Parkinsonism-Related Changes in Activity of Cortical Projection Neurons in Monkeys

猴子皮质投射神经元活动与帕金森症相关的变化

• 批准号: 10495219
• 负责人: Adriana Galvan
• 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/10495219
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Address; Affect; Anatomy; Animal Model; Animals; Antiparkinson Agents; Area; Autopsy; Basal Ganglia; Behavior assessment; Behavioral; Benserazide; Bradykinesia; Brain; Cell Nucleus; Cells; Cervical spinal cord structure; Clinical; Clinical Treatment; Complex; Computer Models; Corpus striatum structure; Corticospinal Tracts; Data; Data Analyses; Deep Brain Stimulation; Dopamine; Dopamine Receptor; Effectiveness; Electric Stimulation; Electrophysiology (science); Family; Frequencies; Functional disorder; Genes; Human; Image; Injections; Interneurons; Intervention; Levodopa; Link; MPTP Poisoning; Macaca mulatta; Monkeys; Motor; Motor Cortex; Motor Manifestations; Movement; Neurons; Opsin; Output; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pattern; Pharmacology; Phenotype; Primates; Protocols documentation; Publishing; Receptor Activation; Research; Rest; Rodent; STN stimulation; Service Statistics; Signs and Symptoms; Slice; Specific qualifier value; Standardization; Statistical Data Interpretation; Structure; Structure of subthalamic nucleus; Synaptic plasticity; Techniques; Thalamic structure; Universities; Virus; Work; arm movement; base; dopamine replacement therapy; experimental study; human disease; imaging study; information processing; nonhuman primate; outreach; parkinsonian non-human primate; response; retrograde transport; symptom treatment

Project Summary – Project 2 Striatal dopamine loss in Parkinson’s disease triggers abnormal neuronal activity in the extrastriatal basal ganglia and thalamus. Such changes undoubtedly influence the processing of information in cortical motor fields, con- tributing to clinical features of parkinsonism such as akinesia or bradykinesia. However, cortical activity changes remain poorly understood, in part because of the complexity of the organization of the cortical areas that partic- ipate in the basal ganglia thalamocortical ‘motor’ circuit. Neurons in the motor portion of the basal ganglia output nuclei project to neurons in the ventral motor thalamus which, in turn, send their projections mostly to the sup- plementary motor area (SMA), with additional projections to the primary motor cortex (M1). Previous studies of cortical activity in MPTP-treated parkinsonian monkeys showed that corticospinal neurons in M1 change their spontaneous and task-related activity in the parkinsonian state. However, much remains to be known about activity changes of corticospinal projection neurons in the SMA and the effects of antiparkinsonian therapies on cortical activity. Under aim 1, we will study the parkinsonism-associated changes in spontaneous and task-re- lated activities of neurons in SMA and M1 that give rise to projections to the cervical spinal cord. To identify these specific neurons, we will inject retrogradely transported viruses (AAV2-retro) into the cervical spinal cord, to express opsins in corticospinal neurons, which will then enable identification of these neurons by opto-tagging during cortical optrode recordings. For aim 2, we will investigate whether antiparkinsonian treatments (systemic levodopa injections, or deep brain stimulation of the subthalamic nucleus) influence the altered cortical activities in the parkinsonian state. We hypothesize that the antiparkinsonian interventions will normalize some of the changes identified in aim 1, but that their primary actions may differ. For example, stimulation of the subthalamic nucleus may induce prominent activity changes in corticospinal projection neurons due to antidromic activation (by stimulation of corticosubthalamic collaterals of the corticospinal pathway), an effect that is obviously not expected to occur with levodopa treatment. The proposed studies will significantly contribute to our understand- ing of the pathophysiology of parkinsonism and of the effects of antiparkinsonian therapies, and may pave the way for new antiparkinsonian treatments, such as chemogenetic approaches or new deep brain stimulation ap- proaches, to normalize activity patterns of the studied corticospinal neurons. The planned studies are closely aligned with those in project 1 (studies with similar questions, examined with wide-field imaging and brain slice recordings in rodents, as well as computational modeling), project 3 (studies of ultrastructural synaptic plasticity affecting specific projection neuron families in the primate SMA and M1), and project 4 (studies of cortical elec- trophysiological effects of parkinsonism or antiparkinsonian therapies on response inhibition functions in hu- mans). The planned work will utilize the administrative help of core A, and the anatomy, behavioral assessment and statistics services provided by core B.

项目摘要-项目2 帕金森病患者纹状体多巴胺丢失触发纹状体外基底节神经元异常活动 还有丘脑。这些变化无疑会影响大脑皮质运动区的信息处理。 归因于帕金森氏症的临床特征，如运动障碍或运动迟缓。然而，大脑皮层活动的变化 仍然知之甚少，部分原因是大脑皮质区域组织的复杂性。 基底节丘脑皮质‘马达’环路中的脂肪。基底神经节输出运动部的神经元 核团投射到丘脑腹侧运动神经元，而丘脑腹侧运动神经元又将它们的投射主要发送到上丘脑。 主要运动区(SMA)，以及向初级运动皮质(M1)的额外投射。以前的研究 MPTP治疗帕金森病猴的皮质活动显示，M1区的皮质脊髓神经元改变了它们的 帕金森氏症患者的自发活动和任务相关活动。然而，仍有许多事情有待了解。 SMA内皮质脊髓投射神经元的活动变化及抗帕金森病治疗对其的影响 大脑皮层活动。在目标1下，我们将研究帕金森病相关的自发和任务-再分配的变化。 SMA和M1内神经元的晚期活动，引起向颈髓的投射。要确定这些 我们将把逆行运输的病毒(AAV2-retro)注射到颈髓中，以 在皮质脊髓神经元中表达视蛋白，这将使通过光标记识别这些神经元成为可能 在大脑皮层视路记录期间。对于目标2，我们将调查抗帕金森症治疗(系统性 注射左旋多巴，或刺激丘脑底核)影响改变的皮质活动 处于帕金森氏症状态。我们假设，抗帕金森病的干预措施将使一些 目标1中确定的变化，但它们的主要行动可能不同。例如，刺激丘脑下部 核团逆行激活可引起皮质脊髓投射神经元活动的显著改变 (通过刺激皮质脊髓通路的皮质下丘脑侧支)，这一效应显然不是 预计会在左旋多巴治疗中发生。拟议的研究将大大有助于我们了解- 帕金森病的病理生理学和抗帕金森病治疗的效果，并可能为 新的抗帕金森病治疗方法，如化学发生方法或新的脑深部刺激方法- 方法，使研究的皮质脊髓神经元的活动模式正常化。计划中的研究正在密切进行中 与项目1(有类似问题的研究，用广域成像和脑切片检查)保持一致 啮齿动物的记录以及计算模型)，项目3(超微结构突触可塑性的研究 影响灵长类SMA和M1中的特定投射神经元家族)，以及项目4(皮质电研究- 帕金森病或抗帕金森病治疗对人的反应抑制功能的生理影响 曼斯)。计划的工作将利用核心A的行政帮助，以及解剖、行为评估 和核心B提供的统计服务。