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: 10495224
• 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/10495224
• 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 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 帕金森氏病（PD）中中脑多巴胺神经元的丧失会引起复杂的解剖学和功能性 整个基底神经节 - 丘脑皮层电路和下游目标的变化。虽然我们的 了解基底神经节输出核和丘脑下核的神经元活性变化的了解 在过去的十年中，显着增加了，关于 帕金森州的皮质脊髓系统。在这个项目中，我们提供了有力的初步证据 是丘脑皮质系统的显着崩溃和锥体细胞形态的重大变化 在猴子的一级运动皮层（M1）和补充运动区域（SMA）中 帕金森氏症具有神经毒素MPTP的长期给药。结合文学的发现 表明皮质脊髓神经元在MPTP处理的帕金森猴的M1中表现出异常活性， 我们项目的假设之一是M1和SMA中的皮质脊髓神经元经历复杂的结构 以及形态学变化，阻碍了它们与丘脑皮质传入的合成连通性，从而 导致基底神经节和运动皮层之间功能连通性的失调 帕金森主义。另一个主要的障碍，这在我们对 PD运动皮质和皮质脊髓系统的病理生理学缺乏可靠的工具来研究 皮质脊髓神经元的完整连接组。尽管常规的追踪研究表明 M1和SMA富含各种各样的重叠投影神经元，这些神经元支配了一系列广泛的阵列 基底神经节，丘脑，脑干和脊髓区域，这些项目起源于 独特或常见的神经元种群在很大程度上尚不清楚，或依赖于从小的数据中收集的数据 鉴定出锥体神经元的样品。在这个项目中，我们将利用独特且高效的优势 新开发的腺相关病毒设计师变体的逆行传输特性用于映射和 比较控制和帕金森猴之间皮质脊髓神经元的连接组。因为 皮质增生神经元特定亚型的行为函数从其复杂的输出投影衍生 模式，不仅是他们的最终终止站点，也是对轴突分支模式的深入了解 正常状态和帕金森氏症的皮质脊髓轴突对我们对我们的理解至关重要 帕金森氏病皮质流出的病理生理学。以及在其他方面提出的功能研究 该应用程序的项目，我们的发现将为开发新疗法奠定基础 方法，例如化学发生方法，直接操纵特定子集的活性 PD中的皮质脊髓神经元。