Targeting NCAM1/FGFR1 Signaling to Alleviate Sleep Disturbance-Induced Neuroinflammation in the Hypothalamus

Abstract

Highlights What are the main findings? Sleep disturbance (SD) induces neuroinflammation and neuronal injury in the hypothalamus, triggering microglial activation and facilitating a pro-inflammatory phenotypic transformation. SD selectively enhances pro-inflammatory responses and functional impairment in multiple hypothalamic inhibitory neuron subpopulations. What are the implications of the main findings? NCAM1/FGFR1 signaling curbs microglial neuroinflammation triggered by SD, suggesting this signaling axis as an endogenous protective mechanism against SD-induced hypothalamic injury. Targeting the NCAM1/FGFR1 signaling pathway may represent a potential therapeutic strategy for alleviating neuroinflammation and neuronal dysfunction associated with sleep disorders. Abstract 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.