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.

项目摘要 /摘要 帕金森氏病（PD）是一种使人衰弱的运动障碍，每年影响超过60,000例新病例 仅美国，其特征是多巴胺释放神经元的逐渐变性 整个基本神经节。据认为，PD的低迷症状是由于不平衡的 纹状体直接途径和间接途径。我们以前的工作表明：1） Globus Pallidus（GPE）广泛支配背纹状体（DSTR），并靶向直接和靶向 间接途径刺刺影神经元（DSPN和ISPNS），2）此GPE-DSTR投影来自 NPAS1+ GPE神经元和3）NPAS1+ GPE-DSTR对ISPN的投影优先在 慢性6-羟基多巴胺（6-OHDA）病变小鼠 - PD的模型。但是，t机制的基础 NPAS1+ pallidostriatal输入对SPN的信号传导尚不清楚。根据它的改变 与慢性6-OHDA病变有关。最重要的是，NPAS1+的功能 SPN的GPE-DSTR输入是完全出乎意料的。我们的总体假设是NPAS1+ GPE-DSTR投影减少了SPN的树突兴奋，这种影响变成 通过增加突触接触数量的增加，在慢性多巴胺消耗后加强了 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，离体贴片钳电生理学，离体钙 成像，定量聚合酶链反应和免疫组织化学。