Ultrastructural Basis of Neurochemical Measures in Brain

大脑神经化学测量的超微结构基础

• 批准号: 7260649
• 负责人: Adrian C Michael
• 金额: $ 30.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7260649
• 关键词: Address; Adopted; Affect; Amphetamines; Animal Model; Animals; Antibodies; Appearance; Attention; Attention deficit hyperactivity disorder; Autoreceptors; Blood Platelets; Blood Vessels; Blood flow; Brain; Brain Chemistry; Brain Diseases; Buffers; Caliber; Cell Adhesion Molecules; Cell Proliferation; Cells; Cocaine; Cognition; Condition; Confocal Microscopy; Corpus striatum structure; Cytoplasm; Detection; Dialysis procedure; Diffuse; Diffusion; Dimensions; Disease; Disruption; Dopamine; Drops; Electrodes; Electron Microscopy; Endothelial Cells; Erythrocytes; Evolution; Excitatory Amino Acid Antagonists; Exhibits; Exocytosis; Experimental Designs; Extracellular Space; Face; Functional disorder; Genes; Glutamate Transporter; Glutamates; Immunohistochemistry; Implant; Infiltration; Infusion procedures; Injury; Knock-out; Knowledge; Label; Lead; Life; Light; Literature; Locomotion; Measurement; Measures; Mediating; Membrane; Methods; Microdialysis; Microelectrodes; Monitor; Mus; Nature; Neuraxis; Neuroglia; Neurons; Neurotransmitters; Nomifensine; Numbers; Outcome; Outcome Study; Parkinson Disease; Patients; Penetration; Perfusion; Pharmaceutical Preparations; Physical Dialysis; Play; Procedures; Process; Property; Rate; Rattus; Recommendation; Recovery; Reporting; Research; Research Design; Research Personnel; Resolution; Ritalin; Role; Schizophrenia; Site; Speed; Staining method; Stains; Stress; Substance abuse problem; Suspension substance; Suspensions; Synapses; System; Technology; Testing; Time; Tissues; Transgenic Mice; Translating; Trauma; Traumatic Brain Injury; Tyrosine 3-Monooxygenase; Uncertainty; Wild Type Mouse; Work; Yang; base; biotinylated dextran amine; brain tissue; carbon fiber; concept; dopamine system; dopamine transporter; emotion regulation; extracellular; implantable device; implantation; improved; in vivo; inhibitor/antagonist; insight; kynurenate; motor control; neurochemistry; prevent; protein transport; research study; response; size; spatiotemporal; transmission process; vascular bed

DESCRIPTION (provided by applicant): Dopamine is a highly significant neurotransmitter in the central nervous system, playing a central role in cognition, motor control, and the regulation of emotion. Dysfunction in central dopamine systems is implicated in a number of disorders, including Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder, and substance abuse. Pathological alterations in the extracellular concentration of dopamine in the brain are generally viewed as the hallmark of dopaminergic dysfunction, which makes the quantitative determination of extracellular dopamine concentrations in the living brain a highly significant objective. However, the penetration of living brain tissue with dopamine-sensitive probes has traumatic consequences that can alter the state of brain dopamine systems and inhibit quantitative dopamine determination. One strategy for diminishing the trauma associated with in vivo measurements is to decrease the size of the probes by adopting amperometric and voltammetric microelectrode technologies. This proposal will investigate whether the diminished trauma associated with microelectrodes enables fundamentally new understanding of brain dopamine systems. Aim 1 will examine extracellular dopamine concentrations in transgenic mice lacking the dopamine transporter to test the hypothesis that previous indications that these hyperactive animals exhibit elevated extracellular dopamine levels were confounded by the uncertainty associated with brain trauma. Aim 2 will test the hypothesis that dopamine:glutamate interactions in the rat striatum involve the diffusion of neurotransmitters between closely apposed dopamine and glutamate terminals located within micrometer distances of implanted voltammetric and amperometric microelectrodes. Aim 3 will evaluate stress and glial activation associated with voltammetric microelectrodes. And, Aim 4 will evaluate disruption of the vascular bed surrounding microelectrode implantation sites as a potential mechanism underlying penetration trauma. Collectively, these studies will establish the extent, time course, and nature of penetration injury associated with in vivo dopamine measurements and show that diminished measurement-injury enables fundamentally new understanding of the role of dopamine systems in normal brain function and the dysfunction associated with brain disorders.

描述（申请人提供）：多巴胺是中枢神经系统中一种非常重要的神经递质，在认知、运动控制和情绪调节中发挥着核心作用。中枢多巴胺系统功能障碍与许多疾病有关，包括帕金森病、精神分裂症、注意力缺陷多动障碍和药物滥用。大脑中细胞外多巴胺浓度的病理改变通常被视为多巴胺能功能障碍的标志，这使得活体大脑中细胞外多巴胺浓度的定量测定成为非常重要的目标。然而，多巴胺敏感探针穿透活体脑组织会产生创伤性后果，可能改变大脑多巴胺系统的状态并抑制定量多巴胺测定。减少与体内测量相关的创伤的一种策略是通过采用电流和伏安微电极技术来减小探针的尺寸。该提案将调查与微电极相关的创伤减少是否能够从根本上对大脑多巴胺系统产生新的理解。目标 1 将检查缺乏多巴胺转运蛋白的转基因小鼠的细胞外多巴胺浓度，以检验以下假设：先前表明这些过度活跃的动物表现出细胞外多巴胺水平升高的迹象因与脑外伤相关的不确定性而被混淆。目标 2 将检验以下假设：大鼠纹状体中的多巴胺：谷氨酸相互作用涉及神经递质在位于植入的伏安和电流微电极的微米距离内的紧密排列的多巴胺和谷氨酸末端之间的扩散。目标 3 将评估与伏安微电极相关的应力和神经胶质活化。并且，目标 4 将评估微电极植入部位周围血管床的破坏，将其作为穿透创伤的潜在机制。总的来说，这些研究将确定与体内多巴胺测量相关的渗透损伤的程度、时间过程和性质，并表明测量损伤的减少可以从根本上对多巴胺系统在正常大脑功能和与大脑疾病相关的功能障碍中的作用有新的认识。