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The Primate External Globus Pallidus as a Critical Node in Normal and Parkinsonian Basal Ganglia Circuits

灵长类外苍白球作为正常和帕金森基底神经节回路的关键节点

基本信息

批准号：
10213846
负责人：
Adriana Galvan
金额：
$ 39.05万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-28 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213846
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Anatomy Animal Model Animals Antiparkinson Agents Autopsy Basal Ganglia Biochemical Biochemical Markers Brain Cell Nucleus Characteristics Corpus striatum structure Data Descriptor Electric Stimulation Electrophysiology (science)Engineering FOXP2 gene Functional disorder Future Genetic Globus Pallidus Goals Histological Techniques Human Individual Knowledge Label Lead Literature Macaca mulatta Measures Methods Modeling Molecular Monkeys Motor Movement Neurons Neurotoxins Opsin Parkinson Disease Parkinsonian Disorders Parvalbumins Pathologic Pathway interactions Patients Pattern Pharmaceutical Preparations Physiological Population Presynaptic Terminals Primates Proteins Research Rodent Rodent Model Role Severities Specificity Structure Structure of subthalamic nucleus Study models Subgroup Substantia nigra structure Therapeutic Tracer Translating base brain abnormalities disability experience experimental study extracellular improved in vivo motor deficit motor impairment nonhuman primate novel novel therapeutics optogenetics parkinsonian animal parkinsonian non-human primate promoter protein expression response side effect therapy development tool trait

项目摘要

PROJECT SUMMARY Patients with Parkinson’s disease (PD) experience progressive motor impairments that lead to severe disability. The motor impairments of PD are associated with abnormal neuronal activity in the basal ganglia, a group of brain structures involved in movement planning and execution. The long-term goal of our research is to elucidate how the abnormal activity of the basal ganglia relates to the motor deficits in PD, with the goal of developing novel therapies to treat parkinsonism with improved specificity and fewer unwanted side effects. The proposed studies are focused on the external segment of the globus pallidus (GPe), a key structure in the basal ganglia circuitry. Traditionally, the GPe was thought to be composed of a single neuron type; it is now established that this nucleus contains different types of neurons that can be classified based on their projection targets (‘upstream’ to the striatum, or ‘downstream’ to the subthalamic nucleus or internal pallidum). In rodent models of PD, there is evidence that PD-related abnormalities occur selectively in specific types of GPe neurons, raising the possibility that different GPe neuron populations might make distinct contributions to the normal and pathological roles of the GPe. However, the translational relevance of these findings is limited by functional and anatomical differences between the rodent and primate GPe. Our experiments will define functional differences between classes of GPe neurons in normal rhesus monkeys and in monkeys rendered parkinsonian by treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Monkeys are an excellent animal model for studying PD-related changes in brain activity, because their basal ganglia and connected brain structures closely resemble those in humans, and because MPTP-treated monkeys show the majority of the motor impairments seen in PD patients. We will use electrophysiological in vivo recordings to evaluate differences in the firing rates and patterns of GPe-upstream and GPe-downstream neurons. The projections of individual GPe neurons will be identified by their antidromic responses to electrical stimulation of the target structures (aim 1). To determine how GPe neurons modulate the activity in the striatum, subthalamic nucleus or internal pallidum, we will selectively silence GPe axonal terminals in each of these nuclei, using optogenetic methods. We will also determine whether selective silencing of GPe terminals alters PD-motor impairments in monkeys (aim 2). Finally, we will use histologic techniques to identify proteins whose expression reveals specific GPe neuron projection patterns (aim 3). Our studies will begin to determine how the activities of primate GPe neuron subtypes differ, how they regulate the activity in other basal ganglia neurons in the normal and parkinsonian states, and whether they are involved in the pathophysiology of parkinsonism. The knowledge gained from these studies is significant, as it may enable us to develop new treatments for PD that harness functional and anatomical differences of GPe neuron types.

项目总结