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.
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.
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