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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

基本信息

批准号：
10404910
负责人：
ANATOL KREITZER
金额：
$ 6.36万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404910
关键词：
Alzheimer&apos 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

项目摘要

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.

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用于区分内部生成的活动和外部生成的活动。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。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Illuminating Neural Circuits: From Molecules to MRI.

照亮神经回路：从分子到 MRI。

DOI：
10.1523/jneurosci.2569-17.2017
发表时间：
2017
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Lee,JinHyung;Kreitzer,AnatolC;Singer,AnnabelleC;Schiff,NicholasD
通讯作者：
Schiff,NicholasD

Pathway-Specific Remodeling of Thalamostriatal Synapses in Parkinsonian Mice.