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OA

SIRT1,an NAD+-dependent deacetylase,plays a pivotal role in maintaining neuronal function and metabolic homeo-stasis.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 neurotransmit-ters,including glutamate and γ-aminobutyric acid(GABA)in the hippocampus,accompanied by marked upregulation of neu-rotransmitter metabolism-related genes like Gad1 and Gad2.Integrated multi-omics analysis further confirmed that SIRT1 defi-ciency 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 main-tains cognitive function through coordinated reprogramming of neurotransmitter metabolism and energy homeostasis,providing potential therapeutic targets for neurodegenerative disorders.