Nat Neurosci:清华大学研究者揭示长期记忆的保护机制

2017-04-03 生物通 生物通

来自清华大学生命科学学院,IDG/McGovern脑科学研究所等处的研究人员发表了题为“Activity-induced histone modifications govern Neurexin-1 splicing and memory preservation”的文章,在分子机制层面揭示了哺乳动物脑中记忆保护机制这个困扰研究界多年的难题,研究指出了脑中长期记忆保护的新机制,为治疗伴随则记忆丧

来自清华大学生命科学学院,IDG/McGovern脑科学研究所等处的研究人员发表了题为“Activity-induced histone modifications govern Neurexin-1 splicing and memory preservation”的文章,在分子机制层面揭示了哺乳动物脑中记忆保护机制这个困扰研究界多年的难题,研究指出了脑中长期记忆保护的新机制,为治疗伴随则记忆丧失的阿尔茨海默症,以及伴随着顽固性创伤记忆的创伤后应激综合症(PTSD)等脑疾病提供了全新的药物开发思路。

这一研究成果公布在3月27日的Nature Neuroscience杂志上,文章的通讯作者是清华大学生命科学学院管吉松研究员,他的研究组主要从事表观遗传机制对神经环路中神经元兴奋性与可塑性的调控机制等方面的研究。联合培养博士研究生项目2012级直博生丁歆璐和生命学院11级直博生柳三雄为共同第一作者。

记忆是外界刺激通过改变脑内神经元的连接得以存储的。然而,用于存储长时程记忆的神经网络却不受外界刺激的影响能够稳定的存在,其背后的机制尚不清楚。过去的研究表明表观遗传修饰参与调控了记忆的形成(encoding),巩固(consolidation)和再巩固(re-consolidation)。此外,表观遗传修饰被报道通过抑制记忆环路的可塑性来保持创伤记忆的回忆强度。

脑内的神经元具有很高的可塑性,即外界信息诱发的神经活动会触发脑中神经环路的改变,从而在脑内留下记忆印迹,并修改之前的神经网络存储信息。这样,脑中存储的信息就会常常受到外界新信息输入的修改,并渐渐丢失。有趣的是,对于某些重要的记忆的内容,脑似乎会产生一个“写保护”机制,使得长期记忆不被丢失。

管吉松研究组发现了学习后记忆印迹相关神经元的活动会引起的表观遗传修饰,从而在记忆相关神经元中留下长期印迹。这种表观遗传改变会通过调控突触蛋白的可变剪体,直接调节记忆相关神经元的可塑性和连接能力,从而保证长时程记忆的稳定性。

研究组成员通过细胞分选,分离了少量小鼠海马齿状回中的记忆相关细胞。从学习后的海马细胞中发现神经元活动能够在24小时后引起长时间维持的组蛋白修饰。这种表观遗传修饰是一种较为稳定的标记,它使得一些基因组特定位点的选择性剪切体发生长期改变,从而抑制了被激活神经元的突触连接,保护了记忆网络中存储的记忆。

之后研究人员进一步发现了从神经元激活到膜蛋白剪切体变化的细胞信号通路。他们的研究揭示了神经元活动会激活腺苷酸活化蛋白激酶(AMPK)通路,从而磷酸化DNA的结合蛋白p66α。结合在神经轴突连接素1(Nrxn1) 可变剪接位点4的p66α蛋白在磷酸化后招募了表观遗传调控因子HDAC2(组蛋白去乙酰化酶2)和Suv39h1,并建立了抑制性的组蛋白修饰。这个组蛋白微环境会通过对转录过程中耦联的RNA剪接过程进行调控,从而形成稳定的新剪切异构体蛋白。当人为干预这个细胞过程(Suv39h1基因敲除小鼠),使得神经元活动诱发的表观修饰印迹消失时,小鼠已经形成的记忆的稳定性下降,容易被新的学习内容覆盖。

这项研究指出了脑中长期记忆保护的新机制,为治疗伴随则记忆丧失的阿尔茨海默症,以及伴随着顽固性创伤记忆的创伤后应激综合症(PTSD)等脑疾病提供了全新的药物开发思路。同时,该研究首次揭示了生物神经网络在瞬时突触可塑性调节之外的中长期调控现象,为具有记忆的新型类脑计算神经网络算法的改进提供了新的思路与生物学证据。

原始出处:

Ding X, Liu S, Tian M,et al.Activity-induced histone modifications govern Neurexin-1 splicing and memory preservation.Nat Neurosci. 2017 Mar 27.

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    2018-01-15 liye789132251
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    2017-12-06 stfoxst
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    2017-04-05 lsndxfj
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    2017-04-05 医生2397
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    2017-04-04 shaosai

    好好学习,涨知识

    0

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    2017-04-04 jacob9231

    谢谢分享,受教了

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    2017-04-04 ann y

    清华大学研究者揭示长期记忆的保护机制

    0

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