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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Transient And Selective Overexpression Of D_2 Receptors In The Striatum Causes Persistent Deficits In Conditional Associative Learning
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Transient And Selective Overexpression Of D_2 Receptors In The Striatum Causes Persistent Deficits In Conditional Associative Learning

机译：纹状体中D_2受体的短暂和选择性过表达导致条件联想学习中的持续性缺陷

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摘要

Cognitive deficits in schizophrenia are thought to derive from a hypofunction of the prefrontal cortex (PFC), but the origin of the hypofunction is unclear. To explore the nature of this deficit, we genetically modified mice to model the increase in striatal dopa-mine D_2 receptors (D_2Rs) observed in patients with schizophrenia. Previously, we reported deficits in spatial working memory tasks in these mice, congruent with the working memory deficits observed in schizophrenia. However, patients with schizophrenia suffer from deficits in many executive functions, including associative learning, planning, problem solving, and nonspatial working memory. We therefore developed operant tasks to assay two executive functions, conditional associative learning (CAL) and nonspatial working memory. Striatal D_2R-overexpressing mice show a deficit in CAL because of perseverative behavior, caused by interference from the previous trial. D_2R up-regulation during development was sufficient to cause this deficit, because switching off the transgene in adulthood did not rescue the phenotype. We validated prefrontal dependency of CAL by using neurotoxic lesions. Lesions of the medial PFC including the anterior cingulate, infralimbic, and prelimbic cortices impair CAL because of increased interference from previously rewarded trials, exactly as observed in D_2R transgenic mice. In contrast, lesions restricted to the infralimbic and prelimbic cortices have no effect on CAL but impair performance in the nonspatial working memory task. These assays not only give us insight into how excess striatal D_2Rs affect cognition but also provide tools for studying cognitive endophe-notypes in mice.
机译：精神分裂症的认知功能障碍被认为是由额叶前额叶皮质（PFC）的功能减退引起的，但功能减退的起因尚不清楚。为了探索这种缺陷的性质，我们对小鼠进行了基因修饰，以模拟在精神分裂症患者中观察到的纹状体多巴胺D_2受体（D_2Rs）的增加。以前，我们报道了这些小鼠的空间工作记忆功能不足，与精神分裂症中观察到的工作记忆不足相吻合。但是，精神分裂症患者的许多执行功能均存在缺陷，包括联想学习，计划，问题解决和非空间工作记忆。因此，我们开发了操作性任务来分析两个执行功能，即条件联想学习（CAL）和非空间工作记忆。过度纹状体D_2R的小鼠由于先前试验的干扰而引起的持久性行为，显示CAL缺乏。在发育过程中D_2R的上调足以引起这一缺陷，因为在成年期关闭转基因不能拯救该表型。我们通过使用神经毒性病变验证了CAL的前额叶依赖性。正像在D_2R转基因小鼠中观察到的那样，内侧PFC的病变（包括前扣带回，下肢皮层和前缘皮层）损害了CAL，这是因为先前获得奖励的试验增加了干扰。相比之下，仅限于下缘和前缘皮质的​​病变对CAL没有影响，但会削弱非空间工作记忆任务的性能。这些测定不仅使我们了解过量的纹状体D_2Rs如何影响认知，而​​且还提供了研究小鼠认知内异型的工具。

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