Ultrastructural Basis of Neurochemical Measures in Brain

描述（由申请人提供）：多巴胺是中枢神经系统中非常重要的神经递质，在认知、运动控制和情绪调节中发挥核心作用。中枢多巴胺系统的功能障碍与许多疾病有关，包括帕金森病、精神分裂症、注意缺陷多动障碍和物质滥用。脑中多巴胺细胞外浓度的病理变化通常被视为多巴胺能功能障碍的标志，这使得定量测定活脑中细胞外多巴胺浓度成为非常重要的目标。然而，用多巴胺敏感探针穿透活体脑组织具有创伤性后果，其可改变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安培和伏安微电极技术来减小探针的尺寸。这项提案将研究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进行新的理解。目的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，以检验先前的迹象表明，这些多动动物表现出细胞外多巴胺水平升高与脑创伤相关的不确定性混淆的假设。目的2将测试的假设，多巴胺：谷氨酸在大鼠纹状体的相互作用涉及的神经递质之间的扩散紧密并列的多巴胺和谷氨酸终端位于植入伏安和安培微电极的微米距离。目的3将评估与伏安微电极相关的应力和胶质细胞活化。并且，目标4将评价微电极植入部位周围血管床的破坏作为穿透性创伤的潜在机制。总的来说，这些研究将建立与体内多巴胺测量相关的穿透损伤的程度、时间过程和性质，并表明减少测量损伤能够从根本上重新理解多巴胺系统在正常脑功能和与脑疾病相关的功能障碍中的作用。

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.