IL-1β/IL-1R1 signaling mediates sleep deprivation-induced memory consolidation impairment and is a target for cognitive enhancement in male mice.

Sleep plays a critical role in memory consolidation; however, the precise molecular mechanisms linking sleep loss to cognitive impairment remain unclear. In this study, we show that even brief (4 h) sleep deprivation, when applied during the post-training consolidation window, selectively disrupts hippocampal-dependent memory in adult male mice, as evidenced by impairments in both novel object recognition and contextual fear conditioning. Proteomic profiling of hippocampal synaptosomes revealed a specific upregulation of interleukin-1 receptor type 1 (IL-1R1) following sleep deprivation. This was accompanied by a selective increase in the levels of its endogenous ligand IL-1β-but not IL-1α-in the hippocampus and serum. Direct intrahippocampal administration of IL-1β recapitulated the memory deficits observed after sleep deprivation, whereas conditional deletion of IL-1R1 in hippocampal excitatory neurons completely prevented these impairments. Strikingly, systemic treatment with an anti-IL-1β neutralizing antibody not only rescued sleep deprivation-induced memory dysfunction but also enhanced memory consolidation in non-sleep-deprived control animals, revealing a tonic inhibitory function of endogenous IL-1β in memory processes. Our results identify IL-1β/IL-1R1 signaling as a pivotal mediator of sleep deprivation-induced memory impairment and highlight this pathway as a promising therapeutic target for enhancing cognitive resilience under conditions of inadequate sleep.