Pallidostriatal Signaling in Parkinson's Disease

帕金森病中的苍白质纹状体信号传导

• 批准号: 9392723
• 负责人: Harry S. Xenias
• 金额: $ 0.09万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9392723
• 关键词: Action Potentials; Affect; Agonist; Analysis of Variance; Anatomy; Area; Axon; Basal Ganglia; Bathing; Brain; Calcium; Cell Separation; Cells; Cholinergic Receptors; Chronic; Confocal Microscopy; Corpus striatum structure; Dendrites; Dopamine; Dorsal; Electrophysiology (science); Etiology; Evoked Potentials; Excitatory Postsynaptic Potentials; Fluorescence; Future; GABA Receptor; Genetic; Globus Pallidus; Hydroxydopamines; Image; Immunohistochemistry; Investigation; Knowledge; Label; Lesion; Location; Measures; Mediating; Modeling; Molecular Target; Motor; Motor output; Movement Disorders; Mus; Neurons; Neurotransmitters; Oranges; Parkinson Disease; Pathway interactions; Physiological; Physiology; Polymerase; Polymerase Chain Reaction; Reaction; Regulation; Reporter; Research; Signal Transduction; Slice; Symptoms; Synapses; Testing; Transgenic Mice; Work; calcium indicator; motor control; motor disorder; mouse model; optogenetics; patch clamp; postsynaptic; presynaptic; quantum; receptor; relating to nervous system; symptomatology; tool

Project Summary / Abstract Parkinson’s disease (PD) is a debilitating movement disorder that affects over 60,000 new cases per year in the US alone and is characterized by a progressive degeneration of dopamine-releasing neurons that innervate the entire basal ganglia. It is thought that the hypokinetic symptoms of PD arise from an imbalance of the striatal direct pathway and indirect pathways. Our previous work has shown that: 1) the external segment of the globus pallidus (GPe) extensively innervates the dorsal striatum (dStr) and targets both the direct and indirect pathway spiny projection neurons (dSPNs and iSPNs), 2) this GPe-dStr projection arise from the Npas1+ GPe neurons, and 3) the Npas1+ GPe-dStr projection to iSPNs is strengthened preferentially in the chronic 6-hydroxydopamine (6-OHDA) lesion mice—a model of PD. However, the t mechanisms underlying the signaling of the Npas1+ pallidostriatal input to SPNs is not known. Accordingly, how its alterations associated with chronic 6-OHDA lesion is not understood. Most importantly, the function of the Npas1+ GPe-dStr input to SPN is completely unexplored. ​Our overarching hypothesis is that the Npas1+ GPe-dStr projection reduces dendritic excitability of SPNs and this effect becomes strengthened after chronic dopamine depletion by an increase in number of synaptic contacts of Npas1+ GPe-SPN input​. To test these ideas the proposed research will be accomplished using an array of tools, including transgenic mice, optogenetics, ​ex vivo patch-clamp electrophysiology, ​ex vivo calcium imaging, quantitative polymerase chain reaction, and immunohistochemistry.

项目概要/摘要 帕金森病 (PD) 是一种使人衰弱的运动障碍，每年影响超过 60,000 例新发病例 仅美国，其特征是支配神经的多巴胺释放神经元进行性退化 人们认为 PD 的运动功能减退症状是由基底神经节的不平衡引起的。 我们前期的工作表明：1）纹状体的外部部分。 苍白球 (GPe) 主要支配背侧纹状体 (dStr)，并针对直接和 间接通路多刺投射神经元（dSPN 和 iSPN），2）此 GPe-dStr 投射源自 Npas1+ GPe 神经元，3) Npas1+ GPe-dStr 到 iSPN 的投影在 慢性 6-羟基多巴胺 (6-OHDA) 损伤小鼠——PD 模型。 Npas1+ 苍白纹状体输入 SPN 的信号传导机制尚不清楚。 与慢性 6-OHDA 病变相关的最重要的是，Npas1+ 的功能尚不清楚。 SPN 的 GPe-dStr 输入完全未经探索。我们的首要假设是 Npas1+。 GPe-dStr 降低了 SPN 的投射树突兴奋性，这种效应变成 慢性多巴胺耗竭后，突触接触数量增加而得到加强 Npas1+ GPe-SPN 输入​为了测试这些想法，建议的研究将使用数组来完成 工具，包括转基因小鼠、光遗传学、离体膜片钳电生理学、离体钙 成像、定量聚合酶链反应和免疫组织化学。