Nigrostriatal dopamine function

黑质纹状体多巴胺功能

• 批准号: 7871877
• 负责人: James M Tepper
• 金额: $ 9.83万
• 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 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871877
• 关键词: Action Potentials; Adult; Affect; 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; Engineering; Enzymes; Financial compensation; Fluorescence; Genetically Engineered Mouse; Globus Pallidus; Glutamate Decarboxylase; Green Fluorescent Proteins; Human; In Vitro; Incidence; Injection of therapeutic agent; Interneurons; Ipsilateral; Label; Lesion; Lighting; Long-Term Survivors; Measures; Mediating; Membrane Potentials; Midbrain structure; Minor; Morphology; Motor; Movement; Mus; Neurons; Nomarski Interference Contrast Microscopy; Oxidopamine; Pathway interactions; Pharmacology; Phenotype; Physiologic pulse; Physiology; Platelet Transfusion; Play; Population; Primates; Probability; Property; Publishing; Replacement Therapy; Reporting; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Slice; Source; Staining method; Stains; Structure; Substantia nigra structure; Synapses; Testing; Time; Training; Transgenic Mice; Tyrosine 3-Monooxygenase; Voltage-Clamp Technics; Whole-Cell Recordings; biocytin; cholinergic; cholinergic neuron; cognitive function; dopamine transporter; dopaminergic neuron; gamma-Aminobutyric Acid; immunocytochemistry; median forebrain bundle; motor learning; neurochemistry; neurotransmission; nigrostriatal pathway; novel; novel therapeutic intervention; postsynaptic; presynaptic; promoter; research study; response; retrograde transport; synthetic enzyme; vesicular monoamine transporter; voltage; voltage clamp

The basal ganglia is a 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 which make up 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. Recently a novel type of striatal neuron has been recognized in a variety of species including humans. This neuron expresses tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA and a reliable marker for DA neurons in the midbrain. 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 in all species following experimental DA denervation, and some of them 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. However, virtually nothing is known about the electrophysiological properties of these neurons, as there are no published reports of recordings from them. Similarly, there are no data on their efferent or afferent synaptic connectivity, or even whether they release DA and/or GABA. The use of striatal slices from mice genetically engineered to express green fluorescent protein (EGFP) under the control of the TH promotor allows visually guided recording from these neurons in vitro. 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 novel populations of striatal interneurons that have been very difficult or impossible to study previously.

基底神经节是控制随意运动的中央回路的重要组成部分， 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。 基底神经节的主要输入结构是纹状体，主要由中等大小的GABA能神经元组成。 棘状投射神经元，占啮齿动物纹状体神经元的95%。剩下的神经元 胆碱能中间神经元和3种GABA能中间神经元。γ-氨基丁酸能中间神经元起着至关重要的作用， 通过参与影响棘波的强大前馈抑制回路，在纹状体功能中发挥作用 多刺神经元中的计时。多巴胺（DA），起源于黑质，长期以来一直被认为是 黑质纹状体DA能通路的退化， 帕金森氏病的病因，一种进行性和不可治愈的疾病，影响1至150万人 美国人 最近，一种新型的纹状体神经元在包括人类在内的多种物种中被发现。 这种神经元表达酪氨酸羟化酶（TH），这是DA合成的限速酶，也是一种可靠的抑制剂。 中脑DA神经元的标记物。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），强烈表明它们是DA能的。这些神经元也表达谷氨酸脱羧酶， 负责GABA合成的酶和GABA能的常见标志物 神经元这些神经元的数量增加了几倍，在所有物种后，实验DA 去神经支配，其中一些已被证明表达L-氨基酸脱羧酶（AADC）， 囊泡单胺转运体（VMAT）。这些神经元可能代表了一个迄今为止未被认可的来源， 纹状体DA和一个潜在的有用来源的补偿DA损失的特发性帕金森病， 以及作为治疗该疾病的新治疗方法的潜在靶点。 然而，实际上对这些神经元的电生理特性一无所知，因为 没有公开的关于他们录音的报道。同样，没有关于它们的传出或传入突触的数据。 连接，甚至是否释放DA和/或GABA。使用小鼠纹状体切片进行遗传学研究 被工程化以在TH启动子的控制下表达绿色荧光蛋白（EGFP）， 视觉引导记录这些体外神经元。使用这些小鼠，无论是未经治疗的还是单侧 多巴胺能去神经和/或左旋多巴替代治疗，我们将描述基本的电生理 纹状体DA神经元的性质，它们的传入和传出连接，DA的代偿性变化 PD耗竭动物模型，以及它们在纹状体DA和GABA能神经传递中的作用。此外，本发明还提供了一种方法， 这些小鼠为研究新种群的电生理学和解剖学特性提供了一种新的方法 纹状体的中间神经元，这在以前是很难或不可能研究的。