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Corticosubthalamic Plasticity in the Parkinsonian State

帕金森状态下的皮质底丘脑可塑性

基本信息

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
项目类别：
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

项目摘要

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.

ABST RACT