Nigrostriatal dopamine function

黑质纹状体多巴胺功能

• 批准号: 7884314
• 负责人: James M Tepper
• 金额: $ 33.46万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884314
• 关键词: Action Potentials; Adult; Affect; Age; Agonist; American; Amino Acids; Anatomy; Animal Model; Animals; Basal Ganglia; Bathing; Brain; Brightfield Microscopy; Calcium-Binding Proteins; Carboxy-Lyases; Cell Count; Cells; Contralateral; Corpus striatum structure; Coupled; Coupling; Data; Denervation; Development; Disease; Dopamine; Dopamine Receptor; Elderly; Engineering; Enzymes; Financial compensation; Fluorescence; Genetically Engineered Mouse; Globus Pallidus; Glutamate Decarboxylase; In Vitro; Incidence; Injection of therapeutic agent; Interneurons; Ipsilateral; Label; Lesion; Lighting; Measures; Mediating; Membrane Potentials; Minor; Molecular Profiling; Morphology; Motor; Movement; Mus; Neostriatum; Neurons; Nomarski Interference Contrast Microscopy; Oxidopamine; Parkinson Disease; Pathway interactions; Pharmacology; Phenotype; Physiologic pulse; Physiology; Play; Population; Primates; Probability; Property; Replacement Therapy; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Slice; Source; Structure; Substantia nigra structure; Symptoms; Synapses; Testing; Time; Training; Transgenic Mice; Translating; Tyrosine 3-Monooxygenase; Voltage-Clamp Technics; Whole-Cell Recordings; biocytin; cell type; cholinergic; cognitive function; dopamine transporter; dopaminergic neuron; enhanced green fluorescent protein; extracellular; gamma-Aminobutyric Acid; immunocytochemistry; median forebrain bundle; motor learning; nervous system disorder; neurochemistry; neurotransmission; nigrostriatal pathway; novel; novel therapeutic intervention; postsynaptic; presynaptic; promoter; public health relevance; research study; response; retrograde transport; synthetic enzyme; vesicular monoamine transporter; voltage; voltage clamp

DESCRIPTION (provided by applicant): The basal ganglia is an essential component of the central circuitry controlling voluntary movement as well as sensorimotor integration, motor and non-motor learning, and a number of higher cognitive functions. The major input structure of the basal ganglia is the striatum, comprised mostly of medium sized GABAergic spiny projection neurons (MSNs) that make up about 95% of striatal neurons in the rodent. The remaining neurons consist of cholinergic interneurons and 3 types of GABAergic interneurons. The GABAergic interneurons play a crucial role in striatal function by participating in a powerful feedforward inhibitory circuit that affects spike timing in the spiny neurons. Dopamine (DA), originating in the substantia nigra, has long been recognized to play an essential role in striatal function, and it is the degeneration of the nigrostriatal DAergic pathway that is the cause of Parkinson's disease, a progressive and incurable disorder that affects between 1 and 1.5 million Americans. In addition to the cell types listed above, a population of striatal neurons has been recognized that expresses tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA. In primates essentially all of these neurons also express the DA transporter (DAT) suggesting strongly that they are DAergic. These neurons also express glutamate decarboxylase, the enzyme responsible for the synthesis of GABA and a common marker for GABAergic neurons. The numbers of these neurons increases several-fold following DA denervation, and some of these neurons have been shown to express L-amino acid decarboxylase (AADC) and the vesicular monoamine transporter (VMAT). These neurons could represent a heretofore-unappreciated source of striatal DA and a potentially useful source of compensation for DA loss in idiopathic Parkinson's disease as well as a potential target for novel therapeutic approaches to the treatment of the disease. These striatal TH+ neurons represent novel components of the intrastriatal circuitry about which little or nothing is known, since they have never been recorded from, but only studied with immunocytochemistry. We used striatal slices from mice genetically engineered to express enhanced green fluorescent protein (EGFP) under the control of the TH promoter to obtain visually guided recording from these neurons in brain slices. We have identified 4 electrophysiologically distinct subtypes and provide preliminary data on their efferent and afferent synaptic connectivity. Using these mice, both untreated and after unilateral dopaminergic denervation and/or L-DOPA replacement therapy, we will describe the basic electrophysiological properties of striatal DA neurons, their afferent and efferent connectivity, compensatory changes in DA depletion animal models of PD, and their role in striatal DA and GABAergic neurotransmission. In addition, these mice afford a novel way to study the electrophysiological and anatomical properties of uncharacterized populations of striatal interneurons that have been difficult or impossible to study previously in any systematic way. PUBLIC HEALTH RELEVANCE Parkinson's disease (PD) is the most common neurological disorder, affecting nearly 15% of people over the age of 65 and over 50% of people over the age of 85. This translates to approximately 1.5 million Americans. The disease is progressive and incurable. PD is caused by a loss of dopamine input to the neostriatum, a brain structure that controls voluntary movement. In this project we will characterize electrophysiologically, neurochemically and neuroanatomically novel dopamine-like neurons in the striatum that have the potential to serve as the focal point for novel therapeutic approaches to ameliorating the symptoms of the PD.

