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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要我们建议在细胞和电路水平上了解前腹侧表达 Kiss1 的神经元如何下丘脑室周（AVPV）调节雌性交配行为。下丘脑腹内侧腹外侧肌 (VMHvl) 和 AVPV 已被证明会影响多种女性生殖行为生理。我们最近发现，表达孕酮受体（PR）的神经元的突触前末端 VMHvl (Pvl) 在整个卵巢周期的 AVPV 中表现出显着的可塑性。光遗传学抑制 Pvl 神经元向 AVPV 的投射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 Kisspeptin (Kiss1) 的 AVPV 神经元子集受 Pvl 支配 Kiss1+ AVPV (Kavpv) 神经元对于调节女性体内性行为非常重要。我们提出的工作与之前的 AVPV 研究不同，因为我们将执行我们的无偏电路专门关注 Kavpv 神经元的绘图、成像和功能研究。 AVPV 是异质的不仅在分子上，而且在功能上，以及不同的大脑范围的连接和行为贡献 AVPV 神经元亚型仍然知之甚少。此外，与该地区之前的工作相比，我们研究将评估女性周期不同阶段的 Kavpv 神经元连接和功能，从而为了解生理上不同的激素状态如何影响 Kavpv 神经元和行为提供了新的线索。在目标 1，我们将在无偏的脑中绘制 Kavpv 神经元的突触前输入和突触后投射。使用电生理学和体内方法广泛地验证整个发情周期的突触连接 2 光子成像。在目标 2 中，我们将确定女性在性行为和性行为期间 Kavpv 神经元的活动模式。自由活动的动物的其他社会行为。在目标 3 中，我们将测试 Kavpv 是否被急性操纵神经元对于女性来说是必不可少的，即使女性处于荷尔蒙状态，使她们无法接受，也足以诱导女性发生性行为。两位 PI 对于拟议的研究具有互补的专业知识，并且因此，团队非常适合这个项目。总之，如果成功，我们的研究将揭示机制卵巢激素敏感的下丘脑回路调节女性的性行为和生殖行为。健康相关性：众所周知，卵巢性激素可以影响行为、认知和情绪妇女的状态。这些激素如何在特定水平上调节不同的行为和其他状态人们对神经元和突触知之甚少。此外，转化研究还发现了多种神经元受这些激素影响的精神疾病。我们的基础研究计划如果成功的话为卵巢激素敏感的下丘脑通路如何调节社会互动提供新的见解健康的动物模型，它们有潜力为转化工作提出新的研究途径专注于卵巢性激素对疾病状态下神经回路的影响。