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:
  • 金额:
    $ 39.05万
  • 依托单位:
  • 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

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

项目成果

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Adriana Galvan其他文献

Adriana Galvan的其他文献

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{{ truncateString('Adriana Galvan', 18)}}的其他基金

Development of a non-invasive method to monitor expression and function of optogenetic tools in non-human primates
开发一种非侵入性方法来监测非人类灵长类动物中光遗传学工具的表达和功能
  • 批准号:
    10451093
  • 财政年份:
    2022
  • 资助金额:
    $ 39.05万
  • 项目类别:
Chemogenetic Inactivation of the Primate Internal Globus Pallidus as a treatment for Parkinsonism
灵长类内部苍白球的化学遗传学灭活治疗帕金森病
  • 批准号:
    10577404
  • 财政年份:
    2022
  • 资助金额:
    $ 39.05万
  • 项目类别:
Development of a non-invasive method to monitor expression and function of optogenetic tools in non-human primates
开发一种非侵入性方法来监测非人类灵长类动物中光遗传学工具的表达和功能
  • 批准号:
    10633118
  • 财政年份:
    2022
  • 资助金额:
    $ 39.05万
  • 项目类别:
Chemogenetic Inactivation of the Primate Internal Globus Pallidus as a treatment for Parkinsonism
灵长类内部苍白球的化学遗传学灭活治疗帕金森病
  • 批准号:
    10710400
  • 财政年份:
    2022
  • 资助金额:
    $ 39.05万
  • 项目类别:
Research Services Core
研究服务核心
  • 批准号:
    10284845
  • 财政年份:
    2021
  • 资助金额:
    $ 39.05万
  • 项目类别:
Parkinsonism-Related Changes in Activity of Cortical Projection Neurons in Monkeys
猴子皮质投射神经元活动与帕金森症相关的变化
  • 批准号:
    10284848
  • 财政年份:
    2021
  • 资助金额:
    $ 39.05万
  • 项目类别:
Parkinsonism-Related Changes in Activity of Cortical Projection Neurons in Monkeys
猴子皮质投射神经元活动与帕金森症相关的变化
  • 批准号:
    10495219
  • 财政年份:
    2021
  • 资助金额:
    $ 39.05万
  • 项目类别:
Research Services Core
研究服务核心
  • 批准号:
    10495209
  • 财政年份:
    2021
  • 资助金额:
    $ 39.05万
  • 项目类别:
Trajectories of Brain Maturation among Youth at Risk for Anxiety
有焦虑风险的青少年的大脑成熟轨迹
  • 批准号:
    10661482
  • 财政年份:
    2017
  • 资助金额:
    $ 39.05万
  • 项目类别:
Trajectories of Brain Maturation among Youth at Risk for Anxiety
有焦虑风险的青少年的大脑成熟轨迹
  • 批准号:
    9312090
  • 财政年份:
    2017
  • 资助金额:
    $ 39.05万
  • 项目类别:

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