Supplement : Contribution of Kisspeptin and Neurokinin B in the Medial Amygdala to Female Reproductive Function

补充：内侧杏仁核中的 Kisspeptin 和 Neurokinin B 对女性生殖功能的贡献

• 批准号: 10392737
• 负责人: Elizabeth McCarthy
• 金额: $ 3.52万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392737
• 关键词: Address; Agonist; Amygdaloid structure; Area; Brain; Brain region; Cell Nucleus; Collaborations; Communication; Cues; Data; Dependovirus; Development; Dynorphin A; Emotions; Estrous Cycle; Feedback; Fellowship; Female; Fertility; Genes; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Grant; Hormonal; Hormone secretion; Hormones; Human; Hypothalamic structure; Impairment; Infertility; Injections; Interneurons; KISS1 gene; Klinefelter' s Syndrome; Knowledge; Lead; Link; Luteinizing Hormone; Maps; Medial; Mentors; Mus; Mutation; Neuroendocrinology; Neurokinin B; Neuromedin K Receptor; Neurons; Neuropeptides; Neurosecretory Systems; Pathway interactions; Pheromone; Physiologic pulse; Play; Population; Puberty; Rattus; Regulation; Reproduction; Reproductive Behavior; Research Personnel; Ribosomes; Role; Sensory; Sex Behavior; Source; Structure of nucleus infundibularis hypothalami; Toxin; Training; Transgenic Mice; Transgenic Organisms; Work; emotion regulation; experience; experimental study; female fertility; hormone regulation; neural network; novel strategies; novel therapeutics; receptor; relating to nervous system; reproductive; reproductive axis; reproductive function; reproductive system disorder; skills; social; training opportunity

ABSTRACT: Kisspeptin (encoded by the Kiss1 gene) and neurokinin B (NKB; encoded by the Tac2 gene) are critical regulators of the female reproductive axis. Inactivating mutations to NKB and its receptor, NK3R or to Kiss1 and its receptor Kiss1R lead to infertility in both humans and mice. There are two major populations of Kiss1 neurons located in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) that directly contact gonadotrophin-releasing hormone (GnRH) neurons and control the negative and positive feedback of sex steroids necessary for reproductive function. In the ARC, Kiss1 neurons co-express both NKB, which stimulates kisspeptin release, and dynorphin A, which inhibits kisspeptin release, in a population of neurons called KNDy neurons. The medial amygdala (MeA), which is involved in emotion and pheromone processing, also contains a population of Kiss1 and NK3R expressing neurons; however, the functional role in the central control of reproduction of these neuron populations in the MeA remains ill-defined. Preliminary experiments from our lab found that injection of senktide, a specific agonist of NK3R, into the area of the MeA where the NK3R neurons are located induces LH release in mice. In Specific Aim 1, a combination of transgenic Kiss1 mice and adeno- associated virus (AAV) injections targeted specifically to Kiss1 neurons in the MeA will be used to manipulate Kiss1 neuron function to determine their role in luteinizing hormone (LH) secretion (which closely mirrors pulses of GnRH), fertility and reproductive behavior. In Specific Aim 2, neurons expressing NK3R in the MeA will be specifically ablated using the ribosomal inactivating toxin saporin conjugated to an agonist for NK3R to determine the role of these MeA neurons in reproductive function. The MeA is a highly interconnected brain region that sends afferent projections to and receives efferent projections from multiple brain areas involved in the regulation of reproduction but the neuronal projections between Kiss1 and Tac2 expressing neurons in this region are unknown. Additionally, while Tac2 is expressed in many brain areas, including the centromedial amygdala (CeM) and the ARC, the source of NKB acting in the MeA through NK3R remains to be identified. In Specific Aim 3, a combination of anterograde and retrograde AAV injections in either Kiss1-Cre or Tac2-Cre transgenic mice will map the neural projections between the MeA and regions that regulate the release of Kisspeptin and GnRH, and regions involved in reproductive behavior and pheromone processing. These results will begin to define the role of MeA Kiss1 and NK3R expressing neurons in the regulation of reproductive function compared to populations of these neurons in other brain regions. Understanding the role of the MeA in the integration of emotions and bonding with reproduction is critical to understanding sexual behavior in many species, including humans, and could aid in the development of new approaches to treat central reproductive disorders.

抽象的： Kisspeptin（由Kiss1基因编码）和Neurokinin B（NKB；由TAC2基因编码）很关键 女性生殖轴的调节剂。向NKB及其受体NK3R或KISS1灭活突变 它的受体亲吻1R导致人类和小鼠的不孕症。 KISS1神经元有两个主要人群 位于弧形核（ARC）和前腹室核（AVPV）中 促性腺营养蛋白释放激素（GNRH）神经元并控制性别的负反馈 生殖功能所需的类固醇。在ARC中，KISS1神经元共表达两个NKB，它刺激了 在一个名为KNDY的神经元中，Kisspeptin释放和抑制Kisspeptin释放的Dynorphin A 神经元。与情感和信息素处理有关的内侧杏仁核（MEA）也包含一个 KISS1和NK3R表达神经元的种群；但是，在中央控制中的功能作用 在MEA中这些神经元种群的再现仍然不明确。我们实验室的初步实验 发现注射NK3R的特定激动剂Senktide进入NK3R神经元的MEA区域 位于小鼠中诱导LH释放。在特定的目标1中，转基因Kiss1小鼠和腺 专门针对MEA中KISS1神经元的相关病毒（AAV）将用于操纵 KISS1神经元的功能，以确定其在黄体生成激素（LH）分泌中的作用（密切反映了脉冲 GnRH），生育和生殖行为。在特定的目标2中，在MEA中表达NK3R的神经元将是 使用核糖体灭活毒素糖蛋白与NK3R的激动剂相结合以确定 这些MEA神经元在生殖功能中的作用。 MEA是一个高度相互联系的大脑区域 将传入的预测发送给并接收来自该法规的多个大脑区域的传出预测 繁殖，但在该地区表达神经元的KISS1和TAC2之间的神经元投影是 未知。此外，虽然TAC2在许多大脑区域表达，包括centromedial杏仁核（CEM） 弧线，通过NK3R在MEA中作用的NKB的来源仍有待鉴定。在特定的目标3中 在KISS1-CRE或TAC2-CRE转基因小鼠中的顺行和逆行AAV注射的组合将 绘制MEA和调节吻肽和GNRH释放的区域之间的神经投影，以及 涉及生殖行为和信息素处理的区域。这些结果将开始定义角色 与种群相比 在其他大脑区域中的这些神经元。了解MEA在情绪整合中的作用 与繁殖结合对于了解许多物种（包括人类）的性行为至关重要 可以帮助发展新方法来治疗中央生殖障碍。