Connectivity, activity, and function of a hypothalamic pathway in female social behaviors

女性社会行为中下丘脑通路的连接性、活动和功能

• 批准号: 10570861
• 负责人: Jun Ding
• 金额: $ 50.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570861
• 关键词: Acute; Anatomy; Animal Model; Animals; Basic Science; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain region; Cell Nucleus; Cells; Cognitive; Communication; Data; Disease; Electrophysiology (science); Emotions; Estrous Cycle; Estrus; Event; Exhibits; Female; Fiber; Fluorescence; Functional disorder; Genetic; Goals; Gonadal Steroid Hormones; Halorhodopsins; Health; Heart; Hormonal; Hormones; Hypothalamic structure; Image; Intervention; KISS1 gene; Knock-in; Maps; Mental disorders; Molecular; Monitor; Mus; Nerve Degeneration; Neural Pathways; Neurobiology; Neurons; Neuropeptides; Neurosciences; Output; Ovarian; Ovarian Cycles; Ovarian hormone; Partner in relationship; Pathway interactions; Pattern; Performance; Phase; Photometry; Photons; Physiological; Physiology; Progesterone Receptors; Rabies; Reagent; Regulation; Reporter; Reproductive Behavior; Reproductive Physiology; Research; Research Proposals; Sex Behavior; Slice; Social Behavior; Social Interaction; Specificity; Synapses; Testing; Translational Research; Ventricular; Viral; Woman; Work; behavior influence; experimental study; in vivo; in vivo imaging; innovation; insight; male; mating behavior; neural circuit; neuropsychiatric disorder; neuropsychiatry; neuroregulation; novel; optogenetics; postsynaptic; postsynaptic neurons; presynaptic; reproductive; reproductive function; sex; sexual dimorphism; two-photon

Project Summary/Abstract We propose to understand at cellular and circuit levels how Kiss1-expressing neurons in the anteroventral periventricular hypothalamus (AVPV) regulate female mating behavior. The ventromedial hypothalamus ventrolateralis (VMHvl) and AVPV have been shown to influence diverse female reproductive behaviors and physiology. We recently showed that presynaptic termini of progesterone receptor (PR)-expressing neurons of the VMHvl (Pvl) exhibit significant plasticity in the AVPV across the ovarian cycle. Optogenetic inhibition of this projection of Pvl neurons to the AVPV essentially eliminates female sexual behavior. In preliminary studies, we find that the subset of AVPV neurons expressing the neuropeptide Kisspeptin (Kiss1) are innervated by Pvl neurons, and that Kiss1+ AVPV (Kavpv) neurons are important for regulating female sexual behavior in vivo. Our proposed work is distinct from previous AVPV studies in that we will perform our unbiased circuit mapping, imaging, and functional studies focusing exclusively on Kavpv neurons. The AVPV is heterogeneous not only molecularly but also functionally, and brain-wide connections and behavioral contributions of distinct AVPV neuronal subtypes remain poorly understood. Moreover, and in contrast to prior work in this region, our studies will assess Kavpv neuronal connectivity and function across distinct phases of the female cycle, thereby shedding new light into how physiologically distinct hormonal states influence Kavpv neurons and behavior. In Aim 1, we will map the presynaptic inputs and postsynaptic projections of Kavpv neurons in an unbiased, brain- wide manner and validate the synaptic connectivity across the estrus cycle using electrophysiology and in vivo 2-photon imaging. In Aim 2, we will determine the activity patterns of Kavpv neurons in female during sexual and other social behaviors in freely moving animals. In Aim 3, we will test whether acute manipulation of Kavpv neurons is essential for and, even when females are in a hormonal state that renders them unreceptive, sufficient to induce female sexual behavior. The two PIs have complementary expertise for the proposed studies, and the team is therefore well suited for this project. In summary, if successful our studies will uncover mechanisms whereby an ovarian hormone sensitive hypothalamic circuit regulates female sexual and reproductive behaviors. Health Relatedness: It is well known that ovarian sex hormones can influence behavioral, cognitive, and emotive states in women. How these hormones regulate distinct behaviors and other states at the level of specific neurons and synapses is poorly understood. In addition, translational research has identified diverse neuro- psychiatric illnesses that are influenced by these hormones. Our basic research proposal, if successful, will provide new insights into how ovarian hormone sensitive hypothalamic pathways regulate social interactions in healthy animal models, and they have the potential to suggest new research avenues in translational work focused on ovarian sex hormone influenced neural circuits in disease states.

项目摘要/摘要 我们建议在细胞和电路水平上了解如何表达亲吻的神经元在前腹膜中 脑室下丘脑（AVPV）调节女性交配行为。腹侧下丘脑 腹侧（VMHVL）和AVPV已显示出影响多样化的女性生殖行为和 生理。我们最近表明，孕酮受体（PR）表达神经元的突触前末端 VMHVL（PVL）在整个卵巢周期中表现出AVPV的显着可塑性。对此的光学抑制作用 PVL神经元对AVPV的投影基本上消除了女性的性行为。在初步研究中，我们 发现表达神经肽亲吻蛋白（KISS1）的AVPV神经元的子集由PVL支配 神经元，而KISS1+ AVPV（KAVPV）神经元对于调节体内女性性行为很重要。 我们提出的工作与以前的AVPV研究不同，因为我们将执行公正的电路 仅关注KAVPV神经元的映射，成像和功能研究。 AVPV是异质的 不仅是分子的，而且在功能上，以及大脑范围的连接和行为贡献 AVPV神经元亚型的理解还不足。而且，与该地区的先前工作形成鲜明对比的是我们的 研究将评估女性周期不同阶段的KAVPV神经元连接性和功能 向生理上不同的激素状态如何影响KAVPV神经元和行为的新光线。在 AIM 1，我们将在无偏见的大脑中绘制KAVPV神经元的突触前输入和突触后投影 用电生理学和体内验证整个发情循环的突触连通性 2光子成像。在AIM 2中，我们将确定性和性期间女性KAVPV神经元的活动模式 自由移动动物的其他社会行为。在AIM 3中，我们将测试是否急性操纵KAVPV 神经元对于雌性处于荷尔蒙状态，使其不可能使其无能为力，足够 诱导女性性行为。这两个PI具有拟议研究的互补专业知识， 因此，团队非常适合该项目。总而言之，如果成功，我们的研究将发现机制 卵巢激素灵敏的下丘脑回路可调节女性性行为和生殖行为。 健康相关性：众所周知，卵巢性激素会影响行为，认知和情感 妇女的国家。这些激素如何调节特定水平的不同行为和其他状态 神经元和突触知之甚少。此外，转化研究已经确定了各种神经 受这些激素影响的精神病。如果成功的话，我们的基础研究建议将 提供有关卵巢激素敏感下丘脑途径如何调节社会互动的新见解 健康的动物模型，他们有可能提出转化工作中的新研究途径 专注于卵巢性激素影响疾病状态的神经回路。