Loss of CELF6 RNA binding protein impairs cocaine conditioned place preference and contextual fear conditioning.
Loss of CELF6 RNA binding protein impairs cocaine conditioned place preference and contextual fear conditioning.
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CELF6 RNA 结合蛋白的缺失会损害可卡因条件性位置偏好和情境恐惧条件反射。
DOI：
10.1111/gbb.12593
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Dougherty,JosephD
中科院分区：
文献类型：
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作者：
Maloney,SusanE;Rieger,MichaelA;Al-Hasani,Ream;Bruchas,MichaelR;Wozniak,DavidF;Dougherty,JosephD
除了不同细胞类型中的基因表达差异外，还存在部分由RNA结合蛋白（RBP）驱动的大量转录后调节。功能丧失RBP突变与神经发育障碍有关，如脆性X综合征和综合征型自闭症。在动物模型中进行的阐明神经发育障碍相关RBP对不同行为的影响的工作表明，正常的转录后调节和条件学习之间存在联系。我们先前报道了RBP CUG-BP，Elav样因子6（CELF 6）无效的小鼠模型的认知能力，我们也发现这与人类自闭症有关。具体而言，这些小鼠未能增强探索性戳洞行为以响应对奖励刺激的熟悉。Celf 6基因表达的特征显示在单胺能群体如多巴胺能中脑群体中高水平表达。为了更好地理解潜在的行为中断介导的阻力改变探索性行为的洞板任务，我们测试了三个假设：DoesCelf 6损失导致全球限制的行为模式，未能立即响应奖励或未能改变行为的奖励（条件反射）。我们发现对奖赏的急性反应是完整的，然而Celf 6突变小鼠对奖赏和厌恶刺激都表现出受损的条件学习。因此，我们发现，对于洞板中Celf 6突变体的改变的抵抗力，最简单的解释是条件反射的失败，因为小鼠甚至对可卡因等强有力的奖励刺激物的反应也变迟钝了。这些发现进一步支持了限制性条件反射在条件学习中的作用。
In addition to gene expression differences in distinct cell types, there is substantial post‐transcriptional regulation driven in part by RNA binding proteins (RBPs). Loss‐of‐function RBP mutations have been associated with neurodevelopmental disorders, such as Fragile‐X syndrome and syndromic autism. Work performed in animal models to elucidate the influence of neurodevelopmental disorder‐associated RBPs on distinct behaviors has showed a connection between normal post‐transcriptional regulation and conditioned learning. We previously reported cognitive inflexibility in a mouse model null for the RBP CUG‐BP, Elav‐like factor 6 (CELF6), which we also found to be associated with human autism. Specifically, these mice failed to potentiate exploratory hole‐poking behavior in response to familiarization to a rewarding stimuli. Characterization ofCelf6gene expression showed high levels in monoaminergic populations such as the dopaminergic midbrain populations. To better understand the underlying behavioral disruption mediating the resistance to change exploratory behavior in the holeboard task, we tested three hypotheses: DoesCelf6loss lead to global restricted patterns of behavior, failure of immediate response to reward or failure to alter behavior in response to reward (conditioning). We found the acute response to reward was intact, yetCelf6mutant mice exhibited impaired conditioned learning to both reward and aversive stimuli. Thus, we found that the resistance to change by theCelf6mutant in the holeboard was most parsimoniously explained as a failure of conditioning, as the mice had blunted responses even to potent rewarding stimuli such as cocaine. These findings further support the role of RBPs in conditioned learning.