Neuron heterogeneity and network dynamic control of synaptic responses in the external globus pallidus

项目总结/摘要 苍白球外核（GPe）传统上被认为是运动中的同质中继核， 抑制间接途径，但现在已知更复杂。间接通路纹状体苍白球神经元 对表达小清蛋白（PV）的GPe神经元提供短暂抑制，但直接通路纹状体神经元 也抑制GPe，主要靶向Npas1神经元。PV和Npas1神经元具有不同的下游 靶点，并通过局部轴突侧支网络相互连接。此外，这两个细胞群都表现出 内在的振荡和快速放电，即使在大脑切片中。在健康的动物中，GPe神经元几乎没有表现出 尖峰时间相关性，出现在帕金森状态，可归因于本地连接或 共同的纹状体-腭部输入。这项建议的目的是调查当地的机制 GPe中的侧支网络（1）在缺乏 纹状体输入，（2）控制GPe神经元对直接和间接突触输入的尖峰反应， 纹状体-苍白球神经元间接通路为了解决这些问题，本提案分为两个目标。 (Aim 1）确定GPe网络如何形成自己的放电模式。来自局部轴突的突触电位 侧支及其对PV和Npas1神经元放电模式的影响将在切片中测量 在阻断局部突触传递之前和之后使用穿孔膜片钳记录的制备 与GABA受体拮抗剂。PV和Npas1神经元的尖峰动力学可以是 总结在其振荡阶段的动力学中。利用相位重置模型，模拟了 将确定PV和Npas1神经元的相位动力学上的局部IPSP屏障，提供 它们对放电模式影响的机制。(Aim 2）确定GPe网络如何形成尖峰 对纹状体苍白球输入的反应。间接途径信号将使用简单的古视紫红质 PV神经元中的Arch（Arch）激活和Npas1神经元中的Arch激活将用于模拟直接通路 信号.相同细胞类型的尖峰反应（Arch直接抑制， 本地网络）和其它小区类型（仅由网络解除抑制）将被测量。的影响 通过减去Arch直接抑制的细胞尖峰响应的局部网络将被分离， 在GABA拮抗剂存在下重复测量。相位重置模型将用于 为GPe网络如何塑造对纹状体苍白球信号的尖峰反应提供了一种机制。根据本 申请人将继续接受切片电生理学和编码方面的培训， 实验主义者和他的定量研究方法。申请人将发展强大的数学 在他的赞助人和一个支持计算导向的神经科学家小组的训练下， 申请人还将通过培训本科生来发展作为导师的技能。

Project Summary/Abstract The external globus pallidus (GPe) is traditionally viewed as a homogenous relay nucleus in the movement- suppressing indirect pathway but is now known to be more complex. Indirect pathway striatopallidal neurons provide transient inhibition to GPe neurons expressing Parvalbumin (PV), but direct pathway striatal neurons also inhibit the GPe, targeting primarily Npas1 neurons. PV and Npas1 neurons have different downstream targets and are interconnected by a network of local axon collaterals. In addition, both cell groups exhibit intrinsic oscillations and fire rapidly, even in brain slices. In healthy animals, GPe neurons exhibit little to no spike-time correlations, which emerge in Parkinsonian states and could be attributed to local connectivity or common striatopallidal input. The goal of this proposal is to investigate the mechanisms by which the local collateral network in the GPe (1) shapes the spontaneous pattern of GPe neuron firing in the absence of striatal input, and (2) controls the spiking responses of GPe neurons to synaptic input from direct and indirect pathway striato-pallidal neurons. To address these questions, this proposal is divided into two aims. (Aim 1) Determine how the GPe network forms its own pattern of firing. Synaptic potentials from local axon collaterals and their effect on the firing patterns of PV and Npas1 neurons will be measured in slice preparations using perforated patch-clamp recordings before and after blocking synaptic transmission in local collaterals with GABA receptor antagonists. The spiking dynamics of PV and Npas1 neurons can be summarized in the dynamics of their oscillation phase. Using a phase resetting model, the effect of simulated local IPSP barrages on the phase dynamics of PV and Npas1 neurons will be determined, providing a mechanism for their influence on firing patterns. (Aim 2) Determine how the GPe networks shape spiking responses to striato-pallidal inputs. Indirect pathway signals will be mimicked using a brief Archaerhodopsin (Arch) activation in PV neurons, and Arch activation in Npas1 neurons will be used to mimic direct pathway signals. The spiking responses of the same cell type (directly inhibited by Arch and indirectly disinhibited by the local network) and the other cell type (disinhibited by the network only) will be measured. The effect of the local network on the spiking responses of cells to direct inhibition by Arch will be isolated by subtracting the measurements repeated in the presence of GABA antagonists. The phase resetting model will be used to provide a mechanism for how the GPe network shapes spiking responses to striato-pallidal signals. Under this fellowship, the applicant will continue his training in slice electrophysiology and coding, honing his skills as an experimentalist and his quantitative approach to research. The applicant will develop a strong mathematical framework by training under his sponsor and a supporting group of computationally oriented neuroscientists. The applicant will also develop skills as a mentor by training undergraduate students.