Targeting NCAM1/FGFR1 signaling to alleviate sleep disturbance-induced neuroinflammation in the hypothalamus

We demonstrated that two-week SD induced significant neuroinflammation in the hypothalamus, characterized by elevated expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, as well as the chemokine Ccl2, alongside progressive neuronal loss, as evidenced by reduced nissl bodies and NeuN+ cells.

Single-nucleus RNA sequencing revealed that inhibitory neurons were the most responsive hypothalamic cell cluster to SD, exhibiting enriched pro-inflammatory pathways (e.g., TNF and IL-17 signaling) and neurodegenerative transcriptional programs. Furthermore, SD triggered microglial activation and a phenotypic shift toward a disease-associated state, with 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.