SIRT1通过调控神经递质代谢稳态影响学习记忆功能的机制研究

doi:10.19586/j.2095-2341.2025.0154

生物技术进展 ›› 2026, Vol. 16 ›› Issue (2): 395-411.DOI: 10.19586/j.2095-2341.2025.0154

• 研究论文 • 上一篇

SIRT1通过调控神经递质代谢稳态影响学习记忆功能的机制研究

乔雅楠¹(), 曾雨冰¹(), 何学佳¹^,², 刘帆¹, 王珊¹()

^1.首都医科大学附属首都儿童医学中心，首都儿科研究所，北京 100020
^2.山东第一医科大学附属省立医院儿科，济南 250021

收稿日期:2025-11-06 接受日期:2025-12-25 出版日期:2026-03-25 发布日期:2026-04-27
通讯作者: 王珊
作者简介:乔雅楠 E-mail: qiaoyanan5114@126.com
曾雨冰 E-mail: awater007@sina.com第一联系人：并列第一作者
基金资助:
首都儿科研究所新质基金项目(XZYC-2025-06)

Mechanism of SIRT1 in Regulating Learning and Memory via Modulating Neurotransmitter Metabolic Homeostasis

Yanan QIAO¹(), Yubing ZENG¹(), Xuejia HE¹^,², Fan LIU¹, Shan WANG¹()

^1.Capital Medical University Affiliated Capital Children's Medical Center，Capital Institute of Pediatrics，Beijing 100020，China
^2.Pediatrics Department，Provincial Hospital Affiliated to Shandong First Medical University，Jinan 250021，China

Received:2025-11-06 Accepted:2025-12-25 Online:2026-03-25 Published:2026-04-27
Contact: Shan WANG

摘要/Abstract

摘要：

SIRT1作为NAD?依赖的组蛋白去乙酰化酶，在维持神经元功能和代谢稳态中发挥关键作用，但其在调控神经递质代谢及认知功能中的分子机制尚不明确。通过构建Sirt1基因缺失小鼠模型（Sirt1^+/- ），对其海马组织进行转录组学和代谢组学分析，系统探究了SIRT1缺失对大脑神经递质代谢网络及认知功能的影响。表型观察显示，Sirt1^+/- 小鼠表现出严重的空间记忆能力和学习能力下降。转录组学和代谢组学结果显示，SIRT1缺失导致海马组织内谷氨酸和γ-氨基丁酸（gamma-aminobutyric acid，GABA）等关键神经递质代谢紊乱，并伴随神经递质代谢关键基因如Gad1和Gad2的显著上调。多组学联合分析进一步证实SIRT1缺失通过抑制神经活性配体-受体通路和cAMP信号通路，引发海马内神经递质代谢失衡，进而影响记忆和学习能力。综上，研究阐明了SIRT1通过协调神经递质代谢重编程和能量稳态维持认知功能的新机制，为神经退行性疾病的干预提供了潜在靶点。

关键词: SIRT1, 神经递质代谢稳态, 谷氨酸, γ-氨基丁酸, 学习记忆功能障碍

Abstract:

SIRT1， an NAD⁺-dependent deacetylase， plays a pivotal role in maintaining neuronal function and metabolic homeostasis. However， its molecular mechanisms in regulating neurotransmitter metabolism and cognitive impairment remain unclear. In this study， we established a Sirt1-deficient mouse model （Sirt1^+/- ） and performed transcriptomic and metabolomic analyses on hippocampus to systematically investigate the impact of SIRT1 loss on cerebral neurotransmitter metabolic networks and cognitive function. Phenotypic observations revealed that Sirt1^+/- mice exhibited significant deficits in spatial memory and learning abilities. Metabolomic and transcriptomic profiling demonstrated that SIRT1 deficiency led to metabolic dysregulation of key neurotransmitters， including glutamate and γ-aminobutyric acid （GABA） in the hippocampus， accompanied by marked upregulation of neurotransmitter metabolism-related genes like Gad1 and Gad2. Integrated multi-omics analysis further confirmed that SIRT1 deficiency suppressed neuroactive ligand-receptor interactions and cAMP signaling pathways， resulting in disrupted neurotransmitter homeostasis and subsequent cognitive dysfunction. In conclusion， this study elucidates a novel mechanism by which SIRT1 maintains cognitive function through coordinated reprogramming of neurotransmitter metabolism and energy homeostasis， providing potential therapeutic targets for neurodegenerative disorders.

