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: 10284848
• 负责人: Adriana Galvan
• 金额: $ 44.93万
• 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/10284848
• 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神经节异常神经元活动 和丘脑。这种变化无疑会影响皮层运动场的信息处理， 归因于帕金森症的临床特征，如运动不能或运动迟缓。然而，大脑皮层的活动 仍然知之甚少，部分原因是大脑皮层组织的复杂性， 在基底神经节丘脑皮质“运动”回路中的ipate。基底神经节输出运动部分的神经元 核投射到腹侧运动丘脑中的神经元，而腹侧运动丘脑又将它们的投射主要发送到上丘脑， 补充运动区（SMA），具有到初级运动皮层（M1）的额外投射。以往的研究 MPTP治疗的帕金森病猴的皮质活动表明，M1中的皮质脊髓神经元改变了它们的 帕金森状态下的自发和任务相关活动。然而，仍有许多事情有待了解。 SMA皮质脊髓投射神经元的活动变化及抗帕金森病治疗的影响 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发生的变化。 SMA和M1中神经元的活动延迟，引起向颈脊髓的投射。识别这些 具体的神经元，我们将注射逆行转运病毒（AAV 2-retro）到颈脊髓， 在皮质脊髓神经元中表达视蛋白，然后通过光标记来识别这些神经元 在皮层光电极记录期间。对于目标2，我们将研究抗帕金森病治疗（全身性） 左旋多巴注射或丘脑底核的深部脑刺激）影响改变的皮层活动 在帕金森状态。我们假设，抗帕金森病干预措施将使一些正常化， 目标1中确定的变化，但它们的主要行动可能不同。例如，刺激丘脑底核 在皮质脊髓投射神经元中，由于逆行激活，核可引起显著的活动变化 (by刺激皮质脊髓通路的皮质底丘脑侧支），这种作用显然不是 预期在左旋多巴治疗中发生。建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，并可能铺平道路， 新的抗帕金森病治疗方法，如化学遗传学方法或新的脑深部电刺激， 方法，使所研究的皮质脊髓神经元的活动模式正常化。计划中的研究与 与项目1中的研究（具有类似问题的研究，用宽视野成像和脑切片检查）一致 记录在啮齿动物，以及计算建模），项目3（研究超微结构突触可塑性 影响灵长类动物SMA和M1中的特定投射神经元家族），以及项目4（皮层神经元的研究， 帕金森病或抗帕金森病治疗对hu- mans）。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 核心B提供的统计服务。