The rodent continuous performance task: Filling the vigilance translational gap

描述（由申请人提供）：在许多神经精神疾病（包括精神分裂症、双相情感障碍、注意缺陷多动障碍和阿尔茨海默病）中，已确定认知表现与整体功能/生活质量之间存在正相关。在这些疾病中受损的几个认知领域中，警觉性功能障碍可能构成核心缺陷，因为无法注意相关刺激对高阶综合认知领域具有随后的有害影响。在人类中，警惕性最常通过连续性能测试（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。虽然这项任务是人类警戒的“金标准”任务，并且对认知功能障碍非常敏感，但没有CPT的直接动物类似物。成功治疗神经精神疾病中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”，部分是通过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式，可以缩小这一差距。rCPT使用信号检测理论措施评估小鼠的警惕性，与人CPT相似。该R21应用程序旨在测试rCPT对人类警戒的预测和结构有效性。具体目标1将根据影响人CPT警戒性能的因素分类，确定小鼠中的rCPT是否符合为验证警戒任务而确立的具体标准。然后，特定目标2将使用剂量反应研究，通过确定精神兴奋剂（如尼古丁、安非他明和哌甲酯）是否会改善表现以及氯胺酮是否会损害警戒表现，评估rCPT的药理学预测有效性，与人体CPT研究一致。目标2还将检验关于顶叶皮质预测参与rCPT表现的特定假设。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，检查17 nAChR是否是尼古丁诱导的警觉增强所必需的。因此，本申请的总体目标是建立这种新型rCPT模型，作为评估警惕性的实用有效的临床前工具。这种工具将允许更完整地评估神经精神疾病动物模型的有效性，这些研究将成为R 01应用的一部分。此外，rCPT将通过确定假定的认知增强剂是否会从临床前转化为临床警戒测试来帮助精神药物开发。公共卫生相关性：改善神经精神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。在临床前和临床测试之间仍然存在翻译差距，限制了在人类中成功的化合物的进展。该项目将验证新型啮齿动物连续警戒性能测试，提供一种方法，通过该方法，在啮齿动物中观察到的化合物的阳性结果可能在人类中获得成功。

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.