Measuring Striatal Neurotransmission in Behaving Rats after Experimental TBI

测量实验性 TBI 后行为大鼠的纹状体神经传递

• 批准号: 7437249
• 负责人: AMY K WAGNER
• 金额: $ 16.24万
• 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: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7437249
• 关键词: Adopted; Affect; Animals; Behavioral; Characteristics; Clinical; Clinical Trials; Cognition; Cognitive; Condition; Corpus striatum structure; Coupled; Daily; Data; Devices; Disease regression; Dopamine; Dopamine Agonists; Dose; Environment; Experimental Models; Exploratory Behavior; Feedback; Fire - disasters; Frequencies; Goals; Hand; Homeostasis; Human; Injury; Investigation; Laboratories; Learning; Link; Measurement; Measures; Mediating; Memory; Methods; Methylphenidate; Microdialysis; Midbrain structure; Modeling; Monitor; Nomifensine; Normal Range; Numbers; Performance; Pharmaceutical Preparations; Placement; Play; Population; Production; Property; Proteins; Range; Rattus; Recovery; Regulation; Rehabilitation therapy; Relative (related person); Reporting; Role; Scanning; Signal Transduction; Site; Structure; System; Techniques; Technology; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Tissues; Trauma; Traumatic Brain Injury; Treatment Efficacy; Week; Work; awake; cognitive function; controlled cortical impact; dopamine system; dopaminergic neuron; extracellular; implantation; improved; in vivo; inhibitor/antagonist; injured; insight; male; neurotransmission; novel; protein expression; psychostimulant; tool; transmission process; uptake

DESCRIPTION (provided by applicant): The striatum interfaces with cortical and subcortical structures to affect cognitive function. Previous work suggests that in the controlled cortical impact (CCI) model of experimental traumatic brain injury (TBI), spatial memory and exploratory behavior in novel environments is impaired. The therapeutic benefits of dopamine (DA) agonists following clinical and experimental models of TBI suggest a role for DA systems in mediating these deficits post-injury. Motivated by these observations, we have used in vivo electrochemical monitoring with fast scan cyclic voltammetry (FSCV) to assess alterations in electrically evoked extracellular DA levels after CCI. After CCI, in vivo evoked overflow of DA is impaired. Additionally there are decrements in DA clearance that correspond to decreased DAT expression after CCI. Additionally, the effects of the neurostimulant, methylphenidate, on DAT function are moderated by CCI. In awake rats after CCI, it also appears that regulation of basal DA levels is impaired. When examining tissue damage sustained directly around striatal placement of microdialysis probes, this type of trauma also suppresses evoked DA release and affects autoregulation of basal DA levels around the injury site. While the effects of CCI and direct striatal injury (DSI) from microdialysis probes on stimulated DA release and basal DA levels is significant, it is critically important to extend these investigations regarding TBI on DA neurotransmission. Currently, we can monitor tonic changes in [DA] in awake animals after pharmacological manipulation using FSCV. However, Mark Wightman has recently improved the performance of his voltammetric recording techniques such that he can now detect spontaneous DA transients, presumably associated with the burst firing of midbrain DA neurons. Wightman's approach has been refined, in part, through the implementation of principle components regression (PCR) to resolve DA signals from other interferents observed in the voltammetric trace. We speculate that adapting this technique would be a viable approach for objectively assessing and refining measurement of tonic changes in DA measured over several minutes, and thus, would provide an additional tool for measuring not only phasic, but also, tonic aspects of DA transmission. Our central hypothesis is that spontaneous striatal DA transients and regulatory mechanisms affecting basal DA are impaired after TBI. Hence, we have the following long-range scientific objectives: 1) to characterize the effects of trauma on naturally occurring, as opposed to electrically evoked, extracellular DA; 2) to characterize the state of regulatory mechanisms governing basal DA after TBI 3) to characterize the effects of DAT inhibitors on striatal extracellular DA post-injury; 4) to temporally link behavioral performance in cognitive tasks with spontaneous DA transients after CCI. In support of these scientific objectives, the technical aim of this R21, is to incorporate this new voltammetric system, including chemometrics with PCR, in to our own studies of phasic and tonic DA transmission in two models of TBI. These scientific objectives derived from adapting in vivo voltammetry monitoring to awake rats with CCI will lay the ground-work for evaluating a number of rehabilitation relevant, dopaminergic, and other therapeutic interventions and the mechanisms by which they restore DA neurotransmission and cognition after injury. The overarching goal is to gain insight into potential mechanisms of action and efficacy of these interventions on cognition and recovery for the clinical population with TBI.

描述（由申请人提供）：纹状体与皮质和皮质下结构连接，影响认知功能。先前的工作表明，在实验性创伤性脑损伤（TBI）的受控皮质撞击（CCI）模型中，空间记忆和探索行为在新环境中受损。多巴胺（DA）激动剂的治疗效益TBI的临床和实验模型表明，DA系统在介导这些赤字损伤后的作用。出于这些观察结果，我们使用了体内电化学监测与快速扫描循环伏安法（FSCV），以评估CCI后电诱发的细胞外DA水平的改变。CCI后，体内诱发的DA溢出受损。此外，CCI后DA清除率降低，这与DAT表达降低相对应。此外，神经兴奋剂哌醋甲酯对DAT功能的影响受到CCI的调节。在清醒的大鼠CCI后，它也出现了基础DA水平的调节受损。当检查直接围绕纹状体放置微透析探针的组织损伤时，这种类型的创伤也抑制诱发的DA释放，并影响损伤部位周围基础DA水平的自动调节。虽然CCI和直接纹状体损伤（DSI）从微透析探针刺激DA释放和基础DA水平的影响是显着的，这是至关重要的，以扩大这些调查TBI对DA神经传递。目前，我们可以使用FSCV监测药物操作后清醒动物[DA]的紧张性变化。然而，Mark Wightman最近改进了他的伏安记录技术的性能，使得他现在可以检测自发的DA瞬变，推测与中脑DA神经元的突发放电有关。Wightman的方法已经得到了改进，部分是通过实施主成分回归（PCR）来解决伏安法跟踪中观察到的其他干扰物的DA信号。我们推测，采用这种技术将是一种可行的方法，客观地评估和完善测量DA的紧张性变化，在几分钟内测量，因此，将提供一个额外的工具，不仅测量相位，但也紧张性方面的DA传输。我们的中心假设是自发纹状体DA瞬变和影响基础DA的调节机制受损后，TBI。因此，我们有以下长期的科学目标：1）表征创伤对自然发生的，而不是电诱发的，细胞外DA的影响; 2）表征TBI后支配基础DA的调节机制的状态; 3）表征DAT抑制剂对损伤后纹状体细胞外DA的影响; 4）将认知任务中的行为表现与CCI后的自发DA瞬变在时间上联系起来。为了支持这些科学目标，R21的技术目标是将这种新的伏安系统，包括PCR化学计量学，纳入我们自己对两种TBI模型中的相位和强直DA传输的研究中。这些科学目标来自适应在清醒的CCI大鼠体内伏安法监测将奠定基础工作，为评估一些康复相关的，多巴胺能，和其他治疗干预和机制，他们恢复DA神经传递和认知损伤后。总体目标是深入了解这些干预措施对TBI临床人群认知和康复的潜在作用机制和功效。