Long non-coding RNA Cerox1 targets components of the mitochondrial electron transport chain to regulate the memory impairment caused by sleep deprivation

AbstractSleep deprivation (SD) impairs long-term memory, but the molecular mechanisms underlying the impact of sleep loss on memory are poorly understood. Molecular changes driven by SD have thus far focused on transcription and translation. Long non-coding RNAs (lncRNAs), a class of regulatory RNAs, have recently been recognized as an important player in memory research. However, it remains unclear how sleep deprivation modulates the expression of lncRNAs or their targets to lead to memory impairment. In this study, we explored the role of lncRNAs in the disruption of spatial memory caused by SD. We examined a set of synapse-associated lncRNAs that were identified through a transcriptome analysis after SD. Among them, we discovered that the lncRNA Cerox1 is downregulated in dorsal hippocampus following SD, and its levels recover after 2.5 hours of rebound sleep. Sleep is critical for the regulation of metabolism and sleep loss impairs mitochondrial function. Both sleep deprivation and Cerox1 knockdown were found to reduce complex I activity of the mitochondrial electron transport chain. This reduction of complex I activity is linked to the decrease in expression of a subset of complex I subunits including Ndufs1, Ndufs3, Ndufa3 and Ndufs6. Overexpression of Cerox1 has the opposite effect, leading to increased complex I activity. Sleep deprivation reduced ATP levels in the dorsal hippocampus, while Cerox1 overexpression restored it. SD disrupted memory consolidation, and this impairment was rescued when Cerox1 was overexpressed. Cerox1 transcript contains multiple miRNA binding sites that regulate the activity of the lncRNA. Notably, overexpression of Cerox1 transcript lacking miRNA binding sites did not rescue the memory deficit caused by SD. Our findings demonstrated that the impairment of memory consolidation after SD is linked to lncRNA-mediated control of mitochondrial electron transport chain activity essential for sustaining energy requirements. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/676326v1_ufig1.gif" ALT="Figure 1000"> View larger version (48K): org.highwire.dtl.DTLVardef@6d72d5org.highwire.dtl.DTLVardef@18e3590org.highwire.dtl.DTLVardef@15e83c9org.highwire.dtl.DTLVardef@1e1f92_HPS_FORMAT_FIGEXP M_FIG C_FIG