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 帕金森氏病的纹状体多巴胺损失触发了层室外神经节神经元的异常神经元活性 和丘脑。这种变化无疑会影响皮质运动场中信息的处理， 为帕金森氏症的临床特征（例如阿肯西亚或金发肌症）提供支持。但是，皮质活动变化 保持不当理解，部分原因是皮质区域组织的复杂性 在基底神经节丘脑皮层“电动机”电路中ipeate。基底神经节输出的运动部分中的神经元 细胞核向腹运动丘脑中的神经元投射，而腹部运动丘脑中的神经元主要将其项目发送到SUP- 培训运动区域（SMA），并提供了主要运动皮层（M1）的其他项目。先前的研究 MPTP处理的帕金森尼猴子的皮质活动表明，M1中的皮质脊髓神经元改变了它们 帕金森州的赞助​​和与任务有关的活动。但是，关于 SMA中皮质脊髓投射神经元的活性变化以及抗帕金森氏疗法对 皮质活动。在AIM 1下，我们将研究帕金森主义相关的赞助和任务变化 SMA和M1中神经元的层压活动为颈椎带来了项目。识别这些 特定的神经元，我们将逆行运输的病毒（AAV2- retro）注入颈脊髓， 皮质脊髓神经元中的快递蛋白，然后通过选择标记来识别这些神经元 在皮质optrode记录中。对于AIM 2，我们将调查是否有抗帕金森氏症治疗（全身治疗 左旋多巴注射，或对丘脑下核的深脑刺激）会影响皮质活性改变 在帕金森州。我们假设抗帕金森尼的干预措施将标准化一些 AIM 1中确定的变化，但其主要行动可能有所不同。例如，刺激丘脑下 核可能引起由于抗肿瘤激活而导致皮质脊髓投射神经元的显着活性变化 （通过刺激皮质脊髓途径的皮质丘脑旁边），显然不是这种作用 预计将发生左旋多巴治疗。拟议的研究将有助于我们的理解 - 帕金森氏症的病理生理学和抗帕金森氏疗法的作用，并可能铺平 新的反帕金森氏治疗方法，例如化学发生方法或新的深脑刺激AP- 促进，以使Stutiod皮质脊髓神经元的活性模式归一化。计划的研究密切 与项目1中的人员保持一致（与宽场成像和大脑切片相似的研究研究 项目3（超微结构突触可塑性的研究） 影响灵长类SMA和M1中的特定投影神经元家族和项目4（皮质ELEC-的研究 帕金森氏症或抗帕金森氏症疗法对HU-的反应抑制功能的营养生理影响 芒）。计划的工作将利用核心A的行政帮助以及解剖学，行为评估 以及CoreB提供的统计服务。