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

苍白球外突触反应的神经元异质性和网络动态控制

基本信息

批准号：
10464917
负责人：
James Jones
金额：
$ 3.8万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10464917
关键词：
Address Animals Axon Basal Ganglia Brain Cell Nucleus Cells Cerebral cortex Closure by clamp Code Cognition Collection Complex Corpus striatum structure Custom Deep Brain Stimulation Electrophysiology (science)Esthesia Exhibits Fellowship Fire - disasters GABA Antagonists Globus Pallidus Goals Heterogeneity Individual Knowledge Learning Mathematics Measurement Measures Membrane Potentials Mentors Midbrain structure Modeling Movement Neurons Output Parkinsonian Disorders Parvalbumins Pathway interactions Pattern Phase Population Predictive Value Preparation Research Series Shapes Signal Pathway Signal Transduction Slice Substantia nigra structure Support Groups Synapses Synaptic Potentials Synaptic Transmission Tertiary Protein Structure Thalamic structure Therapeutic Time Training Work Writing cell type disability dopaminergic neuron experimental study gamma-Aminobutyric Acid in vivo optogenetics patch clamp postsynaptic relating to nervous system response signal processing skills spatiotemporal undergraduate student

项目摘要

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.

项目概要/摘要外部苍白球（GPe）传统上被视为运动中的同质中继核 - 抑制间接途径，但现在已知更为复杂。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，但直接抑制纹状体神经元还抑制 GPe，主要针对 Npas1 神经元。 PV和Npas1神经元有不同的下游目标并通过局部轴突侧支网络互连。此外，两个细胞群都表现出即使在脑切片中，也会发生内在振荡并迅速放电。在健康动物中，GPe 神经元几乎没有表现出尖峰时间相关性，出现在帕金森病状态，可能归因于局部连通性或共同的纹状体苍白球输入。本提案的目标是调查当地政府的机制 GPe 中的侧支网络 (1) 在没有纹状体输入，以及（2）控制 GPe 神经元对来自直接和间接通路纹状体-苍白球神经元。为了解决这些问题，该提案分为两个目标。（目标 1）确定 GPe 网络如何形成自己的发射模式。局部轴突的突触电位将在切片中测量络脉及其对 PV 和 Npas1 神经元放电模式的影响使用穿孔膜片钳记录在局部阻断突触传递之前和之后的准备工作具有 GABA 受体拮抗剂的络合物。 PV 和 Npas1 神经元的尖峰动力学可以是概括为它们振荡阶段的动力学。使用相位重置模型，模拟的效果将确定 PV 和 Npas1 神经元相位动态的局部 IPSP 弹幕，从而提供其对发射模式的影响机制。（目标 2）确定 GPe 网络如何塑造尖峰对纹状体-苍白球输入的反应。将使用简短的古视紫红质来模拟间接途径信号 PV 神经元中的 (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，Arch 间接抑制）本地网络）和其他细胞类型（仅受网络抑制）将被测量。的效果细胞对 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。阶段重置模型将用于提供了 GPe 网络如何塑造对纹状体苍白球信号的尖峰响应的机制。在此之下奖学金后，申请人将继续接受切片电生理学和编码方面的培训，磨练他作为一名实验主义者和他的定量研究方法。申请人将培养强大的数学能力通过在他的赞助商和一个由计算导向的神经科学家组成的支持小组的指导下进行培训来构建框架。申请人还将通过培训本科生来培养作为导师的技能。