Oxytocin regulation of ion channels and canonical circuit operations

项目总结(项目3，合作伙伴：钱学森、布萨基、弗罗梅克、林) 催产素是一种神经肽，可以塑造伴侣关系、育儿和社会竞争等重要行为。 关于这种行为是如何由大脑回路控制的，有许多紧迫的问题。理解 催产素在大脑中的作用进一步受到各种不同类型催产素信号的干扰 神经精神障碍。催产素被广泛认为影响细胞的兴奋性、突触传递和 单个神经元的长期可塑性，但仍缺乏基于机制的行为理解。项目 3和4有一个合适的交汇点来理解调制机制，在 海马和外侧隔(LS)，依次传递来自新皮质区域的输入并将输出发送到 控制社会行为的其他大脑区域。OXTRs在CA2次区域尤其丰富。 海马体。海马CA2区含有直接接受外侧传入的锥体神经元(PYRs) 内嗅皮层对大脑振荡的产生和社会记忆的建立起着关键作用。这个 外侧隔是一种以GABA能为主的结构，在其背侧象限包括接受来自 CA2和其他连接到下丘脑VMHvl的神经元帮助控制一系列行为，包括 攻击性和竞争性。 在这里，我们将研究催产素的细胞、突触和微电路信号机制，重点是 CA2亚区和LS。目标1建立在我们最近发现的催产素如何改变CA2兴奋性的基础上 PYRs：通过减少内向整流钾通道(IKIR)(有利于膜去极化)和关闭 关闭超极化激活的环核苷酸门控通道(Ih)(提供超极化驱动)。这个 Iir和Ih的联合降低抑制了膜电位从静止状态快速去极化(因此 使催产素“信号缓慢”)，但协同提高膜阻力，有利于树突状 整合。事实上，我们观察到了一个巨大的单一突触电流的新群体。我们将测试这些是否 巨型事件来自远端的树突输入，冲击到比At大几倍的局部Glur星团 突触后部位靠近胞体，可能是来自内嗅皮层的部位。在目标2中，我们将追求 新数据显示，快速放电中间神经元(FSIS)在催产素和催产素之间显示出一种不同寻常的协同作用 抑制传播。由OXTR刺激驱动的FSI可以被持续的短时间中断 GABA能抑制。我们将测试这种组合的“信令快速”是否支持突然切换 参与社会选择的电路，这是我们的计算建模核心提出的。在目标3中，我们将在 我们令人惊讶的观察发现，催产素会使某些受抑制的LS神经元超极化，导致它们停止 它们的自发放电(“反向信号”)，通过加重抑制ih。我们将探索 各种LS功能的后果，包括攻击控制和全局催产素能调节。

Project Summary (Project 3, Co-PIs: Tsien, Buzsaki, Froemke, Lin) Oxytocin is a neuropeptide that shapes vital behaviors such as pair bonding, parenting and social competition. There are many pressing questions about how such behaviors are steered by brain circuits. Understanding oxytocin’s actions in the brain is further motivated by possible disruption of oxytocin signaling in various neuropsychiatric disorders. Oxytocin is widely seen as affecting cellular excitability, synaptic transmission, and long-term plasticity in single neurons, but a mechanism-based understanding of behavior is still lacking. Project 3 and 4 have a suitable meeting ground for understanding modulatory mechanisms, examining circuits in hippocampus and lateral septum (LS) that successively relay input from neocortical areas and send output to other brain areas that control social behaviors. OXTRs are particularly enriched in the CA2 subregion of the hippocampus. Hippocampal CA2 harbors pyramidal neurons (PYRs) that directly receive input from lateral entorhinal cortex and are pivotal to generation of brain oscillations and establishment of social memory. The lateral septum, a largely GABAergic structure, includes neurons in its dorsal quadrant that receive inputs from CA2 and other neurons that connect to hypothalamic VMHvl to help control a range of behaviors including aggression and competition. Here we will study the cellular, synaptic and microcircuit signaling mechanisms of oxytocin, focusing on the CA2 subregion and the LS. Aim 1 builds on our recent discovery of how oxytocin alters excitability in CA2 PYRs: by diminishing inward rectifier potassium channels (IKir) (favoring membrane depolarization) and shutting off hyperpolarization-activated cyclic-nucleotide-gated channels (Ih) (providing a hyperpolarizing drive). The combined reduction in both IKir and Ih restrains membrane potential from quickly depolarizing from rest (thus enabling oxytocin to “signal slow”) but synergistically elevates membrane resistance, favoring dendritic integration. Indeed, we observe a new population of huge unitary synaptic currents. We will test whether these giant events arise from distal dendritic inputs, impinging on local GluR clusters several times bigger than at postsynaptic sites nearer the soma, potentially those arriving from entorhinal cortex. In Aim 2, we will pursue new data showing that fast-spiking interneurons (FSIs) display an unusual synergy between oxytocin and inhibitory transmission. A FSI driven to rapidly fire by OXTR stimulation can be persistently interrupted by brief GABAergic inhibition. We will test whether such combinatorial “signaling fast” supports sudden switching of circuits involved in social choice, as proposed by our Computational Modeling Core. In Aim 3, we will build on our surprising observation that oxytocin hyperpolarizes certain inhibitory LS neurons, causing them to cease their spontaneous firing (“signaling in reverse”), by heavily weighting inhibition of Ih. We will explore the consequences for various LS functions, including control of aggression and global oxytocinergic regulation.