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: 10399638
• 负责人: Jun Ding
• 金额: $ 50.17万
• 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/10399638
• 关键词: Acute; Anatomy; Animal Model; Animals; Basic Science; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain region; Cell Nucleus; Cells; Cognitive; 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; Light; 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; 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.

项目总结/摘要 我们建议在细胞和回路水平上理解前腹侧的Kiss 1表达神经元是如何 室周下丘脑（AVPV）调节雌性交配行为。腹内侧下丘脑 腹外侧肌（VMHvl）和AVPV已被证明影响多种雌性生殖行为， physiology.我们最近发现，表达孕激素受体（PR）的神经元的突触前末端， VMHvl（Pvl）在整个卵巢周期的AVPV中表现出显著的可塑性。这种光遗传抑制 PV 1神经元投射到AVPV基本上消除了雌性性行为。在初步研究中，我们 发现表达神经肽Kisspeptin（Kiss 1）的AVPV神经元亚群受Pvl支配 Kiss 1 + AVPV（Kavpv）神经元对体内调节雌性性行为很重要。 我们提出的工作是不同于以往的AVPV研究，我们将执行我们的无偏电路 映射、成像和功能研究，专门关注Kavpv神经元。AVPV是异质性的 不仅在分子上，而且在功能上，大脑范围内的连接和不同的行为贡献， AVPV神经元亚型仍知之甚少。此外，与该地区以往的工作相比， 研究将评估Kavpv神经元的连接和功能在不同阶段的女性周期，从而 为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 目的1，我们将在一个无偏的，大脑中映射Kavpv神经元的突触前输入和突触后投射。 广泛的方式和验证突触连接整个发情周期使用电生理学和体内 2-光子成像在目的2中，我们将确定女性在性行为和性行为过程中Kavpv神经元的活动模式。 其他的社会行为。在目标3中，我们将测试急性操作Kavpv是否 神经元是必不可少的，甚至当女性处于荷尔蒙状态，使他们无法接受，足够的 来诱导女性的性行为这两名首席研究员在拟议研究方面的专业知识互补， 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， 由此卵巢激素敏感的下丘脑回路调节女性性和生殖行为。 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 国家在妇女。这些激素如何在特定的水平上调节不同的行为和其他状态， 对神经元和突触的了解很少。此外，转化研究已经确定了不同的神经- 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， 提供了卵巢激素敏感的下丘脑通路如何调节社会互动的新见解， 健康的动物模型，它们有可能在转化工作中提出新的研究途径 集中研究卵巢性激素对疾病状态下神经回路的影响。