Bo Li

Sleep disturbance is a prevalent public health concern associated with cognitive deficits and emotional dysregulation, yet the mechanisms underlying SD-induced hypothalamic dysfunction remain incompletely understood. Here, we found that two weeks of SD induced marked hypothalamic neuroinflammation, accompanied by increased expression of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, as well as the chemokine Ccl2, together with reduced neuronal markers, including decreased Nissl-body and NeuN⁺ cells. Single-nucleus RNA sequencing (snRNA-seq) suggested that inhibitory neurons exhibited prominent transcriptional responses to SD, including enrichment of inflammatory pathways such as TNF and IL-17 signaling and transcriptional programs associated with neuronal dysfunction. Furthermore, SD was also associated with microglial activation and a phenotypic shift toward a disease-associated state, exhibiting enhanced antigen-presenting and pro-inflammatory capacity. Notably, intercellular communication analysis identified the neural cell adhesion molecule 1 (NCAM1)/fibroblast growth factor receptor 1 (FGFR1) signaling axis as a key mediator of crosstalk between microglia and other cell types. In BV2 cells, recombinant NCAM1 attenuated lipopolysaccharide-induced inflammatory responses in an Fgfr1-dependent manner. Consistently, PVN-targeted Fgfr1 knockdown in vivo exacerbated SD-associated microglial activation, neuroinflammation, and neuronal injury. Collectively, our findings elucidate a critical protective role for the NCAM1/FGFR1 axis in mitigating SD-induced hypothalamic neuroinflammation and neuronal injury. This highlights this pathway as a candidate mechanism for further therapeutic investigation in sleep-related neurological dysfunction.

Age-related decline in learning and memory functions poses significant challenges in an aging society, with epigenetic dysregulation emerging as a key contributor to cognitive deterioration. As the most prevalent internal RNA modification, N6-methyladenosine (m6A) dynamically orchestrates neural transcriptome plasticity through its “writers,” “erasers,” and “readers,” yet its role in aging-associated cognitive impairment remains underexplored. This study employs an integrated epitranscriptomic approach to investigate m6A-mediated regulation in hippocampal aging processes. Through comparative m6A-mRNA epitranscriptomic microarray analysis of senescence-accelerated mouse prone 8 (SAMP8) and senescence-resistant SAMR1 hippocampi, we identified neural cell adhesion molecule 1 (NCAM1) as a key m6A-regulated effector whose decreased expression correlates with accelerated cognitive deterioration. Mechanistically, we revealed that Methyltransferase-like 3 (METTL3)-mediated m6A modification governs Ncam1 mRNA stability through insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) reader protein-dependent mechanisms, forming a regulatory axis that modulates cyclic AMP response element-binding protein (CREB) signaling pathway activity. Remarkably, targeting of this METTL3/IGF2BP1/NCAM1 axis significantly attenuated cognitive deficits in aged SAMP8 mice. Our findings establish an m6A methylation-dependent paradigm for NCAM1-mediated cognitive preservation during aging, uncovering a novel epitranscriptomic layer in age-related neurodegeneration.