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

• 批准号: 8450877
• 负责人: ANATOL KREITZER
• 金额: $ 39.51万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450877
• 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; Cell physiology; Cells; Chronic; Color; Control Animal; Corpus striatum structure; Development; Dopamine; Dopamine D1 Receptor; 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; Health; 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; induced pluripotent stem cell; 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; relating to nervous system; sequence learning; synaptic function

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.

描述(由申请者提供)：控制一个人的行动的能力是生活中必不可少的。涉及基底节的神经回路是锥体外系运动系统的关键组成部分，这是适应性运动控制和程序性学习所必需的。这些回路的中断会导致严重的运动障碍，如帕金森氏症和亨廷顿病。纹状体是基底神经节的输入核，是依赖活动的可塑性和神经调节的主要部位，特别是受多巴胺的调节。由于纹状体位于其他基底节核的上游，该区域内的细胞和突触的可塑性改变了整个基底节回路的信息传递。然而，纹状体功能和功能障碍的研究一直受到主神经元和中间神经元群体显著异质性的阻碍。我建议利用最近开发的转基因小鼠品系来鉴定调节纹状体输出和基底节回路功能的细胞类型特异性和可塑性。我还将研究多巴胺耗竭小鼠的这些特性是如何改变的，以深入了解帕金森病基础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点，目的是使帕金森病小鼠的基底节回路活动正常化，恢复正常的运动功能。这些研究的最终目标是发现治疗纹状体脑部疾病的新治疗策略。