Hippocampal O-GlcNAc homeostasis sustains memory reconsolidation amidst stress hormone exposure

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-07-01 DOI:10.1016/j.neuropharm.2025.110582

Chenran Wang , Jianhui Wang , Feng Liu , Jingying Liu , Yan Huang , Mengting Xia , Hexi Yang , Zhiyong Xiao , Wenxia Zhou

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Abstract

Memory is not always reliable, inherently malleable. The malleability enables organisms to adapt their behavior based on future predictions, increasing survival odds. O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as a modulator of memory, notwithstanding, its impact on memory malleability remains to be comprehensively elucidated. Here, we report that the reliable prediction-mediated strengthening or incomplete reminder-mediated updating of original memories, a process called reconsolidation can alter memory malleability, which is impaired in mice (C57BL/6J, males) under stress. Pharmacologically enhancing O-GlcNAc levels afford dynamic and phase-specific protection of reconsolidation. Meanwhile, overexpression of hippocampal O-GlcNAc transferase (OGT), aimed at elevating O-GlcNAc, recapitulated this protective effect. Inhibiting OGT substrate availability negates this protective effect. Interestingly, the concurrent overexpression of hippocampal OGT alongside substrate supplementation, intended to excessively elevate O-GlcNAc, proves ineffective in affording additional protection. It even triggers a reappearance of reconsolidation resistance in the original memory. This protective role of O-GlcNAc, seemingly acting in a buffering-like manner, insulating reconsolidation from aberrant modifications within an optimal range. These data establish hippocampal O-GlcNAc as a potential target for preserving memory malleability.

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应激激素暴露下海马O-GlcNAc内稳态维持记忆再巩固

记忆并不总是可靠的，它具有固有的可塑性。这种可塑性使生物体能够根据未来的预测来调整自己的行为，从而增加生存几率。O-linked β- n -乙酰氨基葡萄糖（O-GlcNAc）作为一种记忆调节剂已经出现，尽管它对记忆延展性的影响仍有待全面阐明。在这里，我们报告了可靠的预测介导的原始记忆的加强或不完整的提醒介导的更新，一个称为再巩固的过程可以改变记忆的延展性，这在应激小鼠（C57BL/6J，雄性）中受损。药理学上提高O-GlcNAc水平提供了动态和阶段性的再巩固保护。同时，旨在升高O-GlcNAc的海马O-GlcNAc转移酶（OGT）的过表达再现了这种保护作用。抑制OGT底物的可用性会否定这种保护作用。有趣的是，在补充底物的同时过度表达海马OGT，旨在过度提高O-GlcNAc，证明在提供额外保护方面是无效的。它甚至会在原始记忆中引发再巩固阻力的再现。O-GlcNAc的这种保护作用，似乎以类似缓冲的方式起作用，在最佳范围内防止异常修饰的再固结。这些数据表明海马O-GlcNAc是保持记忆可塑性的潜在靶点。

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

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).