DNA After Dark: Sleep Homeostasis Governs Learning-Evoked Double-Stranded DNA Breaks and Retrotransposon Regulation

Sleep facilitates DNA double-strand break (DSB) repair, yet the role of retrotransposon activity in sleep-dependent genomic stabilization remains unclear. We hypothesize that sleep deprivation (SD) exacerbates LINE-1 (L1)-mediated DSBs in hippocampal subregions, impairing memory consolidation. Prior work shows learning-evoked DSBs arise from neuronal activity during memory encoding, not passive wakefulness or exercise, and L1 inhibition via lamivudine disrupts fear memory reconsolidation.1,2 This study will investigate whether SD amplifies L1-driven DSBs. C57BL/6J mice (n=16) will undergo a hippocampal-dependent novel object recognition task followed by SD or undisturbed sleep. DSB intensity is quantified via γ-H2AX immunohistochemistry in CA1, CA3, and dentate gyrus, with L1 activation assessed through ORF1p nuclear localization. Memory retention will be evaluated 24h post-task. Results will clarify whether SD disrupts L1 containment, amplifying DSBs and impairing synaptic plasticity. By integrating neuronal activity-induced genomic instability with retrotransposon biology, this work will advance mechanistic understanding of sleep’s role in neuroprotection. Findings may identify L1 suppression as a therapeutic target for neurodegenerative disorders tied to sleep fragmentation, such as Alzheimer’s disease, where retrotransposon dysregulation and DSB accumulation are hallmark pathologies.