Overexpression of SIRT6 in the hippocampal CA1 impairs the formation of long-term contextual fear memory
首发时间:2015-10-15
Abstract:Histone modifications have been implicated in learning and memory. Our previous transcriptome data showed that expression of sirtuins 6 (SIRT6), a member of Histone deacetylases (HDACs) family in the hippocampal cornu ammonis 1 (CA1) was decreased after contextual fear conditioning. However, the role of SIRT6 in the formation of memory is still elusive. In the present study, we found that contextual fear conditioning inhibited translational expression of SIRT6 in the CA1. Microinfusion of lentiviral vector-expressing SIRT6 into the CA1 region selectively enhanced the expression of SIRT6 and impaired the formation of long-term contextual fear memory without affecting short-term fear memory. The overexpression of SIRT6 in the CA1 had no effect on anxiety-like behaviors or locomotor activity. Also, we also found that SIRT6 overexpression significantly inhibited the expression of insulin-like factor 2 (IGF2) and amounts of proteins and/or phosphoproteins (e.g. Akt, pAkt, mTOR and p-mTOR) related to the IGF2 signal pathway in the CA1. These results demonstrate that the overexpression of SIRT6 in the CA1 impaired the formation of long-term fear memory, and SIRT6 in the CA1 may negatively modulate the formation of contextual fear memory via inhibiting the IGF signaling pathway.
keywords: fear memory formation hippocampus sirtuin 6
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海马CA1脑区过表达SIRT6破坏长时环境关联恐惧记忆的形成
摘要:组蛋白修饰在记忆形成过程中发挥重要作用,前期转录组学研究发现,环境关联的恐惧训练能显著下调大鼠海马CA1脑区沉默信息调节蛋白同源物6 (sirtuin 6 SIRT6),一个组蛋白去乙酰基转移酶家族成员,目前,SIRT6在记忆形成中的作用尚未阐明。本研究利用环境关联恐惧记忆大鼠模型,通过构建SIRT6的慢病毒过表达载体,探讨SIRT6在环境关联的恐惧记忆形成中的作用。研究结果发现,海马CA1区过表达SIRT6能显著降低大鼠环境线索关联的长时恐惧记忆的形成,对短时记忆没有显著影响。海马CA1区过表达SIRT6不影响大鼠环境关联恐惧记忆的获取和表达,对大鼠自发活动和焦虑行为也不存在显著影响。Western blot 实验结果发现,脑区特异性过表达SIRT6能显著抑制胰岛素样生长因子-2及其相关信号通路蛋白(Akt, pAkt, mTOR and p-mTOR等)的表达和活性。综上,本研究发现提示,海马CA1脑区SIRT6负向调控环境关联恐惧记忆的形成,其调控作用可能与抑制胰岛素样生长因子信号通路有关。
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