Analysis of instrumental overactivity in an animal model of ADHD

ADHD 动物模型中仪器过度活动的分析

• 批准号: 8458531
• 负责人: FEDERICO SANABRIA
• 金额: $ 6.68万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-11 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458531
• 关键词: Accounting; Address; Adolescent; Adult; Age; Animal Model; Attention deficit hyperactivity disorder; Behavior; Behavior Therapy; Behavioral; Child; Consensus; Coupling; Data; Development; Drug Formulations; Etiology; Evaluation; Extinction (Psychology); Food; Foundations; Funding; Future; Genetic; Goals; High Prevalence; Impulsivity; Inbred SHR Rats; Inbred WKY Rats; Investigation; Learning; Link; Maintenance; Methods; Modeling; Motivation; Motor; Motor Activity; Neurobiology; Neurologic; Nose; Operant Conditioning; Performance; Pharmacological Treatment; Physical Capacity; Procedures; Process; Qualifying; Rattus; Reporting; Research; Rewards; Schedule; Source; Stimulus; Symptoms; Syndrome; Testing; Training; Validation; Water; Work; alternative treatment; base; cost; executive function; inattention; interest; learning extinction; neurobehavioral disorder; pre-clinical; programs; psychologic; research study; response; reward processing; theories; trait; young adult

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.

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有三个持续的症状：注意力不集中、冲动和过度活跃。大量的证据表明，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，它们从来没有完美地复制过这种综合症它们充其量只是这种综合症症状的模型。这个应用程序集中在ADHD的一个症状，持续过度活跃。本研究的主要目的是表征SHR过度活动，基于最先进的行为理论;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，本申请涉及工具性过度活动，奖励反应的过度发射是ADHD的主要多动-冲动和组合亚型的典型。所提出的方法是支持的辅助验证模型的工具行为，表明大鼠从事奖励活动的间歇分开。因此，响应率可以由3个参数划分：回合内响应率、回合启动率和回合持续时间。过去的研究表明，每个参数对运动、动机和时间表操纵的敏感性不同：每个参数都由一个与运动能力、动机状态和维持反应-奖励关联（“耦合”）相关的独特机制控制。初步研究表明，成年SHR比其正常活动对照组Wistar-Kyoto（WKY）大鼠产生更短但更频繁的反应发作。这些结果表明，反应-回报耦合的降低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。Exp. 1将试图复制初步研究的结果，但将青少年（而不是成年人）SHR和WKY暴露于单独的时间表（而不是多个时间表），其中奖励将每12或192秒编程一次。Exp. 2将通过“再合成”验证菌株差异的解释：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， SHR的基础上，短，但频繁的反应，耦合将增加和回合“正常化”的奖励较长的反应序列。将验证这种归一化是否推广到消光性能。总之，这些实验将使我们对初步研究结果的信心更加坚定（Exp. 1)他们的解释（Exp）。2）的情况。建立SHR过度活动的来源是验证其作为ADHD相关过度活动模型的基本步骤。该模型的建立对于ADHD神经生物学研究的进展和治疗方案的制定至关重要。

项目成果

Detrimental effects of acute nicotine on the response-withholding performance of spontaneously hypertensive and Wistar Kyoto rats.

急性尼古丁对自发性高血压和 Wistar 京都大鼠的反应抑制表现的有害影响。

• DOI: 10.1007/s00213-013-3412-2
• 发表时间: 2014
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Mazur,GabrielJ;Wood-Isenberg,Gabriel;Watterson,Elizabeth;Sanabria,Federico
• 通讯作者: Sanabria,Federico

Longer operant lever-press duration requirements induce fewer but longer response bouts in rats.

较长的操作杠杆按压持续时间要求会引起大鼠较少但较长的反应发作。

• DOI: 10.3758/s13420-021-00464-7
• 发表时间: 2021
• 期刊: Learning & behavior
• 影响因子: 1.8
• 作者: Brackney,RyanJ;Garcia,Raul;Sanabria,Federico
• 通讯作者: Sanabria,Federico

Chronic stress disrupts fear extinction and enhances amygdala and hippocampal Fos expression in an animal model of post-traumatic stress disorder.

• DOI: 10.1016/j.nlm.2014.01.018
• 发表时间: 2014-07
• 期刊: Neurobiology of learning and memory
• 影响因子: 2.7
• 作者: Hoffman AN;Lorson NG;Sanabria F;Foster Olive M;Conrad CD
• 通讯作者: Conrad CD

Nicotine-induced place conditioning and locomotor activity in an adolescent animal model of attention deficit/hyperactivity disorder (ADHD).

注意力缺陷/多动障碍（ADHD）青少年动物模型中尼古丁诱导的位置调节和运动活动。

• DOI: 10.1016/j.bbr.2015.05.031
• 发表时间: 2015
• 期刊: Behavioural brain research
• 影响因子: 2.7
• 作者: Watterson,Elizabeth;Daniels,CarterW;Watterson,LucasR;Mazur,GabrielJ;Brackney,RyanJ;Olive,MFoster;Sanabria,Federico
• 通讯作者: Sanabria,Federico

A microstructural analysis of schedule-induced polydipsia reveals incentive-induced hyperactivity in an animal model of ADHD.

对日程诱发的烦渴的微观结构分析揭示了 ADHD 动物模型中激励诱发的多动症。

• DOI: 10.1016/j.bbr.2014.10.022
• 发表时间: 2015
• 期刊: Behavioural brain research
• 影响因子: 2.7
• 作者: Íbias,Javier;Pellón,Ricardo;Sanabria,Federico
• 通讯作者: Sanabria,Federico