Key words: SIRT1, neurotransmitter metabolic homeostasis, glutamate, gamma-aminobutyric acid, learning and memory dysfunction

中图分类号:

Q756

乔雅楠, 曾雨冰, 何学佳, 刘帆, 王珊. SIRT1通过调控神经递质代谢稳态影响学习记忆功能的机制研究[J]. 生物技术进展, 2026, 16(2): 395-411.

Yanan QIAO, Yubing ZENG, Xuejia HE, Fan LIU, Shan WANG. Mechanism of SIRT1 in Regulating Learning and Memory via Modulating Neurotransmitter Metabolic Homeostasis[J]. Current Biotechnology, 2026, 16(2): 395-411.

图/表 8

表1 本文所用引物

Table 1 Primers used in this study

基因名称	上游引物（5′→3′）	下游引物（5′→3′）
Gad1	5′-AACGTATGATACTTGGTGTGGC-3′	5′-CCAGGCTATTGGTCCTTTGTAAG-3′
Gad2	5′-TCCGGCTTTTGGTCCTTCG-3′	5′-ATGCCGCCCGTGAACTTTT-3′
Gabra2	5′-AGTCAGTGGCCCATAACATGA-3′	5′-TTGTGTAAGCGTAGCTTCCAAA-3′
Trpv1	5′-CCGGCTTTTTGGGAAGGGT-3′	5′-GAGACAGGTAGGTCCATCCAC-3′
Trpv4	5′-ATGGCAGATCCTGGTGATGG-3′	5′-GGAACTTCATACGCAGGTTTGG-3′

图1 SIRT1缺陷损害学习和记忆能力A：实验流程示意图；B：通过CRISPR/Cas9介导的SIRT1-201 KO示意图；C：小鼠基因型鉴定引物设计原则示意图；D：不同小鼠基因型的DNA凝胶电泳基因分型， WT—野生型，KO—SIRT1敲除，HE—杂合（Sirt1+/- ），NC—阳性对照，NT—无模板对照；E：Sirt1- KO小鼠Sirt1靶区Sanger测序图谱；F：RT-qPCR检测Sirt1+/- 小鼠或WT小鼠Sirt1 mRNA水平；G：WB检测Sirt1+/- 小鼠或WT小鼠SIRT1蛋白水平；H：Y型迷宫的自发交替率柱状图；I：Y迷宫可视化运动分布热图；J：新物体识别实验中小鼠探索行为的跟踪记录；K：新物体识别实验中新目标识别指标柱状图；L：旷场实验中心区时间比（左）和总移动距离（右）柱状图；M：旷场中小鼠的运动路径。**、***分别表示与野生型相比，差异在P<0.01、P<0.001水平上具有统计学意义；ns表示无统计学意义（P>0.05）。

Fig. 1 SIRT1 deficiency impairs learning and memory abilities

图2 Sirt1+/- 小鼠海马中的DEGs与神经元突触信号传导密切相关A：转录组学数据集中2个样本组的PCA图；粉色球代表WT小鼠，蓝色球代表Sirt1+/- 小鼠：B：火山图显示了基因的差异变化（P<0.05）。C：与WT小鼠相比，Sirt1+/- 小鼠中DEGs上调和下调的数量；D：与WT小鼠相比，Sirt1+/- 小鼠中DEGs的热图聚类；E：弦图显示了转录组学的GO分析，根据P值突出前10个条目：F：气泡图显示了与WT小鼠相比，Sirt1+/- 小鼠中与神经发育和信号转导相关的前10个显著富集的GO分析生物过程条目；G：气泡图显示了Sirt1+/- 小鼠与WT小鼠相比，前10个显著富集的GO分析细胞组分条目；H：气泡图显示了Sirt1+/- 小鼠与WT小鼠相比，前10个显著富集的GO分析分子功能条目

