Translational Studies on Cognitive Flexibility

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DESCRIPTION (provided by applicant): Cognitive disorganization is a fundamental aspect of the psychopathology of schizophrenia, contributing to the overall morbidity of the disease process and greatly impacting outcome. Current antipsychotic medications have minimal beneficial effects on cognitive deficits of schizophrenia, and design of novel treatments is contingent upon translational research that will lead to a better understanding of the neural basis of these deficits. However, feasibility of such translational studies has been limited, primarily because of the scarcity of cognitive tasks for laboratory animals that assess similar cognitive constructs as those assessed in the routinely used clinical test paradigms. One such construct is "behavioral flexibility" or attentional set-shifting, which is assessed commonly in patients with schizophrenia using the Wisconsin Card Sort Test (WCST). While the limited cognitive capacity of laboratory animals, in particular rodents, hinders the design of cognitive tasks that would be considered entirely "analogous" to complex tasks such as the WCST, it is possible to design behavioral paradigms that can evaluate cognitive constructs that are "comparable" to those measured in many clinical test paradigms. However, while studies with laboratory animals have primarily relied on validating a task based on "theoretical homology" with human tasks, to carry out clinically relevant mechanistic studies, we believe, it is crucial that "functional homology" also be established. The principal aim of this application is to initiate collaborations between basic and clinical researchers and work toward standardizing quantitative measures that can be used to establish functional homology between human and animal cognitive tasks that are relevant to schizophrenia. The initial aspect of this collaboration will involve the use of parallel basic and clinical quantitative measures to establish the construct validity of a newly developed rodent task that has theoretical homology with WCST. Specific aims are designed to characterize the structural and neurochemical homology between these tasks.