Nigrostriatal dopamine function
黑质纹状体多巴胺功能
基本信息
- 批准号:8289646
- 负责人:
- 金额:$ 33.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1997
- 资助国家:美国
- 起止时间:1997-02-01 至 2013-09-29
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAdultAffectAgeAgonistAmericanAmino AcidsAnatomyAnimal ModelAnimalsBasal GangliaBathingBrainBrightfield MicroscopyCalcium-Binding ProteinsCarboxy-LyasesCell CountCellsContralateralCorpus striatum structureCoupledCouplingDataDenervationDevelopmentDiseaseDopamineDopamine ReceptorElderlyEngineeringEnzymesFinancial compensationFluorescenceGenetically Engineered MouseGlobus PallidusGlutamate DecarboxylaseHealthIn VitroIncidenceInjection of therapeutic agentInterneuronsIpsilateralLabelLearningLesionLightingMeasuresMediatingMembrane PotentialsMinorMolecular ProfilingMorphologyMovementMusNeostriatumNeuronsNomarski Interference Contrast MicroscopyOxidopamineParkinson DiseasePathway interactionsPharmacologyPhenotypePhysiologic pulsePhysiologyPlayPopulationPrimatesProbabilityPropertyReplacement TherapyResistanceReverse Transcriptase Polymerase Chain ReactionRodentRoleSliceSourceStructureSubstantia nigra structureSymptomsSynapsesTestingTimeTrainingTransgenic MiceTranslatingTyrosine 3-MonooxygenaseVoltage-Clamp TechnicsWhole-Cell Recordingsbiocytincell typecholinergiccognitive functiondopamine transporterdopaminergic neuronenhanced green fluorescent proteinextracellulargamma-Aminobutyric Acidimmunocytochemistryinduced pluripotent stem cellmedian forebrain bundlemotor learningnervous system disorderneurochemistryneurotransmissionnigrostriatal pathwaynovelnovel therapeutic interventionpostsynapticpresynapticpromoterresearch studyresponseretrograde transportsynthetic enzymevesicular monoamine transportervoltagevoltage clamp
项目摘要
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):基底神经节是控制随意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,主要由中等大小的 GABA 能棘投射神经元 (MSN) 组成,约占啮齿动物纹状体神经元的 95%。其余神经元由胆碱能中间神经元和 3 种类型的 GABA 能中间神经元组成。 GABA 能中间神经元通过参与影响多刺神经元尖峰时间的强大前馈抑制电路,在纹状体功能中发挥着至关重要的作用。起源于黑质的多巴胺 (DA) 长期以来被认为在纹状体功能中发挥着重要作用,而黑质纹状体 DAergic 通路的退化是帕金森病的原因,帕金森病是一种进行性且无法治愈的疾病,影响1和150万美国人。除了上面列出的细胞类型外,还发现纹状体神经元群体表达酪氨酸羟化酶 (TH),这是 DA 合成中的限速酶。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),强烈表明它们是 DA 能的。这些神经元还表达谷氨酸脱羧酶,这种酶负责合成 GABA,也是 GABA 能神经元的常见标记。 DA 去神经支配后,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)。这些神经元可能代表了迄今为止未被认识到的纹状体 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成分,但人们对此知之甚少或一无所知,因为它们从未被记录,而仅通过免疫细胞化学进行研究。我们使用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 种电生理学上不同的亚型,并提供了它们传出和传入突触连接的初步数据。使用这些未经治疗和单侧多巴胺能去神经和/或 L-DOPA 替代治疗后的小鼠,我们将描述纹状体 DA 神经元的基本电生理特性、它们的传入和传出连接、PD 缺乏 DA 动物模型的代偿性变化及其在纹状体 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,而这些特性以前很难或不可能以任何系统的方式进行研究。公共卫生相关性 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。这意味着大约有 150 万美国人。这种疾病是进行性的且无法治愈。 PD 是由于新纹状体(控制自主运动的大脑结构)输入的多巴胺缺失引起的。在这个项目中,我们将从电生理学、神经化学和神经解剖学角度描述纹状体中新型多巴胺样神经元,这些神经元有可能成为改善帕金森病症状的新型治疗方法的焦点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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James M Tepper其他文献
James M Tepper的其他文献
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{{ truncateString('James M Tepper', 18)}}的其他基金
INTERNEURONAL MICROCIRCUITRY OF THE RAT NEOSTRIATUM
大鼠新纹状体的神经元微循环
- 批准号:
2891128 - 财政年份:1998
- 资助金额:
$ 33.12万 - 项目类别:
INTERNEURONAL MICROCIRCUITRY OF THE RAT NEOSTRIATUM
大鼠新纹状体的神经元微循环
- 批准号:
2688311 - 财政年份:1998
- 资助金额:
$ 33.12万 - 项目类别:
ANATOMY AND PHYSIOLOGY OF SUBSTANTIA NIGRA AFFERENTS
黑质传入神经的解剖学和生理学
- 批准号:
6318693 - 财政年份:1997
- 资助金额:
$ 33.12万 - 项目类别:
ANATOMY AND PHYSIOLOGY OF SUBSTANTIA NIGRA AFFERENTS
黑质传入神经的解剖学和生理学
- 批准号:
6151601 - 财政年份:1997
- 资助金额:
$ 33.12万 - 项目类别:
Functional Striatal Microcircuits in vivo and in vitro
体内和体外功能性纹状体微电路
- 批准号:
8632129 - 财政年份:1997
- 资助金额:
$ 33.12万 - 项目类别:
ANATOMY AND PHYSIOLOGY OF SUBSTANTIA NIGRA AFFERENTS
黑质传入神经的解剖学和生理学
- 批准号:
2873187 - 财政年份:1997
- 资助金额:
$ 33.12万 - 项目类别:
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