Corticosubthalamic Plasticity in the Parkinsonian State

帕金森状态下的皮质底丘脑可塑性

• 批准号: 10181087
• 负责人: NOAM HAREL
• 金额: $ 67.96万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10181087
• 关键词: 3-Dimensional; Affect; Affective; Age; Anatomy; Animal Model; Animals; Anisotropy; Autopsy; Basal Ganglia; Behavior; Cognitive; Corpus striatum structure; Data; Denervation; Development; Diffusion; Disease; Disease Progression; Dopamine; Dose; Early Diagnosis; Electrocorticogram; Electrons; Electrophysiology (science); Enrollment; Equilibrium; Evolution; Exhibits; Exposure to; Functional Magnetic Resonance Imaging; Functional disorder; Globus Pallidus; Glutamates; Human; Impairment; Intervention; Label; Lead; Light; Link; Magnetic Resonance Imaging; Measures; Methods; Microscopic; Monkeys; Morphology; Motor; Mus; Neurons; Neuropsychological Tests; Neurotoxins; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Participant; Pathologic; Pathway interactions; Patients; Pattern; Physiological; Play; Proliferating; Resolution; Rest; Role; Scheme; Severities; Signs and Symptoms; Stains; Structure; Structure of subthalamic nucleus; Symptoms; Synapses; Testing; Tissues; Treatment Efficacy; Work; behavior test; clinical examination; density; imaging biomarker; motor control; motor disorder; nerve supply; neuroimaging marker; nonhuman primate; novel; optogenetics; parkinsonian non-human primate; prevent; reconstruction; response; therapy design

ABST RACT In current schemes of the pathophysiology of Parkinson’s disease (PD), neuronal activity changes in the sen- sorimotor region of the subthalamic nucleus (STN) play a central role in the development of parkinsonism. Until recently, the changes in STN activity were thought to result solely from reduced inhibition from the external globus pallidus (GPe). However, recent findings from animal models of advanced parkinsonism have suggested that a profound loss of glutamatergic cortico-subthalamic terminals and an increased strength of GABAergic pallidosubthalamic synapses may contribute to activity changes in the STN and to the development of parkin- sonism. Our preliminary data demonstrate that a loss of cortico-subthalamic terminals is also present in the sensorimotor STN territory of people with advanced PD. It remains unclear, however, how these anatomical and physiologic changes relate to the degree of nigrostriatal dopamine loss and to the expression of parkinsonism. Further, it is unknown if these changes also affect non-motor regions of the STN, perhaps contributing to cogni- tive or affective PD symptoms. We will examine these issues with neuropathological and electrophysiological studies in monkeys with different degrees of MPTP-induced dopamine loss (Aim 1), and with longitudinal 7T ultra-high field MRI studies in people with early PD (Aim 2). In Aim 1, we will record responses of STN neurons to optogenetic activation of cortical and pallidal inputs in monkeys that remained either asymptomatic after ex- posure to small dose of the dopamine-depleting neurotoxin MPTP or became parkinsonian after exposure to (larger doses of) MPTP. We will also assess changes in local field potentials (LFPs) and abnormal spiking activity in STN, and in the coherence between STN LFPs and motor cortical electrocorticograms. In postmortem studies of the same animals, we will use high resolution microscopic immunohistochemical studies and 3D-EM reconstructions to assess whether the number, localization, and morphology of glutamatergic and GABAergic synapses in the STN changes as a function of dopamine loss. We will also compare the number of cortico- subthalamic terminals and examine changes in GABAergic markers in STN tissue from patients with PD and age-matched controls. In Aim 2, we will use state-of-the-art diffusion and resting state functional MRI to test whether humans with early stage PD exhibit significant changes in the volume and microstructural organization of the STN and its cortical and pallidal afferents, and determine if these changes are related to the expression and progression of motor and non-motor impairments. The same patients will be studied at enrollment and 30 months later to examine changes in the MRI measures. The results of this project will increase our understanding of the temporal evolution of parkinsonism-associated plastic changes in the STN, and determine their potential relationships to the development and severity of motor and non-motor signs and symptoms of the disease. These studies may lead to novel interventions to control or prevent abnormal firing patterns in STN and may contribute to the development of imaging biomarkers to identify early stages of PD and predictors of disease progression.

抽象的 在当前的帕金森氏病（PD）病理生理方案中，神经元活性变化 下部核（STN）的索形象区在帕金森氏症的发展中起着核心作用 最近，STN活性的变化是导致Soly因降低外部抑制作用而导致Soly的变化 Globus Pallidus（GPE）。 谷氨酸皮质甲状腺丘脑末端的严重丧失和gabaergic的奇怪 胶囊丘脑突触可能有助于在STN和Parkin-的发展中 我们的初步数据表明，在 具有高级PD的人的感觉运动领域尚不清楚 生理变化与骨纹状体多巴胺丧失的程度和帕金森氏症的表达有关。 此外，尚不清楚这些变化是否也影响了STN的非运动区域，也许有助于认知 Tive或情感PD症状。 在具有MPTP诱导的多巴胺损失（AIM 1）和纵向7T的猴子中进行的研究 在早期PD的人中进行超高的现场MRI研究（AIM 2），我们将记录STN神经元的反应 在猴子中的皮质和苍白球输入的光遗传学激活，这些猴子是在猴子中恢复无症状的 对少量多巴胺的神经毒素MPTP或暴露后成为帕金森氏症 （较大的剂量）MPTP。 STN的活性以及STN LFP和运动皮质图之间的相干性 对同一动物的研究，我们将使用高分辨率微观免疫组织化学研究和3D-EM 评估谷氨酸能和GABA能的数量，定位和形态的重建 STN中的突触为多巴胺损失的AS AS AS。 丘脑下末端并检查PD患者的STN组织中GABA能标记的变化 年龄匹配的控件。 早期PD的人是否在体积和微型组织中表现出重要的意义 STN及其皮质和苍白的强化，并确定这些变化是否与表达相关 运动和非运动障碍的进展将在入学率和30中研究相同的患者 几个月后检查MRI措施的变化。 帕金森主义相关的塑料变化的时间演变，并确定其潜力 与运动的发展和严重程度的关系，这些疾病的症状和症状。 研究可能会导致新的干预措施，以控制STN中的或未经证实的异常射击模式，并可能有助于 发展成像生物标志物以确定PD的早期阶段和疾病计划的预测指标。