Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia
Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia
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DOI：
10.1007/s00213-003-1710-9
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发表时间：
2004-06-01
影响因子：
3.4
通讯作者：
Williams, GV
中科院分区：
文献类型：
--
作者：
Castner, SA;Goldman-Rakic, PS;Williams, GV
背景和理论基础。工作记忆表现被认为是精神分裂症的核心缺陷，也是重新融入社会和复发倾向的最佳预测因子。这一基本的认知过程对人类的推理和判断至关重要，并依赖于前额叶功能的完整性。精神分裂症的前额叶功能障碍与多巴胺和谷氨酸能传递的改变有关。然而，到目前为止，抗精神病药物并没有从这种疾病的认知衰弱后果中得到实质性的缓解。目标。本文综述了关键的啮齿动物和非人类灵长类动物模型，以阐明工作记忆的神经机制及其神经调节。我们比较了正常状态和实验诱导的前额叶功能障碍模型的工作记忆的生理学和药理学，并评估了它们与精神分裂症的相关性。结果与结论。啮齿动物模型已经证明了内侧前额叶皮质中异常的多巴胺和谷氨酸能信号对工作记忆的意义。然而，关于啮齿动物对工作记忆的测试在多大程度上利用了精神分裂症患者受到损害的同一过程，仍存在一些问题。非人灵长类动物为研究前额叶功能和工作记忆的影响提供了一个很好的模型，因为人类和非人灵长类动物在前额叶皮质和较高的认知能力之间的关系上具有高度的同源性。此外，前额叶功能障碍的非人类灵长类动物模型，包括苯丙胺敏化、亚慢性苯环利定和神经发育侮辱，是分析治疗精神分裂症认知功能障碍的新化合物的理想选择，从而促进临床前药物开发和临床试验之间的转换。
Background and rationale. Working memory performance is considered to be a core deficit in schizophrenia and the best predictor of social reintegration and propensity for relapse. This cardinal cognitive process is critical for human reasoning and judgment and depends upon the integrity of prefrontal function. Prefrontal dysfunction in schizophrenia has been linked to altered dopaminergic and glutamatergic transmission. However, to date, antipsychotics provide no substantial relief from the debilitating cognitive consequences of this disease. Objectives. This review examines the key rodent and non-human primate models for elucidating the neural mechanisms of working memory and their neuromodulation. We compare the physiology and pharmacology of working memory between the normal state and experimentally induced models of prefrontal dysfunction and evaluate their relevance for schizophrenia. Results and conclusions. Rodent models have demonstrated the significance of aberrant dopaminergic and glutamatergic signaling in medial prefrontal cortex for working memory. However, there is some question as to the extent to which rodent tests of working memory tap into the same process that is compromised in schizophrenia. Non-human primates provide an unexcelled model for the study of influences on prefrontal function and working memory due to the high degree of homology between human and non-human primates in the relationship between prefrontal cortex and higher cognitive capacities. Moreover, non-human primate models of prefrontal dysfunction including amphetamine sensitization, subchronic phencyclidine, and neurodevelopmental insult are ideal for the analysis of novel compounds for the treatment of cognitive dysfunction in schizophrenia, thereby facilitating the translation between preclinical drug development and clinical trials.