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The rodent continuous performance task: Filling the vigilance translational gap

啮齿动物连续执行任务：填补警惕性转化缺口

基本信息

批准号：
7888383
负责人：
Jared William Young
金额：
$ 19.31万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-07 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888383
关键词：
Abbreviations Acetylcholine Acute Address Adherence Affect Aftercare Alzheimer&apos s Disease Amphetamines Animal Model Animals Attention Attention deficit hyperactivity disorder Behavioral Model Bipolar Disorder Breeding C57BL/6 Mouse Chronic Clinical Clinical assessments Cognition Cognitive Cognitive deficits Crossover Design Data Detection Development Disease Dose Event Exhibits Face Fatigue Functional disorder Future Genetic Genetically Engineered Mouse Goals Gold Heterozygote Human Impaired cognition Impairment Ketamine Knock-out Lesion Ligands Light Link Literature Measurement Measures Mecamylamine Mediating Methods Methylphenidate Modeling Mouse Strains Mus Mutant Strains Mice National Institute of Mental Health Nicotine Nicotinic Receptors Nootropic Agents Outcome Parietal Parietal Lobe Patients Performance Pharmaceutical Preparations Process Quality of life Rattus Reaction Time Research Rodent Role Schizophrenia Signal Detection Analysis Signal Transduction Sleep Deprivation Stimulus Task Performances Taxonomy Testing Therapeutic TimeLine Toxic effect Training Transgenic Organisms Translating Variant addiction analog base cohort design drug development drug discovery drug testing effective therapy falls improved interest man meetings neuropsychiatry novel performance tests pre-clinical psychostimulant public health relevance receptor receptor expression research clinical testing response tool vigilance

项目摘要

DESCRIPTION (provided by applicant): A positive link between cognitive performance and global functioning/quality of life has been established in numerous neuropsychiatric disorders including schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, and Alzheimer's disease. Of the several cognitive domains impaired in these disorders, vigilance dysfunction may constitute a core deficit, since inability to attend to relevant stimuli has a subsequently deleterious effect on higher-order integrative cognitive domains. In humans, vigilance is most often assessed with the continuous performance test (CPT), which requires that the subject attend to relevant stimuli while ignoring irrelevant stimuli. Although this task is a "gold standard" task of vigilance in humans and is very sensitive to cognitive dysfunction, there are no direct animal analogues of the CPT. The successful treatment of cognitive deficits in neuropsychiatric disorders first requires the 'translational gap' between preclinical and clinical cognitive testing to be filled, in part by the development of more predictive behavioral models. The rodent continuous performance test (rCPT) is a newly developed paradigm in mice that may narrow this gap. The rCPT assesses vigilance in mice using signal detection theory measures, similar to the human CPT. This R21 application is designed to test the predictive and construct validity of rCPT for human vigilance. Specific Aim 1 will determine whether the rCPT in mice fulfills the specific criteria that have been established for validating a vigilance task, based on the taxonomy of factors that affect vigilance performance in the human CPT. Specific Aim 2 will then use dose-response studies to assess the pharmacological predictive validity of the rCPT by determining whether psychostimulants such as nicotine, amphetamine, and methylphenidate will improve performance and whether ketamine will impair vigilance performance, consistent with human CPT studies. Aim 2 will also test a specific hypothesis regarding the predicted involvement of parietal cortex in performance on the rCPT. Specific Aim 3 will investigate the utility of the rCPT in drug discovery research. Acute and sub-chronic treatment studies will examine whether the 17 nicotinic acetylcholine receptor (nAChR) is necessary for nicotine-induced enhancement of vigilance by comparing the effects of nicotine on mutant mice with 100%, 50%, and 0% 17 nAChR expression in the rCPT. Thus the overall goal of this application is to establish this novel rCPT model as a practical and valid preclinical tool for assessing vigilance. Such a tool will allow a more complete assessment of the validity of animal models of neuropsychiatric disorders, studies which will form part of a R01 application. Furthermore, the rCPT will aid in psychiatric drug development by determining whether a putative cognitive enhancer will translate from preclinical to clinical vigilance testing. PUBLIC HEALTH RELEVANCE: Improving cognitive deficiencies in neuropsychiatric patients is vitally important, yet there has been limited progress in developing effective treatments. There remains a translational gap between preclinical and clinical testing, limiting the progression of compounds that succeed in humans. This project will validate the novel rodent continuous performance test of vigilance, providing a means by which positive results for compounds observed in rodents will likely succeed in man.

描述（由申请人提供）：在许多神经精神疾病中，包括精神分裂症、双相情感障碍、注意力缺陷多动障碍和阿尔茨海默氏病，认知表现和整体功能/生活质量之间已建立了正相关关系。在这些疾病中受损的几个认知领域中，警惕性功能障碍可能构成核心缺陷，因为无法关注相关刺激会对高阶整合认知领域产生有害影响。在人类中，警惕性最常通过连续表现测试（CPT）进行评估，该测试要求受试者注意相关刺激，同时忽略不相关刺激。尽管这项任务是人类警惕性的“黄金标准”任务，并且对认知功能障碍非常敏感，但 CPT 没有直接的动物类似物。成功治疗神经精神疾病的认知缺陷首先需要填补临床前和临床认知测试之间的“翻译差距”，部分方法是开发更具预测性的行为模型。啮齿动物连续性能测试（rCPT）是一种新开发的小鼠范例，可能会缩小这一差距。 rCPT 使用信号检测理论测量来评估小鼠的警惕性，类似于人类 CPT。该 R21 应用程序旨在测试 rCPT 对人类警惕性的预测和构建有效性。具体目标 1 将根据影响人类 CPT 警戒表现的因素分类，确定小鼠的 rCPT 是否满足为验证警戒任务而制定的具体标准。然后，具体目标 2 将使用剂量反应研究来评估 rCPT 的药理学预测有效性，确定尼古丁、安非他明和哌醋甲酯等精神兴奋剂是否会提高表现以及氯胺酮是否会损害警惕表现，这与人类 CPT 研究一致。目标 2 还将测试关于预测顶叶皮层参与 rCPT 表现的具体假设。具体目标 3 将研究 rCPT 在药物发现研究中的效用。急性和亚慢性治疗研究将通过比较尼古丁对 rCPT 中 17 nAChR 表达为 100%、50% 和 0% 的突变小鼠的影响，检验 17 烟碱乙酰胆碱受体 (nAChR) 是否是尼古丁诱导的警惕性增强所必需的。因此，本申请的总体目标是建立这种新颖的 rCPT 模型作为评估警惕性的实用且有效的临床前工具。这样的工具将能够更全面地评估神经精神疾病动物模型的有效性，这些研究将成为 R01 应用程序的一部分。此外，rCPT 将通过确定假定的认知增强剂是否能从临床前警戒测试转化为临床警戒测试来帮助精神科药物的开发。公共卫生相关性：改善神经精神病患者的认知缺陷至关重要，但在开发有效治疗方法方面进展有限。临床前和临床测试之间仍然存在转化差距，限制了化合物在人类身上取得成功的进展。该项目将验证新型啮齿动物的连续警觉性能测试，提供一种方法，使在啮齿动物中观察到的化合物的阳性结果很可能在人类身上取得成功。