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.

项目概要（项目3，共同主要研究者：Tsien、Froemke、Buzsaki） 神经调质的作用跨越许多时间尺度--这是它们释放动力学的结果， 激活和下游信号传导。它们的作用针对许多亚细胞区室， 突触传递、内在兴奋性和长期可塑性。这些现象又是如何转化为 行为是神经科学研究的基本目标。在项目3中，我们通过以下方式来解决这种复杂性： 解构肽和催产素的作用。以其在周边地区和 社会行为，催产素信号在中枢神经系统中的生物物理和细胞后果 描述得不好。深入了解催产素在大脑中的作用是如何进一步激发的， 在各种神经精神疾病中，包括ASD和精神分裂症中，催产素信号的中断。到 为了解决这一知识差距，我们将研究细胞，突触和微电路信号机制， 海马中的催产素，集中在CA 2亚区。长期被忽视，CA 2富含OXTRs 有趣的是，它与社会行为有关。我们最近的努力集中在如何 OXTR的激活使CA 2锥体细胞去极化并使它们进入爆发放电模式。这 效应归因于抑制Kv 7介导的钾电流（或M电流），Gq- 偶联信号通路在项目3中，我们将这些生物物理学结果应用于越来越多的生理学研究， contexts.在目标1中，我们询问催产素能纤维的内源性活动模式如何转化为催产素 释放、受体激活和内在兴奋性的变化。在目标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电流抑制介导的），通过发展 光学工具，测试M电流抑制催产素信号的充分性和必要性。在目标3中，我们 问海马活动的深刻变化，特别是在CA 2，是如何传递到大脑以外的。 海马体。我们主要集中精力在外侧隔上，这是一个长期与社会行为有关的区域， 由海马体密集地支配并且自身富含OXTRs。 总之，我们提出了一个研究计划，将海马体中的催产素信号提取到最基本的水平， 主要成分：肽释放、受体激活和M电流的细胞类型特异性调节。然后如 作为对我们理解的一个严峻考验，我们试图用我们的新方法来重建催产素的调节作用。 开发了光学工具。最后，我们考虑如何催产素信号在海马可能传播， 下游结构，最终影响社会行为。