1] Medical Scientist Training Program (MD/PhD), University of Minnesota, Minneapolis, MN, USA [2] Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA [3] Brain Sciences Center, VA Medical Center, Minneapolis, MN, USA.
Neuropsychopharmacology. 2013 Oct;38(11):2090-100. doi: 10.1038/npp.2013.118. Epub 2013 May 10.
Cognitive deficits are at the crux of why many schizophrenia patients have poor functional outcomes. One of the cognitive symptoms experienced by schizophrenia patients is a deficit in context processing, the ability to use contextual information stored in working memory to adaptively respond to subsequent stimuli. As such, context processing can be thought of as the intersection between working memory and executive control. Although deficits in context processing have been extensively characterized by neuropsychological testing in schizophrenia patients, they have never been effectively translated to an animal model of the disease. To bridge that gap, we trained monkeys to perform the same dot pattern expectancy (DPX) task, which has been used to measure context-processing deficits in human patients with schizophrenia. In the DPX task, the first stimulus in each trial provides the contextual information that subjects must remember in order to appropriately respond to the second stimulus in the trial. We found that administration of ketamine, an N-methyl-D-aspartate receptor antagonist, in monkeys caused a dose-dependent failure in context processing, replicating in monkeys the same specific pattern of errors committed by patients with schizophrenia when performing the same task. Therefore, our results provide the first evidence that context-processing dysfunction can be modeled in animals. Replicating a schizophrenia-like behavioral performance pattern in monkeys performing the same task used in humans provides a strong bridge to better understand the biological basis for this psychiatric disease and its cognitive manifestations using animal models.
认知缺陷是许多精神分裂症患者功能预后不良的核心原因。精神分裂症患者的认知症状之一是语境处理缺陷，即使用工作记忆中存储的语境信息来适应后续刺激的能力。因此，可以将语境处理视为工作记忆和执行控制之间的交叉点。尽管神经心理学测试已经广泛描述了精神分裂症患者的语境处理缺陷，但这些缺陷从未在该疾病的动物模型中得到有效转化。为了弥补这一差距，我们训练猴子执行相同的点模式预期（DPX）任务，该任务用于测量人类精神分裂症患者的语境处理缺陷。在 DPX 任务中，每个试验中的第一个刺激提供了受试者必须记住的语境信息，以便正确响应试验中的第二个刺激。我们发现，在猴子中给予 N-甲基-D-天冬氨酸受体拮抗剂氯胺酮会导致语境处理能力的剂量依赖性失败，这在猴子中复制了精神分裂症患者在执行相同任务时所犯的相同特定错误模式。因此，我们的结果首次提供了证据，表明可以在动物中模拟语境处理功能障碍。在猴子中复制类似于精神分裂症的行为表现模式，执行与人类相同的任务，为使用动物模型更好地理解这种精神疾病及其认知表现的生物学基础提供了强有力的桥梁。
