Neuron- and Circuit-Specific Mechanisms and Adaptations Regulating Striatal Funct

调节纹状体功能的神经元和电路特异性机制和适应

基本信息

批准号：
7741833
负责人：
ANATOL KREITZER
金额：
$ 41.78万
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 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7741833
关键词：
Acetylcholine Acute Address Adenosine Animals Atlases Attention deficit hyperactivity disorder BAC (bacterial artificial chromosome)Basal Ganglia Base of the Brain Behavior Behavior Disorders Brain Brain Diseases Brain region Cell Nucleus Cells Chronic Color Control Animal Corpus striatum structure Development Dopamine Dopamine D2 Receptor Dystonia Electrophysiology (science)Endocannabinoids Frequencies Functional disorder Gene Expression Gilles de la Tourette syndrome Globus Pallidus Glutamate Receptor Goals Green Fluorescent Proteins Heterogeneity Human Huntington Disease Interneuron function Interneurons Learning Life Long-Term Depression Long-Term Potentiation Mammals Medial Midbrain structure Motor Motor Activity Motor output Movement Movement Disorders Mus N-Methyl-D-Aspartate Receptors Nervous System Physiology Nervous system structure Neuromodulator Neuronal Plasticity Neurons Obsessive-Compulsive Disorder Output Oxidopamine Parkinson Disease Parkinsonian Disorders Pathway interactions Physiologic pulse Physiological Population Potassium Property Prosencephalon Proteins Pyramidal Cells Receptor Activation Rodent Role Signal Pathway Signaling Molecule Site Slice Stereotyping Structure of subthalamic nucleus Substantia nigra structure Synapses Synaptic plasticity System Testing Thalamic structure Therapeutic Transgenic Mice cell type dopaminergic neuron in vivo insight locomotor deficit motor control motor learning mouse model nerve supply nervous system disorder neural circuit neuroregulation neurotransmission novel novel therapeutics pars compacta patch clamp postsynaptic public health relevance relating to nervous system sequence learning synaptic function

Acetylcholine Acute Address Adenosine Animals Atlases Attention deficit hyperactivity disorder BAC (bacterial artificial chromosome)Basal Ganglia Base of the Brain Behavior Behavior Disorders Brain Brain Diseases Brain region Cell Nucleus Cells Chronic Color Control Animal Corpus striatum structure Development Dopamine Dopamine D2 Receptor Dystonia Electrophysiology (science)Endocannabinoids Frequencies Functional disorder Gene Expression Gilles de la Tourette syndrome Globus Pallidus Glutamate Receptor Goals Green Fluorescent Proteins Heterogeneity Human Huntington Disease Interneuron function Interneurons Learning Life Long-Term Depression Long-Term Potentiation Mammals Medial Midbrain structure Motor Motor Activity Motor output Movement Movement Disorders Mus N-Methyl-D-Aspartate Receptors Nervous System Physiology Nervous system structure Neuromodulator Neuronal Plasticity Neurons Obsessive-Compulsive Disorder Output Oxidopamine Parkinson Disease Parkinsonian Disorders Pathway interactions Physiologic pulse Physiological Population Potassium Property Prosencephalon Proteins Pyramidal Cells Receptor Activation Rodent Role Signal Pathway Signaling Molecule Site Slice Stereotyping Structure of subthalamic nucleus Substantia nigra structure Synapses Synaptic plasticity System Testing Thalamic structure Therapeutic Transgenic Mice cell type dopaminergic neuron in vivo insight locomotor deficit motor control motor learning mouse model nerve supply nervous system disorder neural circuit neuroregulation neurotransmission novel novel therapeutics pars compacta patch clamp postsynaptic public health relevance relating to nervous system sequence learning synaptic function

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项目摘要

DESCRIPTION (provided by applicant): The ability to control one's movements is essential to life. Neural circuits involving the basal ganglia are a key component of the extrapyramidal motor system, which is required for adaptive motor control and procedural learning. Disruption of these circuits leads to profound movement disorders, such as Parkinson's disease and Huntington's disease. The striatum, which is the input nucleus of the basal ganglia, is a major site of activity- dependent plasticity and neuromodulation, particularly by dopamine. Because the striatum lies upstream of other basal ganglia nuclei, cellular and synaptic plasticity within this region alters the transfer of information throughout basal ganglia circuits. However, studies of the striatal function and dysfunction have been hampered by significant heterogeneity in both principal and interneuron populations. I propose to utilize recently developed transgenic mouse lines to identify cell-type-specific properties and plasticity that regulate striatal output and basal ganglia circuit function. I will also examine how these properties are altered in dopamine-depleted mice in order to gain insight into the mechanisms underlying basal ganglia dysfunction in Parkinson's disease. Finally, I will seek to identify pharmacological targets that enable in vivo manipulation of striatal output, with the goal of normalizing basal ganglia circuit activity and restoring proper locomotor function in Parkinsonian mice. The ultimate goal of these studies is to uncover novel therapeutic strategies for treating striatal-based brain disorders. PUBLIC HEALTH RELEVANCE The control of movement is among the most fundamental of all nervous system functions. Movement disorders such as Parkinson's disease and Huntington's disease are debilitating neurological disorders that result from altered neural activity in the striatum, a core region of the brain involved in motor control. We propose to characterize how different cells interact in the striatum to produce output that controls motor activity. The long- term goal is to develop a framework for the development of novel therapies for treating movement disorders involving the striatum.

描述（由申请人提供）：控制自己的运动的能力对生活至关重要。涉及基底神经节的神经回路是锥体外运动系统的关键组成部分，这是自适应运动控制和程序学习所必需的。这些电路的破坏会导致严重的运动障碍，例如帕金森氏病和亨廷顿氏病。纹状体是基底神经节的输入核，是活性依赖性可塑性和神经调节的主要部位，尤其是多巴胺。因为纹状体位于其他基底神经节核的上游，所以该区域内的细胞和突触可塑性会改变整个基底神经节电路的信息的传递。然而，对主体和神经元间种群的显着异质性，对纹状体功能和功能障碍的研究受到了阻碍。我建议利用最近开发的转基因小鼠系来识别调节纹状体输出和基底神经节电路功能的细胞类型特异性特性和可塑性。我还将研究如何改变多巴胺耗尽小鼠的这些特性，以了解帕金森氏病基底神经节功能障碍的机制。最后，我将寻求确定能够在体内操纵纹状体输出的药理靶标，其目的是使基底神经节电路活性正常并恢复帕金森氏症小鼠的适当运动功能。这些研究的最终目的是发现治疗基于纹状体的脑疾病的新型治疗策略。公共卫生相关性运动的控制是所有神经系统功能中最基本的。诸如帕金森氏病和亨廷顿氏病等运动障碍是使神经系统疾病的使人衰弱，这些神经系统疾病是由于纹状体的神经活动改变而导致的，纹状体的神经活动是参与运动控制的大脑的核心区域。我们建议表征不同细胞在纹状体中如何相互作用以产生控制运动活动的输出。长期目标是为开发涉及纹状体的运动障碍的新疗法开发框架。