Corticosubthalamic Plasticity in the Parkinsonian State

帕金森状态下的皮质底丘脑可塑性

• 批准号: 10164113
• 负责人: NOAM HAREL
• 金额: $ 6.38万
• 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/10164113
• 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; Hydroxydopamines; Impairment; Intervention; Label; Lead; Light; Link; Magnetic Resonance Imaging; Measures; Methods; Microscopic; Monkeys; Morphology; Motor; Mus; Neurons; Neuropsychological Tests; Neurotoxins; 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; prevent; reconstruction; response; therapy design

ABSTRACT 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.

摘要 在帕金森病（PD）的病理生理学的当前方案中，感觉神经元活动的变化， 丘脑底核（subthalamic nucleus，简称丘脑底核）的运动区（sorimotor region）在帕金森综合征的发生发展中起着重要作用。直到 最近，研究人员认为，细胞活性的变化仅仅是由于外界抑制作用的减弱所致。 苍白球（GPe）。然而，最近从晚期帕金森病动物模型中的发现表明， 皮质-丘脑底神经末梢的大量丢失和GABA能神经末梢强度的增加， 苍白球底丘脑突触可能有助于活动的变化，在丘脑和帕金森氏病的发展， sonism。我们的初步数据表明，皮质-丘脑底核终末的丢失也存在于 感觉运动障碍是晚期帕金森病患者的主要领域。然而，目前尚不清楚这些解剖学和 生理变化与黑质纹状体多巴胺损失的程度和帕金森综合征的表现有关。 此外，尚不清楚这些变化是否也影响了小脑的非运动区，可能有助于认知功能。 或情感性PD症状。我们将用神经病理学和电生理学来研究这些问题 在具有不同程度MPTP诱导的多巴胺丢失（Aim 1）的猴子中进行的研究， 早期PD患者的超高场MRI研究（Aim 2）。在目标1中，我们将记录神经元的反应， 猴子的皮质和苍白球输入的光遗传学激活， 服用小剂量的多巴胺消耗性神经毒素MPTP或在暴露于 （大剂量）MPTP。我们还将评估局部场电位（LFP）和异常尖峰的变化 活动的大脑皮层，并在连贯性之间的运动LFPs和运动皮层脑电图。宰后 研究相同的动物，我们将使用高分辨率显微镜免疫组织化学研究和3D-EM 重建，以评估是否有数量，定位和形态的谷氨酸能和GABA能 突触的变化是多巴胺丢失的函数。我们也会比较皮质的数量- 丘脑底核终末，并检查PD患者的丘脑组织中GABA能标记物的变化， 年龄匹配的对照组。在目标2中，我们将使用最先进的弥散和静息状态功能MRI来测试 早期PD患者是否表现出体积和微结构组织的显著变化 以及皮质和苍白球的传入，并确定这些变化是否与表达 以及运动和非运动损伤的进展。相同的患者将在入组时进行研究， 几个月后，检查MRI测量的变化。这个项目的结果将增加我们对 帕金森病相关的可塑性变化的时间演变，并确定其潜力 与疾病的运动和非运动体征和症状的发展和严重程度的关系。这些 研究可能会导致新的干预措施，以控制或防止异常放电模式，并可能有助于 开发成像生物标志物以识别PD的早期阶段和疾病进展的预测因素。