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

摘要 帕金森病（PD）是仅次于阿尔茨海默病的第二大常见神经退行性疾病 疾病），困扰着全世界数千万人。典型的疾病症状来自基底神经节 继发于黑质部多巴胺神经元丢失的功能障碍。 症状治疗的重点是取代多巴胺或破坏异常活动，通过深- 在灵长类动物的丘脑底核或初级基底神经节输出核中的脑刺激， 苍白球（GPi）。本提案旨在了解基底神经节的功能和功能障碍 在小鼠中，在基底神经节到运动丘脑的输出处。在目标1中，我们将制定战略， 在腹侧前/腹侧丘脑（VA/VL）中鉴定基底节受体运动丘脑神经元， 并在清醒的、有行为的动物中描述他们的投射目标和皮层输入。在目标2中，我们将使用 复杂的体内策略，以记录从后部EP神经元和VA/VL神经元作为动物移动他们的神经元。 四肢在运动过程中，一个固定的重复行为。我们将使用光遗传学来干扰这一通路的活性 以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 在纹状体多巴胺丧失后，该途径的活性发生改变。在目标3中，我们将在 小鼠执行一项拉弓任务，一种灵活的前肢运动。我们将检查提示和未提示 此任务的不同版本，以区分内部和外部生成的活动。最后，我们将研究如何损失 纹状体多巴胺的影响EP和VA/VL活动在灵活的前肢运动。我们的首要目标是 了解PD患者纹状体多巴胺的丢失如何导致基底神经节回路功能中断， 运动缺陷，以便开发用于治疗PD运动症状的新的治疗策略。

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.