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

项目摘要/摘要 我们建议在细胞和电路水平上了解Kiss1在前腹侧神经元中的表达 脑室周围下丘脑(AVPV)调节雌性交配行为。下丘脑腹内侧 腹侧核(VMHvl)和动静脉曲张病毒(AVPV)已被证明影响各种女性生殖行为和 生理学。我们最近发现，表达孕激素受体(PR)的神经元的突触前终末。 在整个卵巢周期中，VMHvl(PVL)在AVPV中表现出显著的可塑性。光遗传学对此的抑制 PVL神经元投射到AVPV实质上消除了女性的性行为。在初步研究中，我们 发现PVL对表达神经肽Kispeptin(Kiss1)的AVPV神经元亚群起支配作用 Kiss1Avpv(Kavpv)神经元在体内对调节女性性行为是重要的。 我们提议的工作不同于以前的AVPV研究，因为我们将执行我们的无偏电路 仅专注于Kavpv神经元的测绘、成像和功能研究。AVPV是异质的 不仅在分子上，而且在功能上，以及全脑的联系和行为贡献 AVPV神经元亚型仍然知之甚少。此外，与该地区以前的工作不同，我们的 研究将评估Kavpv神经元在女性周期不同阶段的连接和功能，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……里面 目标1，我们将在一个无偏见的大脑中映射Kavpv神经元的突触前输入和突触后投射- 使用电生理学和活体实验验证整个发情周期的突触连接 双光子成像。在目标2中，我们将确定Kavpv神经元在雌性性行为和性行为中的活动模式 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的急性操作 神经元是必不可少的，即使当女性处于无法接受的荷尔蒙状态时，神经元也是足够的 来诱导女性的性行为。两个私人投资总监在建议的研究方面有互补的专业知识，而 因此，团队非常适合这个项目。总而言之，如果我们的研究成功，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。 与健康相关：众所周知，卵巢性激素可以影响行为、认知和情绪 女性所在的州。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 人们对神经元和突触知之甚少。此外，翻译研究已经确定了不同的神经细胞- 受这些激素影响的精神疾病。我们的基础研究提案如果成功，将 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，它们有可能在翻译工作中提出新的研究途径 重点是卵巢性激素在疾病状态下影响神经回路。

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.