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病，认知表现和全球功能/生活质量之间已经建立了积极的联系。在这些障碍中受损的几个认知域中，警戒功能障碍可能构成核心缺陷，因为无法注意到相关刺激会对更高阶的综合认知域产生有害影响。在人类中，警觉性通常是通过连续表现测试(CPT)来评估的，这要求受试者注意相关的刺激，而忽略不相关的刺激。虽然这项任务是人类警觉的“黄金标准”任务，对认知功能障碍非常敏感，但没有直接与CPT类似的动物。成功治疗神经精神障碍的认知缺陷首先需要填补临床前和临床认知测试之间的“翻译空白”，部分是通过开发更具预测性的行为模型来实现的。啮齿动物持续表现测试(RCPT)是在小鼠身上开发的一种新范式，可能会缩小这一差距。RCPT使用类似于人类CPT的信号检测理论方法来评估小鼠的警觉性。此R21应用程序旨在测试RCPT对人类警觉的预测性和构造性有效性。具体目标1将根据人类CPT中影响警觉表现的因素的分类，确定小鼠的RCPT是否符合为验证警戒任务而建立的特定标准。然后，特定目标2将使用剂量反应研究来评估RCPT的药理学预测有效性，方法是确定尼古丁、苯丙胺和哌醋甲酯等精神刺激剂是否会改善表现，以及氯胺酮是否会损害警觉表现，这与人类CPT研究一致。Aim 2还将测试一个关于顶叶皮质在RCPT表现中的预测参与的特定假设。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中表达100%、50%和0%17nAChR的突变小鼠的影响，来检验17尼古丁乙酰胆碱受体(NAChR)是否对于尼古丁诱导的增强警觉性是必要的。因此，这项应用的总体目标是建立这一新的RCPT模型，作为评估警觉性的实用和有效的临床前工具。这样的工具将允许对神经精神障碍动物模型的有效性进行更全面的评估，这项研究将成为R01应用的一部分。此外，RCPT将通过确定假定的认知增强剂是否将从临床前测试转化为临床警觉测试，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。临床前试验和临床试验之间仍然存在翻译差距，限制了在人类身上成功的化合物的进展。该项目将验证新的啮齿动物警觉持续表现测试，提供一种在啮齿动物身上观察到的化合物的积极结果很可能在人类身上成功的手段。

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.