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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）和神经激肽 B（NKB；由 Tac2 基因编码）至关重要女性生殖轴的调节者。 NKB 及其受体 NK3R 或 Kiss1 和 Kiss1 的失活突变其受体 Kiss1R 会导致人类和小鼠不育。 Kiss1 神经元有两个主要群体位于弓状核（ARC）和前腹室周围核（AVPV）直接接触促性腺激素释放激素（GnRH）神经元控制性的负反馈和正反馈生殖功能所需的类固醇。在 ARC 中，Kiss1 神经元共同表达 NKB，这会刺激在称为 KNDy 的神经元群中，Kisspeptin 释放，以及抑制 Kisspeptin 释放的强啡肽 A 神经元。内侧杏仁核 (MeA) 参与情绪和信息素处理，还包含一个表达 Kiss1 和 NK3R 的神经元群；然而，在中央控制中的职能作用这些神经元群在 MeA 中的繁殖仍然不明确。我们实验室的初步实验发现将 NK3R 的特异性激动剂 Senktide 注射到 NK3R 神经元所在的 MeA 区域位于诱导小鼠体内 LH 释放的位置。在特定目标 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）注射将用于操纵 Kiss1 神经元的功能是确定其在黄体生成素 (LH) 分泌中的作用（这与脉冲密切相关） GnRH）、生育力和生殖行为。在具体目标 2 中，MeA 中表达 NK3R 的神经元将被使用与 NK3R 激动剂缀合的核糖体灭活毒素皂草素进行特异性消融，以确定这些 MeA 神经元在生殖功能中的作用。 MeA 是一个高度互连的大脑区域向参与调节的多个大脑区域发送传入投射并接收传出投射但该区域表达 Kiss1 和 Tac2 的神经元之间的神经元投射是未知。此外，虽然 Tac2 在许多大脑区域表达，包括中央杏仁核 (CeM) 和 ARC，NKB 通过 NK3R 在 MeA 中发挥作用的来源仍有待确定。在具体目标 3 中， Kiss1-Cre 或 Tac2-Cre 转基因小鼠中顺行和逆行 AAV 注射的组合将绘制 MeA 与调节 Kisspeptin 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群体相比，表达 MeA Kiss1 和 NK3R 的神经元在生殖功能调节中的作用其他大脑区域的这些神经元。了解 MeA 在整合情绪和情绪方面的作用与繁殖的联系对于理解包括人类在内的许多物种的性行为至关重要，并且可能有助于开发治疗中枢生殖疾病的新方法。