Simultaneous Analysis of Neurochemical and Behavioral/Cognitive Events In Vivo

描述(由申请人提供)：使用快速扫描循环伏安法(FSCV)结合离散行为事件，如习得性杠杆按压，已被证明是研究成瘾和基于奖励的学习的有用方法。然而，它忽略了杠杆按压之间发生的行为事件，并且受到限制，因为许多行为的发生可能无法通过人工观察来识别，这对行为可以归因于多少神经化学信息施加了根本限制。因此，迫切需要开发一种能够将细微运动与神经化学测量相关联的方法。长期目标是开发有助于研究人员了解大脑功能的方法。这项建议的中心目标是通过将FSCV与高分辨率行为方法相结合，提高实验室科学家将大脑DA瞬变与正在进行的行为相关联的能力。其基本原理是，将FSCV与力板活动计相结合，能够在时间兼容的时间尺度上客观地测量啮齿动物的细微运动，将使研究人员能够将FSCV测量与更复杂、更有信息量的行为分析相结合。为了便于将这种综合方法用于复杂的认知/行为范式，将使用一个以力-板式动作计为底层的混合操作室，在收集FSCV数据的同时研究低比率行为范式的差异强化。由于拟议的方法将有助于弥合运动和认知功能以及神经化学之间的差距，因此它将广泛适用于许多研究领域，包括但不限于：(1)多巴胺信号和行为/认知的基础神经生物学研究；(2)与多巴胺相关的运动障碍[如亨廷顿病(HD)、帕金森病(PD)、抽动障碍(TS)]；(3)成瘾和强迫的研究；以及(4)中枢神经系统活性药理制剂的作用机制。因此，拟议的研究与NIH任务中与基础知识发展有关的部分相关，这可能有助于减轻人类疾病和残疾的负担。中心目标将通过完成以下两个具体目标来实现：(1)应用行为/伏安法相结合的范式来监测亚秒级行为以及与奖励期望和给予相关的相应的神经化学变化；(2)应用行为/伏安法相结合的方法来测量与自我启动行为相关的多巴胺瞬变。这种组合的高时间分辨率方法是创新的，因为它是第一种在复杂认知任务中同时使用高时间分辨率神经化学和行为测量的方法。这项拟议的研究意义重大，因为它将扩大神经科学家将大脑多巴胺系统功能与习得的、有动机的啮齿动物行为联系起来的能力，从而为理解多巴胺在其中发挥作用的一系列健康问题提供新的基本信息。 与公共健康相关：拟议的研究旨在提高研究人员进行体内实验的能力，旨在解决细胞外多巴胺水平的亚秒级变化如何影响微妙和复杂的认知行为。这项拟议的研究与公共健康相关，因为这种方法可以用于解开与多巴胺相关的神经疾病相关的潜在机制。

DESCRIPTION (provided by applicant): The use of fast scan cyclic voltammetry (FSCV) in conjunction with discrete behavioral events, such as learned lever presses, has proven to be a useful approach for studies of addiction and reward-based learning. Nevertheless, it neglects behavioral events that occur between lever presses and is limited in that the occurrence of many behaviors may not be identifiable by unaided human observation, placing a fundamental limitation on how much neurochemical information can be attributed to behaviors. Therefore, there is a critical need to develop an approach capable of correlating subtle movement with neurochemical measurements. The long-term goal is to develop methods that facilitate researchers' efforts to understand brain function. The central aim of this proposal is to advance the ability of laboratory scientists to correlate brain DA transients with ongoing behavior by combining FSCV with high-resolution behavioral methods. The rationale is that integration of FSCV with the force-plate actometer, which is capable of objectively measuring subtle rodent movements on temporally compatible timescales, will empower investigators to combine FSCV measurement with more complex, and more informative, behavioral assays. To facilitate the use of this integrated approach for complex cognitive/behavioral paradigms, a hybrid operant chamber with a force-plate actometer as its floor will be used to study the differential reinforcement of low rates behavioral paradigm while collecting FSCV data. Because the proposed methods will help bridge the gap between motor and cognitive function and neurochemistry, it will have broad applicability to many areas of research including, but not limited to: (1) fundamental neurobiological studies of dopamine signaling and behavior/cognition; (2) dopamine-related movement disorders [e.g. Huntington's disease (HD), Parkinson's disease (PD), Tourette's syndrome (TS)]; (3) studies of addiction and compulsion; and (4) mechanisms of action of CNS-active pharmacological agents. Thus, the proposed research is relevant to that part of NIH's mission pertaining to the development of fundamental knowledge that will potentially help reduce the burdens of human illness and disability. The central aim will be accomplished by completion of the following two specific aims: (1) Apply a combined behavioral/voltammetric paradigm for monitoring sub-second behaviors and corresponding neurochemical changes associated with reward expectation and delivery and (2) Apply the combined behavioral/voltammetric methodology to measure dopamine transients associated with self-initiated behaviors. This combined, high time resolution approach is innovative because it is the first approach to make use of simultaneous high temporal resolution neurochemical and behavioral measurements in a complex cognitive task. The proposed research is significant because it will expand the ability of neuroscientists to correlate brain dopamine system functions with learned, motivated rodent behaviors and thereby provide new information fundamental to understanding a range of health problems in which dopamine plays a role. PUBLIC HEALTH RELEVANCE: The proposed studies are designed to enhance the ability of investigators to conduct in vivo experiments aimed at resolving how sub-second alterations in extracellular dopamine levels impact subtle and complex cognitive behaviors. The proposed research has relevance to public health because this approach can be applied towards unraveling the underlying mechanisms associated with dopamine-related neurological disorders.