Fig. 2 DEGs in the hippocampus of Sirt1+/- mice are closely related to synaptic signal transduction in neurons

图3 SIRT1缺失抑制神经递质突触信号传递A：Sirt1+/- 小鼠转录组学中上调基因KEGG富集分析的前10条通路柱状图；B：Sirt1+/- 小鼠与WT小鼠相比转录组学中下调基因KEGG富集分析的前10条通路柱状图；C：参与突触囊泡循环、GABA能突触、谷氨酸能突触和神经活性配体-受体相互作用的DEGs热图；D：GESA结果显示突触囊泡循环、GABA能突触、谷氨酸能突触和神经活性配体-受体相互作用的途径；E：RT-qPCR检测Sirt1+/- 小鼠或WT小鼠中Gad1、Gad2、Gabra2、Trpv1和Trpv4 mRNA水平。**、***、****分别表示差异在P<0.01、P<0.001、P<0.000 1水平上具有统计学意义。

Fig. 3 The loss of SIRT1 inhibits neurotransmitter synaptic signaling

图4 SIRT1缺失触发海马区代谢谱的广泛重编程A：OPLS-DA通过其独特的特征区分WT和Sirt1+/-小鼠；B：模型验证参数证明了模型的稳定性和不存在过拟合；C：火山图显示代谢物的差异变化（P<0.05）；D：Sirt1+/-小鼠与WT小鼠相比，代谢产物上调或下调的饼状图；E：Sirt1+/-小鼠和WT小鼠差异代谢物的分层聚类热图

Fig. 4 SIRT1 deficiency triggers extensive reprogramming of the hippocampal metabolome

图5 SIRT1的缺失会破坏海马体中关键神经递质的代谢稳态A：Sirt1+/- 小鼠中KEGG富集分析中上调基因的前10条通路气泡图；B：热图显示了参与蛋白质消化和吸收、氨基酰基tRNA生物合成和氨基酸代谢的差异表达代谢物；C：代谢组学中Sirt1+/- 小鼠下调基因KEGG富集分析的前10条通路气泡图；D：热图显示了cAMP信号通路、甘油脂代谢和甘油磷脂代谢的差异表达代谢物；E：比较WT和SIRT1小鼠脑内关键神经递质水平。*、**、***分别表示在P<0.05、P<0.01、P<0.001水平上具有统计学意义。

Fig. 5 The absence of SIRT1 disrupts the metabolic homeostasis of key neurotransmitters in the hippocampus

图6 多组学分析揭示了SIRT1缺乏对神经递质代谢相关途径的影响A：韦恩图显示了转录组学和代谢组学筛选的途径；B：柱状图显示了转录组学和代谢组学根据基因数量共同筛选的前10条通路；C：热图显示了参与神经活性配体-受体相互作用的差异表达代谢物；D：韦恩图显示了转录组和代谢组筛选的通路，上图为上调基因和代谢物筛选通路，下图为下调基因和代谢物筛选通路；E：棒棒糖图显示了转录组学和代谢组学联合筛选的前8条通路

Fig. 6 Multi-omics analysis reveals the impact of SIRT1 deficiency on pathways related to neurotransmitter metabolism

图7 SIRT1在调节神经递质代谢和维持认知功能中起关键作用A：筛选神经活性配体-受体相互作用、cAMP信号通路和蛋白质消化吸收通路的DEGs进行PPI分析；B：示意图说明SIRT1缺乏通过改变海马内兴奋性神经递质与抑制性神经递质代谢的稳态，抑制cAMP通路和神经活性配体-受体相互作用，影响认知和记忆功能

Fig. 7 SIRT1 plays a pivotal role in regulating neurotransmitter metabolism and preserving cognitive function

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SIRT1通过调控神经递质代谢稳态影响学习记忆功能的机制研究

Mechanism of SIRT1 in Regulating Learning and Memory via Modulating Neurotransmitter Metabolic Homeostasis

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