Translational Studies on Cognitive Flexibility

描述(由申请者提供)：认知障碍是一种根本 精神分裂症的精神病理学方面，对整体 疾病进程的发病率和对预后的极大影响。当前 抗精神病药物对认知障碍的益处微乎其微 精神分裂症，而新的治疗方法的设计取决于 翻译研究将导致更好地理解神经 这些赤字的基础。然而，这种翻译研究的可行性已经 有限，主要是因为认知任务的稀缺性 评估与被评估的认知结构相似的认知结构的实验动物 在常规使用的临床测试范例中。一种这样的构造是 “行为灵活性”或注意力定势转移，这是评估 威斯康星卡片分类测验在精神分裂症患者中的常见应用 (WCST)。虽然实验动物有限的认知能力，在 特别是啮齿动物，阻碍了认知任务的设计 它被认为完全类似于WCST这样的复杂任务， 有可能设计能够评估认知结构的行为范式 这与在许多临床测试范例中测量的结果是“可比的”。 然而，尽管对实验室动物的研究主要依赖于 验证一项任务与人工任务的“理论同源性”，以便携带 在临床相关的机制研究之外，我们认为，至关重要的是 “功能同调”也是成立的。这样做的主要目的是 应用是启动基础和临床之间的协作 研究人员并致力于标准化量化措施，这些措施可以 用于建立人类和动物认知任务之间的功能同源性 与精神分裂症有关的基因。这种合作的最初方面是 将涉及使用平行的基础和临床量化措施来 建立新开发的啮齿动物任务的结构效度 与WCST的理论同源性。特定的目标旨在描述 这些任务之间的结构和神经化学同源性。

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.