Connectome of Motor Corticofugal Neurons in Parkinsonian Monkeys

帕金森猴运动皮质神经元的连接组

• 批准号: 10284849
• 负责人: Yoland Smith
• 金额: $ 45.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-29 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10284849
• 关键词: Address; Affect; Anatomy; Animal Model; Antiparkinson Agents; Area; Axon; Basal Ganglia; Behavioral; Brain; Brain Stem; Cell Nucleus; Cells; Chronic; Complex; Data; Deafferentation procedure; Dendritic Spines; Dependovirus; Development; Disease; Dissection; Electron Microscopy; Electrons; Electrophysiology (science); Face; Foundations; Functional disorder; Glutamates; Goals; Image; Knowledge; Label; Laboratories; Lead; Light; Literature; Macaca mulatta; Maps; Methods; Midbrain structure; Modeling; Monkeys; Morphology; Motor; Motor Cortex; Neuronal Plasticity; Neurons; Neurotoxins; Optics; Output; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Patients; Pattern; Physiology; Population; Population Heterogeneity; Presynaptic Terminals; Prevalence; Primates; Property; Pyramidal Cells; Recombinant adeno-associated virus (rAAV); Research; Resolution; Sampling; Scanning Electron Microscopy; Serotyping; Site; Source; Spinal Cord; Structure; Structure of subthalamic nucleus; Synapses; System; Techniques; Thalamic structure; Therapeutic; Universities; Variant; Vertebral column; base; connectome; dopaminergic neuron; experimental study; hippocampal pyramidal neuron; nerve supply; nonhuman primate; novel therapeutic intervention; parkinsonian non-human primate; retrograde transport; tool; vector

Project Summary - Project 3 The loss of midbrain dopamine neurons in Parkinson’s disease (PD) induces complex anatomical and functional changes throughout the basal ganglia-thalamocortical circuitry and downstream targets. Although our understanding of neuronal activity changes in basal ganglia output nuclei and the subthalamic nucleus has increased significantly over the past decade, much remains to be known about the pathophysiology of the corticospinal system in the parkinsonian state. In this project, we provide strong preliminary evidence that there is a significant breakdown of the thalamocortical system and major changes in the morphology of pyramidal cells in the primary motor cortex (M1) and supplementary motor area (SMA) of monkeys that have been rendered parkinsonian with chronic administration of the neurotoxin MPTP. Combined with findings from the literature suggesting that corticospinal neurons display abnormal activity in M1 of MPTP-treated parkinsonian monkeys, one of the hypotheses of our project is that corticospinal neurons in M1 and SMA undergo complex structural and morphological changes that hamper their synaptic connectivity with the thalamocortical afferents, thereby contributing to the dysregulation of functional connectivity between basal ganglia and motor cortices in parkinsonism. Another major roadblock that significantly limited progress in our understanding of the pathophysiology of motor cortices and the corticospinal system in PD has been the lack of reliable tools to study the full connectome of corticospinal neurons. Although conventional tracing studies have demonstrated that both M1 and SMA are enriched in a large variety of overlapping projection neurons that innervate a wide array of basal ganglia, thalamic, brainstem and spinal cord regions, the extent to which these projections originate from distinct or common neuronal populations remains largely unknown, or relies on data gathered from small samples of identified pyramidal neurons. In this project, we will take advantage of the unique and highly efficient retrograde transport properties of a newly developed designer variant of adeno-associated virus to map and compare the connectome of corticospinal neurons between control and parkinsonian monkeys. Because the behavioral functions of specific subtypes of corticofugal neurons derive from their complex output projection patterns, not just their final termination site, an in-depth knowledge of the axonal branching pattern of corticospinal axons in normal and parkinsonian states is of utmost significance in our understanding of the pathophysiology of cortical outflow in Parkinson’s disease. Together with functional studies proposed in the other projects of this application, our findings will lay the foundation for the development of new therapeutic approaches, such as chemogenetic methods, to directly manipulate the activity of specific subsets of corticospinal neurons in PD.

项目摘要-项目3 帕金森病(PD)中脑多巴胺神经元的丢失导致复杂的解剖和功能 整个基底节-丘脑皮质回路和下游靶点的变化。虽然我们的 对基底神经节输出核团和丘脑底核神经元活动变化的认识 在过去的十年中显著增加，关于这种疾病的病理生理学仍有许多有待了解的地方。 帕金森病患者的皮质脊髓系统。在这个项目中，我们提供了强有力的初步证据 是丘脑皮质系统的显著崩溃和锥体细胞形态的主要变化 在猴子的主运动皮质(M1)和辅助运动区(SMA)中 帕金森病患者长期服用神经毒素MPTP。结合文献中的发现 提示MPTP治疗帕金森病猴的M1区皮质脊髓神经元异常活动， 我们项目的一个假设是M1和SMA的皮质脊髓神经元经历了复杂的结构 以及阻碍它们与丘脑皮质传入的突触连接的形态变化，从而 基底节和运动皮质之间功能连接的失调 帕金森症。另一个主要障碍严重限制了我们对 帕金森病患者运动皮质和皮质脊髓系统的病理生理学一直缺乏可靠的研究工具 皮质脊髓神经元的完整连接体。尽管传统的追踪研究已经证明， M1和SMA富含各种各样的重叠投射神经元，这些神经元支配着广泛的 基底节、丘脑、脑干和脊髓区域，这些投射起源的程度 不同的或共同的神经元群体在很大程度上仍不清楚，或依赖于从小的 已鉴定的锥体神经元样本。在这个项目中，我们将利用独特而高效的 一种新开发的腺相关病毒设计变种的逆行转运特性 比较对照组和帕金森病猴皮质脊髓神经元的连接体。因为 特定亚型皮质分离神经元的行为功能源自其复杂的输出投射 模式，而不仅仅是其最终终止位置，深入了解轴突分支模式 正常状态和帕金森病状态下的皮质脊髓轴突对于我们理解 帕金森病皮质流出的病理生理学研究。与另一份报告中提出的功能研究一起 项目的这一应用，我们的研究成果将为开发新的治疗方法奠定基础 直接操纵特定子集的活性的方法，如化学遗传学方法 帕金森病患者的皮质脊髓神经元。