Neuron- and Circuit-Specific Mechanisms and Adaptations Regulating Motor Function in Parkinson Disease Models

帕金森病模型中调节运动功能的神经元和电路特异性机制和适应

• 批准号: 10093142
• 负责人: ANATOL KREITZER
• 金额: $ 46.86万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10093142
• 关键词: Alzheimer' s Disease; Animals; Anterior; Axon; Basal Ganglia; Behavior; Brain Stem; Cell Nucleus; Cerebral cortex; Characteristics; Corpus striatum structure; Cues; Deep Brain Stimulation; Disease; Disease model; Dopamine; Electrophysiology (science); Eye Movements; Forelimb; Functional disorder; Globus Pallidus; Goals; Head; Homologous Gene; Laboratories; Lateral; Limb structure; Locomotion; Measures; Methods; Midbrain structure; Modeling; Modernization; Motor; Movement; Mus; Neurodegenerative Disorders; Neurons; Neurosciences; Output; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Periodicity; Phase; Play; Population; Primates; Psychological reinforcement; Regulation; Research; Rodent; Role; Scheme; Secondary to; Shapes; Site; Structure of subthalamic nucleus; Substantia nigra structure; Subthalamic structure; Symptoms; Testing; Thalamic structure; Therapeutic; Time; Wild Type Mouse; awake; base; body position; cell type; deep learning; density; dopaminergic neuron; endopeduncular nucleus; experimental study; flexibility; in vivo; insight; kinematics; limb movement; motor behavior; motor control; motor deficit; motor disorder; motor symptom; mouse model; novel; novel therapeutic intervention; optogenetics; parkinsonian rodent; pars compacta; predictive modeling; programs; repetitive behavior; symptom treatment; tool

ABSTRACT Parkinson's disease (PD) is the second most common neurodegenerative disease (after Alzheimer's disease), afflicting tens of millions worldwide. The characteristic disease symptoms arise from basal ganglia dysfunction that occurs secondary to loss of dopamine neurons in the substantia nigra pars compacta. Symptomatic treatment is focused either on replacing dopamine or disrupting aberrant activity through deep- brain stimulation in the subthalamic nucleus or the primary basal ganglia output nucleus in the primate, internal globus pallidus (GPi). This proposal is aimed at understanding the function and dysfunction of basal ganglia circuitry in mice, at the output of the basal ganglia to motor thalamus. In Aim 1, we will develop strategies to identify basal ganglia-recipient motor thalamus neurons in ventral anterior/ventral lateral thalamus (VA/VL), and characterize their projection targets and cortical inputs in awake, behaving animals. In Aim 2, we will use sophisticated in vivo strategies to record from posterior EP neurons and VA/VL neurons as animals move their limbs during locomotion, a fixed repetitive behavior. We will perturb activity in this pathway using optogenetics to determine the contribution of activity in these neurons to forelimb movements, and we will examine how activity in this pathway is altered after loss of striatal dopamine. In Aim 3, we will perform similar experiments in mice performing a lever-pulling task, a flexible forelimb movement. We will examine both cued and uncued versions of this task to distinguish activity generated internally vs. externally. Finally, we will examine how loss of striatal dopamine impacts EP and VA/VL activity during flexible forelimb movements. Our overarching goal is to understand how loss of striatal dopamine in PD leads to disruptions in basal ganglia circuit function and motor deficits, in order to develop novel therapeutic strategies for treating PD motor symptoms.

抽象的 帕金森病 (PD) 是第二常见的神经退行性疾病（仅次于阿尔茨海默病） 病），困扰着全世界数千万人。特征性的疾病症状源自基底神经节 继发于黑质致密部多巴胺神经元丧失而发生的功能障碍。 对症治疗的重点是替代多巴胺或通过深层治疗来破坏异常活动。 灵长类动物的丘脑底核或初级基底神经节输出核的脑刺激，内部 苍白球（GPi）。该提案旨在了解基底神经节的功能和功能障碍 小鼠的基底神经节到运动丘脑的输出电路。在目标 1 中，我们将制定战略 识别腹侧前/腹外侧丘脑 (VA/VL) 中的基底神经节受体运动丘脑神经元， 并描述它们在清醒、有行为的动物中的投射目标和皮质输入。在目标 2 中，我们将使用 当动物移动其后部 EP 神经元和 VA/VL 神经元时，采用复杂的体内策略进行记录 四肢在运动过程中，进行固定的重复行为。我们将使用光遗传学扰乱该途径的活动 为了确定这些神经元的活动对前肢运动的贡献，我们将研究如何 该通路的活性在纹状体多巴胺丧失后发生改变。在目标 3 中，我们将进行类似的实验 小鼠执行拉杆任务，即灵活的前肢运动。我们将检查有提示和无提示的情况 该任务的版本用于区分内部生成的活动与外部生成的活动。最后，我们将研究损失如何 纹状体多巴胺在灵活的前肢运动过程中影响 EP 和 VA/VL 活动。我们的总体目标是 了解帕金森病中纹状体多巴胺的丧失如何导致基底神经节回路功能中断，以及 运动缺陷，以便开发治疗 PD 运动症状的新治疗策略。