350. Transcriptomic analysis of mouse brain tissue demonstrates similarity between sleep deprivation and neuronal hyperexcitation-induced gene expression

Abstract

Abstract Background Sleep deprivation is associated with numerous health problems and has been linked to neuronal hyperexcitation, a potential driver of its neurological harm. Aims & Objectives This study aimed to elucidate the transcriptomic relationship between sleep deprivation and neuronal hyperexcitation. Method To achieve this aim, publicly available gene expression data from acutely sleep-deprived mice and neuronal hyperexcitation model mice were compared using the running Fisher algorithm in the bioinformatics platform BaseSpace. In total 21 bulk-RNA datasets (hippocampus, hypothalamus and cerebellum), 11 scRNA-seq sleep deprivation datasets (hypothalamus and cortex) containing cell population data from neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells, and 23 bulk-RNA hippocampal hyperexcitation datasets (models: optogenetics, bicuculline, KCl depolarization, kainite and pilocarpine) were analyzed. The data spanned diverse conditions of sex, age and sampling time. Results The comparative transcriptomic analysis yielded several key findings. The data revealed a significant positive transcriptomic correlation between sleep deprivation and neuronal hyperexcitation models. Neuronal hyperexcitation datasets whose samples were collected within 1-12 hours post seizure induction showed higher correlation with sleep deprivation. Analysis of a bulk-RNA sleep deprivation dataset revealed gene functional groups shared between the two conditions were associated with plasticity, immune response, and inflammation pathways. Among the most commonly overexpressed genes shared by the two conditions were immediate early genes such as Jun, Egr1/2/4, Fos, Bdnf, Arc and Homer1 and injury-associated genes such as Ptgs2 and Ctgf. The scRNA datasets revealed that microglia, neurons, and endothelial cells from sleep-deprived mice are the cell types most closely connected with hyperexcitation. Microglia hyperexcitation-associated genes included stress- and immune-response related genes such as Junb/d, Cebpb and Cd14. Neurons highly expressed immediate early genes such as Jun/d, Fos, H3f3b, Tubb3 and Prkar1b. Endothelial cells showed high expression of metabolism-related genes such as Plat, Ucp2 and Dbp. Discussion & Conclusions The molecular findings provide insight into the potential mechanisms underlying the link between sleep deprivation and neuronal hyperexcitation. Specificially, the higher correlation observed in datasets collected 1-12 hours post seizure induction aligns with the expression patterns of immediate early genes in neuronal hyperexcitation models. Furthermore, the overexpression of injury-related genes such as Ptgs2 and Ctgf suggests potentially toxic levels of excitation. Increased microglial activation, neuronal immediate early gene expression, and upregulation of metabolism related genes are all consistent with hyperexcitation-related molecular changes. These mechanisms may be capable of causing long-term changes in brain activity through microglial mediated-inhibitory synapse pruning, neuronal long-term potentiation facilitated by plasticity-associated immediate early gene overexpression and increased brain angiogenesis linked to Dbp overexpression. Together these findings suggest sustained sleep deprivation could result in long-term increases in brain excitation, potentially exacerbating excitatory/inhibitory imbalances and contributing to the development of neuropsychiatric disorders.