Ultrastructural Basis of Neurochemical Measures in Brain

大脑神经化学测量的超微结构基础

基本信息

批准号：
7414093
负责人：
Adrian C Michael
金额：
$ 30.64万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/7414093
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

项目摘要

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（由申请人提供）：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起着核心作用。中央多巴胺系统功能障碍与多种疾病有关，包括帕金森氏病，精神分裂症，注意力缺陷多动障碍和药物滥用。通常将大脑中多巴胺细胞外浓度的病理改变视为多巴胺能功能障碍的标志，这可以定量确定活体大脑中的细胞外多巴胺浓度是非常重要的目标。然而，用多巴胺敏感探针的活脑组织穿透会产生创伤后的后果，可以改变脑多巴胺系统的状态并抑制定量多巴胺的测定。减少与体内测量相关的创伤的一种策略是通过采用安培和伏安微电极技术来减少探针的大小。该提案将调查与微电极相关的创伤是否可以从根本上对脑多巴胺系统产生新的了解。 AIM 1将检查缺乏多巴胺转运蛋白的转基因小鼠中的细胞外多巴胺浓度，以检验以下假设：以前的迹象表明，这些过度活跃动物表现出升高的细胞外多巴胺水平与脑创伤相关的不确定性混淆。 AIM 2将检验大鼠纹状体中多巴胺：谷氨酸相互作用的假设涉及在植入伏伏术和放大学微电极的千分尺距离内的紧密含有多巴胺和谷氨酸末端之间的神经递质扩散。 AIM 3将评估与伏安微电极相关的应力和神经胶质激活。并且，AIM 4将评估微电极植入部位的血管床的破坏，作为渗透创伤的潜在机制。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，并表明降低的测量受伤使得对多巴胺系统在正常脑功能以及与脑部障碍相关的功能障碍的作用方面有了新的新理解。