Biophysical and Circuit Mechanisms of OXTR signaling

OXTR信号的生物物理和电路机制

• 批准号: 10438594
• 负责人: RICHARD W TSIEN
• 金额: $ 40.72万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438594
• 关键词: Acids; Address; Affect; Agonist; Area; Axon; Behavior; Biological Assay; Biophysics; Blood; Brain; Brain region; Cations; Cells; Color; Coupled; Dense Core Vesicle; Dependence; Fiber; Frequencies; Genes; Goals; Hippocampus (Brain); Hypothalamic structure; Individual; Interneurons; Knowledge; Lateral; Lead; Light; Link; Measurement; Mediating; Memory; Methods; Modeling; Neuraxis; Neuromodulator; Neurons; Neuropeptides; Neurosciences; Neurosciences Research; Noise; Optics; Output; Oxytocin; Oxytocin Receptor; Parvalbumins; Pattern; Peptides; Performance; Physiological; Potassium; Property; Pyramidal Cells; Radioimmunoassay; Receptor Activation; Receptor Cell; Research; Resolution; Retrieval; Role; Route; Schizophrenia; Shapes; Signal Pathway; Signal Transduction; Social Behavior; Spatial Behavior; Structure; Sum; Synapses; Synaptic Transmission; System; Testing; Translating; Vasopressin Receptor; Vesicle; autism spectrum disorder; behavior test; cell type; excitatory neuron; experimental study; hippocampal pyramidal neuron; in vivo evaluation; information processing; inhibitory neuron; interest; maternal aggression; melanopsin; neural circuit; neuropsychiatric disorder; novel; optogenetics; peptide hormone; postsynaptic; presynaptic; pup; receptor; response; social; social influence; spatial memory; spatiotemporal; tool

Project Summary (Project 3, Co-PIs: Tsien, Froemke, Buzsaki) Neuromodulators act across many timescales—a consequence of the dynamics of their release, receptor activation and downstream signaling. Their actions target numerous subcellular compartments, shaping synaptic transmission, intrinsic excitability and long-term plasticity. How, in turn, these phenomena translate to behavior is a fundamental goal of neuroscience research. In Project 3, we grapple with this complexity by deconstructing the actions of the peptide and hormone oxytocin. Famous for its roles in the periphery and in social behavior, the biophysical and cellular consequences of oxytocin signaling in the central nervous system are poorly described. A thorough understanding of how oxytocin’s role in the brain is further motivated by disruption of oxytocin signaling in various neuropsychiatric disorders, including ASD and schizophrenia. To address this gap in knowledge, we will study the cellular, synaptic and microcircuit signaling mechanisms of oxytocin in the hippocampus, focusing on the CA2 subregion. Long overlooked, CA2 is enriched in OXTRs and, intriguingly, has been implicated in social behavior. Our most recent efforts have focused on how activation of the OXTR depolarizes CA2 pyramidal cells and causes them to enter into a burst firing mode. This effect was attributable to inhibition of a Kv7-mediated potassium current (or M-current), downstream of a Gq- coupled signaling pathway. In Project 3, we take these biophysical results into increasingly more physiological contexts. In Aim 1, we ask how endogenous activity patterns of oxytocinergic fibers translate into oxytocin release, receptor activation and changes in intrinsic excitability. In Aim 2, we test the strength of our model (in which oxytocin’s effects in the hippocampus are primarily mediated by M-current inhibition), by developing optical tools that test the sufficiency and necessity of M-current inhibition in oxytocin signaling. In Aim 3, we ask how profound changes in hippocampal activity, specifically in CA2, are transmitted beyond the hippocampus. We primarily focus our efforts on the lateral septum; a region long implicated in social behaviors, densely innervated by the hippocampus and rich itself in OXTRs. In sum, we propose a research plan that distills oxytocin signaling in the hippocampus into its most elementary components: peptide release, receptor activation and cell-type specific modulation of the M-current. Then, as an acid test of our understanding, we attempt to reconstruct oxytocin’s modulatory actions using our newly developed optical tools. Finally, we consider how oxytocin signaling in the hippocampus may propagate to downstream structures, ultimately influencing social behavior.

项目摘要（项目3，Co-Pis：Tsien，Froemke，Buzsaki） 神经调节剂在许多时间尺度上起作用 - 发行动力的结果，接收器 激活和下游信号传导。他们的行为针对众多细胞隔室，塑造 突触传递，内在的兴奋性和长期可塑性。反过来，这些现象如何转化为 行为是神经科学研究的基本目标。在项目3中，我们通过 解构胡椒和同种催产素的作用。以其在外围和中的角色而闻名 社会行为，中枢神经系统中氧信号的生物物理和细胞后果 描述很差。对氧气在大脑中的作用如何进一步成熟 包括ASD和精神分裂症在内的各种神经精神疾病中氧信号的破坏。到 解决这一知识的差距，我们将研究细胞，突触和微电路信号传导机制 海马中的催产素，重点是Ca2子区域。长期被忽视的Ca2富含Oxtrs 而且，有趣的是，在社会行为中暗示了。我们最近的努力集中在如何 OXTR的激活使Ca2锥体细胞去极化，并使它们进入爆发模式。这 效应归因于抑制Kv7介导的钾电流（或M-电流），在GQ-下游 耦合信号通路。在项目3中，我们将这些生物物理结果越来越多地生理 上下文。在AIM 1中，我们询问氧气纤维的内源性活性模式如何转化为氧加毒素 释放，受体激活和内在令人兴奋的变化。在AIM 2中，我们测试了模型的强度（在 催产素在海马中的作用主要是通过M-电流抑制来介导的） 光学工具测试氧信号中M-电流抑制的充分性和必要工具。在AIM 3中，我们 询问海马活动的深刻变化，特别是在CA2中 海马。我们主要将精力集中在侧隔隔膜上；一个长期与社会行为有关的地区， 不受海马的神经支配，并在Oxtrs中富裕。 总而言之，我们提出了一个研究计划，该计划将海马中的氧信号提取到其最基本的 成分：肽释放，受体激活和细胞类型的特异性调节。然后，为 对我们的理解的酸测试，我们尝试使用新的 开发的光学工具。最后，我们考虑海马中的氧信号如何传播到 下游结构，最终影响社会行为。