神经元激活

• DOI: 10.1210/en.2017-00301
• 发表时间: 2017
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Yang, Jennifer A;Song, Christopher I;Hughes, Jessica K;Kreisman, Michael J;Parra, Ruby A;Haisenleder, Daniel J;Kauffman, Alexander S;Breen, Kellie M
• 通讯作者: Breen, Kellie M

Estrogen Stimulation of Kiss1 Expression in the Medial Amygdala Involves Estrogen Receptor-α But Not Estrogen Receptor-β

雌激素对内侧杏仁核 Kiss1 表达的刺激涉及雌激素受体-α，但不涉及雌激素受体-β

• DOI: 10.1210/en.2016-1431
• 发表时间: 2016
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Stephens, Shannon B.;Chahal, Navdeep;Munaganuru, Nagambika;Parra, Ruby A.;Kauffman, Alexander S.
• 通讯作者: Kauffman, Alexander S.

Corticosterone Blocks Ovarian Cyclicity and the LH Surge via Decreased Kisspeptin Neuron Activation in Female Mice

• DOI: 10.1210/en.2015-1711
• 发表时间: 2016-03-01
• 期刊: ENDOCRINOLOGY
• 影响因子: 4.8
• 作者: Luo, Elena;Stephens, Shannon B. Z.;Breen, Kellie M.
• 通讯作者: Breen, Kellie M.