LncRNA Dleu2 regulates fear extinction memory through Celf2-driven synaptic plasticity

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2026-03-01 Epub Date: 2026-01-31 DOI:10.1016/j.brainresbull.2026.111757

Ziwei Pi , Jiazhi Jiang , Lixin Dong , Ziyue Xu , Yi Zhang , Gaomeng Luo , Junhui Liu , Runming Liu , Zhehao Li , Sha Liu , Jincao Chen , Wei Wei , Xiang Li

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Abstract

Long noncoding RNAs (lncRNAs) are diverse regulators that shape many aspects of brain function. Nonetheless, their role in the mechanisms underlying fear extinction memory remains insufficiently explored. We profiled lncRNAs following the RNA capture-seq in the infralimbic prefrontal cortex (ILPFC) and identified the processed-transcript lncRNA deleted in lymphocytic leukemia-2 (Dleu2). The knockdown of Dleu2 by antisense oligonucleotide (ASO) impaired extinction memory, which demonstrated an essential role of Dleu2 in this process. To elucidate the underlying mechanism, CHIRP-seq and ATAC-seq analyses demonstrated an increased binding of Dleu2 within the intronic region of Celf2, accompanied by enhanced chromatin accessibility. This modulation subsequently promotes the transcription of Celf2, a critical gene involved in synaptic plasticity. Functionally, Celf2 knockdown in ILPFC recapitulated the fear extinction memory deficit and reduced the number of dendritic spines. Together, these results indicate that lncRNA Dleu2 may serve as a potential therapeutic entry point for memory-related disorders.

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LncRNA delu2通过celf2驱动的突触可塑性调节恐惧消退记忆

长链非编码rna （lncRNAs）是多种多样的调节因子，影响着大脑功能的许多方面。尽管如此，它们在恐惧消退记忆机制中的作用仍未得到充分探讨。我们在边缘下前额叶皮层（ILPFC）中通过RNA捕获序列分析了lncRNA，并鉴定了在淋巴细胞白血病-2 （leu2）中缺失的加工转录lncRNA。反义寡核苷酸（ASO）对Dleu2的敲除使灭绝记忆受损，表明Dleu2在这一过程中发挥了重要作用。为了阐明其潜在的机制，CHIRP-seq和ATAC-seq分析表明，在Celf2的内含子区域内，Dleu2的结合增加，同时染色质可及性增强。这种调节随后促进了参与突触可塑性的关键基因Celf2的转录。在功能上，ILPFC中的Celf2敲低重现了恐惧消退记忆缺陷，并减少了树突棘的数量。总之，这些结果表明lncRNA dele2可能作为记忆相关疾病的潜在治疗切入点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.