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

• 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
• 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

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.

项目摘要/摘要 传统上，pallidus（GPE）的外部球形（GPE）被视为运动中的同质继电器核 抑制间接途径，但现在已知更为复杂。间接途径纹状体神经元 提供对表达白蛋白（PV）的GPE神经元的短暂抑制，但直接途径纹状体神经元 还抑制GPE，主要针对NPAS1神经元。 PV和NPAS1神经元的下游不同 目标并由局部轴突侧支网络互连。另外，两个细胞组都表现出 固有的振荡和迅速发射，即使在脑切片中也是如此。在健康动物中，GPE神经元几乎没有表现 在帕金森州出现的尖峰时间相关性，可以归因于本地连通性或 常见的纹状体输入。该提议的目的是研究本地的机制 GPE（1）中的附带网络在没有的情况下塑造了GPE神经元触发的自发模式 纹状体输入，（2）控制GPE神经元的尖峰响应，从直接和 间接途径纹状体 - 帕利德神经元。为了解决这些问题，该提议分为两个目标。 （AIM 1）确定GPE网络如何形成自己的射击模式。局部轴突的突触电位 侧支及其对PV和NPAS1神经元发射模式的影响将在切片中测量 在阻止本地的突触传输之前和之后，使用穿孔贴片钳记录的准备工作 带有GABA受体拮抗剂的侧支。 PV和NPAS1神经元的尖峰动态可能是 总结在其振荡阶段的动力学中。使用相位重置模型，模拟的效果 将确定PV和NPAS1神经元相位动力学上的本地IPSP弹幕，提供一个 其对射击模式的影响的机制。 （AIM 2）确定GPE网络如何形成峰值 对纹状体 - 帕利德输入的响应。间接途径信号将使用简短的古细菌模仿 （ARCH）PV神经元的激活和NPAS1神经元中的ARCH激活将用于模仿直接途径 信号。同一细胞类型的尖峰反应（被拱形直接抑制并间接抑制 将测量本地网络）和其他单元格（仅由网络抑制）。效果 通过减去细胞对弓形抑制的峰值响应的本地网络将通过减去隔离 在GABA拮抗剂存在下重复测量。相位重置模型将用于 提供了一种机制，可以为GPE网络如何塑造对纹状体 - 帕利德信号的尖峰响应。在此 奖学金，申请人将继续他在SLICE电生理学和编码方面的培训，并磨练他的技能 实验主义者及其定量研究方法。申请人将发展强大的数学 框架通过其赞助商和支持计算为导向的神经科学家的支持小组。 申请人还将通过培训本科生来发展作为导师的技能。