描述（由申请人提供）：基底神经节是控制自主运动以及感觉运动整合、运动和非运动学习以及许多高级认知功能的中枢回路的重要组成部分。基底神经节的主要输入结构是纹状体，其主要由中等大小的GABA能多刺投射神经元（MSN）组成，其构成啮齿动物中纹状体神经元的约95%。其余神经元包括胆碱能中间神经元和3种类型的GABA能中间神经元。GABA能中间神经元通过参与影响棘状神经元中的发放时间的强大前馈抑制回路而在纹状体功能中发挥关键作用。起源于黑质的多巴胺（DA）长期以来被认为在纹状体功能中起重要作用，并且黑质纹状体DA能通路的退化是帕金森病的原因，帕金森病是一种影响1至150万美国人的进行性和不可治愈的疾病。除了上面列出的细胞类型，纹状体神经元的人口已被确认，表达酪氨酸羟化酶（TH），在DA合成的限速酶。在灵长类动物中，基本上所有这些神经元也表达DA转运蛋白（DAT），强烈表明他们是DA能。这些神经元还表达谷氨酸脱羧酶，该酶负责GABA的合成，并且是GABA能神经元的常见标记物。这些神经元的数量增加了几倍以下DA去神经，这些神经元中的一些已被证明表达L-氨基酸脱羧酶（AADC）和囊泡单胺转运蛋白（VMAT）。这些神经元可能代表了迄今为止未被重视的纹状体DA的来源和潜在有用的来源，在特发性帕金森病的DA损失的补偿，以及一个潜在的目标，新的治疗方法来治疗疾病。这些纹状体TH+神经元代表纹状体内电路的新组件，很少或根本不知道，因为他们从来没有被记录，但只研究了免疫细胞化学。我们使用了基因工程小鼠的纹状体切片，在TH启动子的控制下表达增强型绿色荧光蛋白（EGFP），以获得大脑切片中这些神经元的视觉引导记录。我们已经确定了4个电生理不同的亚型，并提供了初步的数据，他们的传出和传入突触连接。使用这些小鼠，无论是未经处理的和单侧多巴胺能去神经支配和/或左旋多巴替代治疗后，我们将描述纹状体DA神经元的基本电生理特性，其传入和传出连接，DA耗竭PD动物模型的代偿性变化，以及它们在纹状体DA和GABA能神经传递中的作用。此外，这些小鼠提供了一种新的方法来研究未表征的纹状体中间神经元群体的电生理学和解剖学特性，这些群体以前很难或不可能以任何系统的方式进行研究。帕金森病（PD）是最常见的神经系统疾病，影响近15%的65岁以上人群和超过50%的85岁以上人群。这相当于大约150万美国人。这种疾病是渐进的，无法治愈。帕金森病是由新纹状体多巴胺输入的损失引起的，新纹状体是一种控制随意运动的大脑结构。在这个项目中，我们将电生理学，神经化学和神经解剖学的特点新的多巴胺样神经元在纹状体，有可能作为新的治疗方法，以改善PD症状的焦点。