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

项目摘要/摘要 苍白球外区(GPE)传统上被视为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 对表达小白蛋白(PV)的GPE神经元提供一过性抑制，但对纹状体神经元提供直接通路 也抑制GPE，主要针对Npas1神经元。PV和Npas1神经元具有不同的下游 靶点通过局部轴突侧支网络相互连接。此外，两组细胞都表现出 固有的振荡和快速放电，即使在脑片中也是如此。在健康动物中，GPE神经元几乎没有表现出 尖峰时间相关性，出现在帕金森氏症状态，可能归因于局部连接或 常见的纹状体丘脑输入。这项提案的目标是调查地方政府 GPE中的侧支网络(1)形成GPE神经元的自发放电模式 纹状体输入，以及(2)控制GPE神经元对来自直接和 间接通路纹状核-苍白球神经元。为了解决这些问题，这项提议分为两个目标。 (目标1)确定GPE网络如何形成自己的激发模式。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薄片上测量 穿孔膜片钳记录阻断局部突触传递前后的准备 与GABA受体拮抗剂的侧支。PV和Npas1神经元的放电动力学可以是 总结了它们的动力学振荡相。利用一个相位重置模型，模拟了 将确定局部IPSP对PV和Npas1神经元的相动力学的影响，提供 它们对发射模式的影响机制。(目标2)确定GPE网络如何形成尖峰 对纹状苍白球输入的反应。间接途径信号将使用简短的古紫质模拟 PV神经元的Arch激活和Npas1神经元的Arch激活将被用来模拟直接通路 信号。同一细胞类型的尖峰反应(直接受Arch抑制，间接受Arch抑制 本地网络)和其他小区类型(仅由网络禁止)将被测量。美国政府的影响 细胞对Arch直接抑制的尖峰反应的局部网络将通过减去 在GABA拮抗剂存在的情况下重复测量。相位重置模型将用于 为GPE网络如何形成对纹状苍白球信号的尖峰反应提供了一种机制。在这下面 奖学金，申请者将继续他的切片电生理学和编码方面的培训，磨练他作为 实验家和他的定量研究方法。申请者将发展出一种强大的数学 在他的赞助商和一群以计算为导向的神经科学家的支持下，他通过培训建立了一个框架。 申请者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.