The rodent continuous performance task: Filling the vigilance translational gap

描述（由申请人提供）：认知表现和整体功能/生活质量之间的积极联系已经在许多神经精神疾病中建立起来，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。在这些疾病的几个认知领域受损中，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会对高阶综合认知领域产生有害影响。在人类中，警惕性通常是通过连续表现测试（CPT）来评估的，该测试要求受试者注意相关的刺激，同时忽略无关的刺激。虽然这项任务是人类警惕性的“黄金标准”任务，对认知功能障碍非常敏感，但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“转化差距”，部分是通过开发更具预测性的行为模型来填补的。啮齿动物连续表现测试（rCPT）是一种新开发的范式，可以缩小这一差距。与人类CPT类似，rCPT使用信号检测理论来评估小鼠的警惕性。这个R21应用程序旨在测试rCPT对人类警惕性的预测和构造有效性。Specific Aim 1将根据影响人类CPT警觉表现的因素分类，确定小鼠的rCPT是否满足验证警戒任务的特定标准。然后，Specific Aim 2将使用剂量反应研究来评估rCPT的药理学预测有效性，通过确定尼古丁、安非他明和哌醋甲酯等精神兴奋剂是否会改善表现，氯胺酮是否会损害警惕性表现，与人类CPT研究一致。目的2还将测试一个关于预测顶叶皮层参与rCPT表现的特定假设。具体目标3将调查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乙酰胆碱受体（nAChR）表达100%、50%和0%的突变小鼠的影响，来检验17尼古丁乙酰胆碱受体（nAChR）对尼古丁诱导的警觉性增强是否必要。因此，本应用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和有效的临床前工具。这种工具将允许对神经精神疾病动物模型的有效性进行更完整的评估，这些研究将构成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将从临床前转化为临床警觉性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是至关重要的，但在开发有效的治疗方法方面进展有限。在临床前和临床试验之间仍然存在转化差距，限制了化合物在人类中取得成功的进展。该项目将验证新的啮齿动物警惕性连续性能测试，为在啮齿动物中观察到的化合物的阳性结果可能在人类中成功提供一种手段。

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.