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，联合负责人：Tsien、Froemke、Buzsaki） 神经调节剂在多个时间尺度上发挥作用——这是其释放、受体动力学的结果 激活和下游信号传导。它们的作用针对众多的亚细胞区室，塑造 突触传递、内在兴奋性和长期可塑性。这些现象又如何转化为 行为是神经科学研究的基本目标。在项目 3 中，我们通过以下方式解决这种复杂性： 解构肽和催产素的作用。因其在周边和地区的作用而闻名 社会行为、中枢神经系统催产素信号传导的生物物理和细胞后果 描述得很差。彻底了解催产素在大脑中的作用是如何进一步激发的 各种神经精神疾病（包括自闭症谱系障碍和精神分裂症）中催产素信号传导的破坏。到 为了解决这一知识空白，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，重点关注 CA2 亚区。 CA2 富含 OXTR，长期被忽视 有趣的是，它还与社会行为有关。我们最近的努力重点是如何 OXTR 的激活使 CA2 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 Gq-下游的 Kv7 介导的钾电流（或 M 电流） 耦合信号通路。在项目 3 中，我们将这些生物物理结果转化为越来越多的生理学结果 上下文。在目标 1 中，我们询问催产素纤维的内源性活动​​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，我们测试模型的强度（在 催产素在海马体中的作用主要是通过 M 电流抑制介导的） 测试催产素信号传导中 M 电流抑制的充分性和必要性的光学工具。在目标 3 中，我们 询问海马活动（特别是 CA2 活动）的深刻变化是如何传递到大脑以外的？ 海马体。我们主要集中精力于外侧隔膜；一个长期与社会行为有关的地区， 受海马体密集支配，并且自身富含 OXTR。 总之，我们提出了一项研究计划，将海马体中的催产素信号提炼成最基本的信号 组成部分：肽释放、受体激活和 M 电流的细胞类型特异性调节。那么，作为 为了对我们的理解进行严峻的考验，我们尝试使用我们的新方法重建催产素的调节作用 开发了光学工具。最后，我们考虑海马体中的催产素信号如何传播到 下游结构，最终影响社会行为。