Biophysical and Circuit Mechanisms of OXTR signaling

项目总结(项目3，合作伙伴：钱学森、弗罗梅克、布萨基) 神经调节剂在许多时间尺度上发挥作用--这是它们释放的动力学的结果，受体 激活和下行信令。他们的行动针对许多亚细胞隔间，塑造 突触传递、内在兴奋性和长期可塑性。反过来，这些现象又是如何转化为 行为是神经科学研究的一个基本目标。在项目3中，我们通过以下方式应对这种复杂性 解构多肽和激素催产素的作用。以其在周边地区的作用而闻名 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 都描述得很差。彻底了解催产素在大脑中的作用是如何由 催产素信号在包括自闭症和精神分裂症在内的各种神经精神障碍中的干扰。至 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。 催产素在海马区，集中在CA2亚区。长期被忽视的CA2富含OXTRs 而且，耐人寻味的是，它与社会行为有牵连。我们最新的努力集中在如何 OXTR的激活使CA2锥体细胞去极化，并使它们进入突发性放电模式。这 这种作用归因于抑制KV7介导的钾电流(或M电流)，该电流位于Gq-1下游。 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，我们测试我们模型的强度(in 催产素在海马区的作用主要是通过M-电流抑制介导的)，通过 测试催产素信号中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 问一问，海马区活动的深刻变化，特别是CA2区，是如何传递到 海马体。我们主要关注外侧隔区；这是一个长期与社会行为有关的区域， 由海马体密集支配，本身富含氧合酶受体。 总而言之，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部分 成分：多肽释放、受体激活和M-电流的细胞类型特异性调制。那么，就像 这是对我们理解的一次严峻考验，我们试图用我们的新技术重建催产素的调节作用 开发了光学工具。最后，我们考虑了海马区催产素信号如何传播到 下游结构，最终影响社会行为。

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.