Simultaneous Analysis of Neurochemical and Behavioral/Cognitive Events In Vivo

描述（由申请人提供）：将快速扫描循环伏安法（FSCV）与离散行为事件（如习得杠杆按压）结合使用，已被证明是研究成瘾和基于奖励的学习的有用方法。然而，它忽略了发生在杠杆按压之间的行为事件，并且由于许多行为的发生可能无法通过独立的人类观察来识别，因此对可以归因于行为的神经化学信息的多少存在根本性限制。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。该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脑DA瞬态与持续行为联系起来的能力。其基本原理是将FSCV与力板动计相结合，后者能够在时间相容的时间尺度上客观地测量细微的啮齿动物运动，这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应用于复杂的认知/行为范式，在收集FSCV数据的同时，我们将使用一个以力板行为计为基础的混合操作室来研究低率行为范式的差异强化。由于所提出的方法将有助于弥合运动和认知功能与神经化学之间的差距，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)多巴胺相关运动障碍[如亨廷顿病（HD）、帕金森病（PD）、妥瑞特综合征（TS）]；(3)成瘾与强迫研究；(4)中枢神经系统活性药物的作用机制。因此，拟议的研究与NIH的使命有关，即发展基础知识，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/伏安法联合范式来监测亚秒行为和与奖励预期和传递相关的相应神经化学变化；(2)应用行为/伏安法联合方法来测量与自我启动行为相关的多巴胺瞬变。这种综合的高时间分辨率方法是创新的，因为它是第一个在复杂的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。这项拟议中的研究意义重大，因为它将扩大神经科学家将脑多巴胺系统功能与学习、动机性啮齿动物行为联系起来的能力，从而为理解多巴胺发挥作用的一系列健康问题提供新的基础信息。

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.