Nigrostriatal dopamine function

黑质纹状体多巴胺功能

• 批准号: 8132776
• 负责人: James M Tepper
• 金额: $ 6.35万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8132776
• 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、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央电路的重要组成部分。基底神经节的主要输入结构是纹状体，纹状体主要由中等大小的GABAergic spiny projection neurons （MSNs）组成，约占鼠纹状体神经元的95%。其余神经元由胆碱能中间神经元和3种氨基丁酸能中间神经元组成。gaba能中间神经元在纹状体功能中起着至关重要的作用，它参与了一个强大的前馈抑制回路，影响棘神经元的峰值时间。多巴胺（DA）起源于黑质，长期以来一直被认为在纹状体功能中起着至关重要的作用，而正是黑质纹状体DAergic通路的退化导致了帕金森病，这是一种进行性且无法治愈的疾病，影响了100万至150万美国人。除了上面列出的细胞类型，纹状体神经元群体也表达酪氨酸羟化酶（TH），这是合成DA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），这强烈表明它们是DAergic。这些神经元也表达谷氨酸脱羧酶，这种酶负责GABA的合成，是GABA能神经元的共同标记物。DA失神经支配后，这些神经元的数量增加了数倍，其中一些神经元已被证明表达l-氨基酸脱羧酶（AADC）和囊泡单胺转运蛋白（VMAT）。这些神经元可能是迄今为止未被认识的纹状体DA来源，也是特发性帕金森病中DA损失的潜在有用补偿来源，也是治疗该疾病的新治疗方法的潜在靶点。这些纹状体TH+神经元代表了纹状体内回路的新组成部分，由于它们从未被记录下来，但仅用免疫细胞化学进行了研究，因此对其知之甚少或一无所知。在TH启动子的控制下，我们使用基因工程小鼠纹状体切片表达增强的绿色荧光蛋白（EGFP），以获得脑切片中这些神经元的视觉引导记录。我们已经确定了4种不同的电生理亚型，并提供了它们的传出和传入突触连通性的初步数据。我们将描述纹状体DA神经元的基本电生理特性，它们的传入和输出连接，在PD的DA耗竭动物模型中的代偿变化，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纹状体中间神经元的电生理和解剖特性，这些特性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，影响了近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。这种疾病是进行性的，无法治愈。PD是由多巴胺输入新纹状体（一种控制自主运动的大脑结构）的缺失引起的。在这个项目中，我们将在电生理学、神经化学和神经解剖学上描述纹状体中新的多巴胺样神经元，这些神经元有可能成为改善PD症状的新治疗方法的焦点。