Impaired associative taste learning and abnormal brain activation in kinase-defective eEF2K mice
Impaired associative taste learning and abnormal brain activation in kinase-defective eEF2K mice
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DOI：
10.1101/lm.023937.111
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发表时间：
2012-03-01
影响因子：
2
通讯作者：
Rosenblum, Kobi
中科院分区：
文献类型：
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作者：
Gildish, Iness;Manor, David;Rosenblum, Kobi
记忆巩固的时间定义基于药物干预，如mRNA翻译抑制剂（分子巩固）或特定脑区习得后失活（系统水平巩固）。然而，分子和系统巩固之间的关系却知之甚少。参与翻译起始和延伸的分子巩固机制先前已经在皮层中使用味觉学习范式进行了研究。例如，真核延伸因子2 （eEF2）的磷酸化水平被发现与味觉皮层（GC）的味觉学习相关，在学习后几分钟。为了分离eEF2在Thr-56位点磷酸化状态在分子和系统巩固中的作用，我们分析了eEF2K （eEF2唯一已知的激酶）ki小鼠的皮质依赖性味觉学习，这些小鼠表现出eEF2磷酸化水平降低，但eEF2和eEF2K水平正常。这些小鼠表现出明显的皮层依赖性联想性味觉学习的衰减，而不是偶然性味觉学习的衰减。为了更好地了解潜在的机制，我们比较了eEF2K ki小鼠和WT小鼠在条件味觉厌恶（CTA）学习期间的MEMRI（锰增强磁共振成像）测量的大脑活动，发现两者之间存在明显差异，但在基础条件下没有发现差异。我们的研究结果表明，足够水平的eEF2磷酸化对于皮层依赖性联想学习至关重要，并表明在系统水平上记忆处理的故障是这种联想记忆障碍的基础。
Memory consolidation is defined temporally based on pharmacological interventions such as inhibitors of mRNA translation (molecular consolidation) or post-acquisition deactivation of specific brain regions (systems level consolidation). However, the relationship between molecular and systems consolidation are poorly understood. Molecular consolidation mechanisms involved in translation initiation and elongation have previously been studied in the cortex using taste-learning paradigms. For example, the levels of phosphorylation of eukaryotic elongation factor 2 (eEF2) were found to be correlated with taste learning in the gustatory cortex (GC), minutes following learning. In order to isolate the role of the eEF2 phosphorylation state at Thr-56 in both molecular and system consolidation, we analyzed cortical-dependent taste learning in eEF2K (the only known kinase for eEF2) ki mice, which exhibit reduced levels of eEF2 phosphorylation but normal levels of eEF2 and eEF2K. These mice exhibit clear attenuation of cortical-dependent associative, but not of incidental, taste learning. In order to gain a better understanding of the underlying mechanisms, we compared brain activity as measured by MEMRI (manganese-enhanced magnetic resonance imaging) between eEF2K ki mice and WT mice during conditioned taste aversion (CTA) learning and observed clear differences between the two but saw no differences under basal conditions. Our results demonstrate that adequate levels of phosphorylation of eEF2 are essential for cortical-dependent associative learning and suggest that malfunction of memory processing at the systems level underlies this associative memory impairment.