Connectome of Motor Corticofugal Neurons in Parkinsonian Monkeys

项目概要-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障碍， 整个基底神经节-丘脑皮质回路和下游靶点的变化。虽然我们的 了解基底神经节输出核和丘脑底核的神经元活动变化， 在过去的十年中显著增加，仍然有很多关于病理生理学的了解。 皮质脊髓系统在帕金森状态。在这个项目中，我们提供了强有力的初步证据， 是丘脑皮质系统的重大崩溃和锥体细胞形态的重大变化 在猴子的初级运动皮层（M1）和辅助运动区（SMA）， 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处理的帕金森病猴的M1期皮质脊髓神经元显示异常活动， 我们项目的一个假设是，M1和SMA中的皮质脊髓神经元经历了复杂的结构变化， 以及形态学变化，阻碍了它们与丘脑皮层传入神经的突触连接， 导致基底神经节和运动皮质之间的功能连接失调， 帕金森综合征另一个严重限制我们在了解 帕金森病的运动皮质和皮质脊髓系统的病理生理学一直缺乏可靠的工具来研究 皮质脊髓神经元的完整连接体尽管传统的追踪研究表明， M1和SMA富含大量的重叠投射神经元，这些神经元支配广泛的神经元。 基底神经节、丘脑、脑干和脊髓区域，这些投射起源于 不同的或共同的神经元群体在很大程度上仍然是未知的，或者依赖于从小样本中收集的数据。 已识别的锥体神经元样本。在这个项目中，我们将利用独特和高效的 一种新开发的腺相关病毒设计变异体的逆行转运特性， 比较对照组和帕金森病猴皮质脊髓神经元的连接体。因为 离皮质神经元的特定亚型的行为功能源自它们的复杂输出投射 模式，而不仅仅是它们的最终终止位点，深入了解轴突分支模式， 正常和帕金森病状态下的皮质脊髓轴突在我们理解帕金森病中具有极其重要的意义。 帕金森病皮质外流的病理生理学与其他研究中提出的功能研究一起 该应用的项目，我们的研究结果将为开发新的治疗方法奠定基础 方法，如化学遗传学方法，以直接操纵特定亚群的活性， PD中的皮质脊髓神经元。

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.