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 在帕金森氏病（PD）病理生理学的当前方案中，神经元活性变化 丘脑核核（STN）的s虫区域在帕金森氏症的发展中起着核心作用。直到 最近，认为STN活性的变化仅是由于外部抑制作用而导致的 Globus Pallidus（GPE）。但是，高级帕金森主义动物模型的最新发现提出了 严重丧失了谷氨酸能皮质甲状腺丘脑末端和加巴能的强度增加 胶囊丘脑突触可能会导致STN的活性变化和帕金蛋白的发展 sonism。我们的初步数据表明，在 具有高级PD的人的感觉运动STN领土。但是，尚不清楚这些解剖学和如何 生理变化涉及鼻纹质多巴胺损失的程度和帕金森氏症的表达。 此外，未知这些变化是否也影响STN的非运动区域，也许有助于认知 表面或情感PD症状。我们将研究神经病理和电生理学的这些问题 在具有不同程度的MPTP诱导多巴胺损失的猴子中的研究（AIM 1），纵向7T 对早期PD患者的超高现场MRI研究（AIM 2）。在AIM 1中，我们将记录STN神经元的响应 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 （较大剂量）MPTP。我们还将评估本地田间电位（LFP）和异常尖峰的变化 STN的活性以及STN LFP和运动皮质皮质图之间的相干性。在验尸中 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中的突触随多巴胺损失的函数而变化。我们还将比较皮质的数量 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。在AIM 2中，我们将使用最新的扩散和静止状态功能MRI进行测试 早期PD的人是否暴露了数量和微观结构组织的重大变化 STN及其皮质和苍白的传入，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。同一患者将在入学时研究和30例 几个月后，以检查MRI测量的变化。该项目的结果将增加我们的理解 帕金森主义相关的塑料变化的暂时进化，并确定其潜力 与运动和非运动体征的发展和严重程度的关系以及疾病的症状。这些 研究可能导致新的干预措施来控制或预防STN中异常的发射模式，并可能有助于 成像生物标志物的开发，以确定PD的早期阶段和疾病进展的预测指标。