Analysis of instrumental overactivity in an animal model of ADHD

描述（由申请人提供）：注意缺陷多动障碍（ADHD）是一种神经行为障碍，损害行为的正常发展，特别是执行功能。ADHD有三种持续的症状：注意力不集中、冲动和过度活跃。大量证据表明，自发性高血压大鼠（SHR）表现出ADHD的所有三种症状，因此可以作为实验研究的模型。然而，SHR作为ADHD模型的有效性受到了挑战。动物模型的一个问题是，它们永远不能完美地复制综合症——它们充其量只是综合症症状的模型。这个应用程序的重点是多动症的一个症状，持续过度活动。本研究的主要目的是根据最先进的行为理论，描述SHR过度活动的特征；其结果将作为评估该菌株作为adhd相关过度活动模型的基础。特别地，这个应用涉及到工具性过度活动，奖励反应的过度释放，这是典型的多动症的主要多动-冲动和合并亚型。所提出的方法得到了经验验证的工具行为模型的支持，该模型表明大鼠在被暂停分开的回合中参与奖励活动。响应率因此可由3个参数划分：回合内响应率、回合起始率和回合持续时间。过去的研究表明，每个参数对运动、动机和时间表操作的不同敏感性：每个参数都由与运动能力、动机状态和反应-奖励关联维持（“耦合”）相关的独特机制控制。初步研究表明，与正常活动对照Wistar-Kyoto （WKY）大鼠相比，年轻成年SHR产生的反应时间更短，但频率更高。这些结果表明，较低的反应-奖励耦合是造成菌株之间差异的原因。这一重要发现受到大鼠年龄和使用多种相互作用时间表的影响。实验1将试图复制初步研究的结果，但将青少年（而不是成人）SHR和WKY置于单独的时间表（而不是多个时间表）中，其中奖励将每12或192秒进行编程。实验2将通过“再合成”验证对菌株差异的解释：在这种情况下，通过实验逆转它们的主要性状差异。例如，如果Exp. 1验证了响应-奖励耦合缺陷

DESCRIPTION (provided by applicant): Attention Deficit Hyperactivity Disorder (ADHD) is a neurobehavioral disorder that impairs the normal development of behavior, in particular of executive functioning. Three persistent symptoms characterize ADHD: inattention, impulsivity, and overactivity. A large body of evidence suggests that the Spontaneously Hypertensive rat (SHR) displays all three symptoms of ADHD, and may thus serve as a model for experimental research. The validity of SHR as a model of ADHD has, nonetheless, been challenged. A concern with animal models is that they never perfectly replicate the syndrome-they are at best models of symptoms of that syndrome. This application focuses on one symptom of ADHD, persistent overactivity. The primary aim of this research is to characterize SHR overactivity, grounded on state-of-the-art behavioral theory; its results will serve as foundation for the evaluation of this strain as a model of ADHD-related overactivity. In particular, this application s concerned with instrumental overactivity, the excessive emission of rewarded responses that is typical of the predominantly hyperactive-impulsive and combined subtypes of ADHD. The proposed methods are supported by empirically-validated models of instrumental behavior that indicate that rats engage in rewarded activities in bouts separated by pauses. Response rate may be thereby partitioned by 3 parameters: within-bout response rate, bout-initiation rate, and bout duration. Past research has shown the differential sensitivity of each parameter to motor, motivational, and schedule manipulations: Each is controlled by a distinct mechanism linked with motor capacity, motivational status, and the maintenance of response-reward associations ("coupling"). Preliminary research suggests that young-adult SHR produce shorter but more frequent response bouts than its normoactive control, the Wistar-Kyoto (WKY) rat. Those results indicated that a reduced response-reward coupling was responsible for the differences between strains. This important finding is compromised by the age of the rats and the use of multiple interacting schedules. Exp. 1 will seek to replicate the results from the preliminary study, but exposing adolescent (instead of adult) SHR and WKY to separate schedules (instead of multiple schedules), in which rewards will be programmed every 12 or 192 s. Exp. 2 will validate the interpretation of strain differences by "resynthesis": in this case, by experimentally reversing their main trait difference. For instance, if Exp. 1 verifies a response-reward coupling deficit in SHR on the basis of short-but-frequent bouts of responses, coupling would be increased and bouts "normalized" by rewarding longer response sequences. It will be verified whether such normalization generalizes to extinction performance. Taken together, these experiments will qualify our confidence in the preliminary findings (Exp. 1) and their interpretation (Exp. 2). Establishing the source of SHR overactivity is a fundamental step to its validation as a model of ADHD-related overactivity. The development on such model is critical for the progress of neurobiological research on ADHD and for the formulation of treatment alternatives.