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首页> 外文期刊>Genes, brain, and behavior >Extinction of an instrumental response: a cognitive behavioral assay in Fmr1 knockout mice
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Extinction of an instrumental response: a cognitive behavioral assay in Fmr1 knockout mice

机译：仪器反应的消退：Fmr1基因敲除小鼠的认知行为测定。

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Fragile X (FX) is the most common genetic cause of intellectual disability and autism. Previous studies have shown that partial inhibition of metabotropic glutamate receptor signaling is sufficient to correct behavioral phenotypes in a mouse model of FX, including audiogenic seizures, open-field hyperactivity and social behavior. These phenotypes model well the epilepsy (15%), hyperactivity (20%) and autism (30%) that are comorbid with FX in human patients. Identifying reliable and robust mouse phenotypes to model cognitive impairments is critical considering the 90% comorbidity of FX and intellectual disability. Recent work characterized a five-choice visuospatial discrimination assay testing cognitive flexibility, in which FX model mice show impairments associated with decreases in synaptic proteins in prefrontal cortex (PFC). In this study, we sought to determine whether instrumental extinction, another process requiring PFC, is altered in FX model mice, and whether downregulation of metabotropic glutamate receptor signaling pathways is sufficient to correct both visuospatial discrimination and extinction phenotypes. We report that instrumental extinction is consistently exaggerated in FX model mice. However, neither the extinction phenotype nor the visuospatial discrimination phenotype is corrected by approaches targeting metabotropic glutamate receptor signaling. This work describes a novel behavioral extinction assay to model impaired cognition in mouse models of neurodevelopmental disorders, provides evidence that extinction is exaggerated in the FX mouse model and suggests possible limitations of metabotropic glutamate receptor-based pharmacotherapy.
机译：脆弱X（FX）是导致智障和自闭症的最常见遗传原因。先前的研究表明，对代谢型谷氨酸受体信号的部分抑制足以纠正FX小鼠模型中的行为表型，包括音源性癫痫发作，开放视野亢进和社交行为。这些表型很好地模拟了人类患者中与FX并存的癫痫症（15％），活动过度（20％）和自闭症（30％）。考虑到90％的FX合并症和智力残疾，识别可靠且健壮的小鼠表型以建模认知障碍至关重要。最近的工作特征是一种五种选择的视觉空间辨别试验，用于测试认知灵活性，其中FX模型小鼠显示与额叶前皮质（PFC）中的突触蛋白减少相关的损伤。在这项研究中，我们试图确定是否在FX模型小鼠中改变了工具的灭绝过程（另一个需要PFC的过程），以及代谢型谷氨酸受体信号通路的下调是否足以纠正视觉空间辨别和灭绝表型。我们报告说，在FX模型小鼠中，工具的灭绝现象一直被夸大。但是，通过靶向代谢型谷氨酸受体信号传导的方法，既没有消除灭绝表型也没有视觉空间辨别表型。这项工作描述了一种新的行为消光测定法，以对神经发育障碍小鼠模型中的认知障碍进行建模，提供了证据表明FX小鼠模型中的消光现象被夸大，并暗示了基于代谢型谷氨酸受体的药物治疗的可能局限性。

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