Sleep and memory: The impact of sleep deprivation on transcription, translational control, and protein synthesis in the brain

Abstract

In countries around the world, sleep deprivation represents a widespread problem affecting school-age children, teenagers, and adults. Acute sleep deprivation and more chronic sleep restriction adversely affect individual health, impairing memory and cognitive performance as well as increasing the risk and progression of numerous diseases. In mammals, the hippocampus and hippocampus-dependent memory are vulnerable to the effects of acute sleep deprivation. Sleep deprivation induces changes in molecular signaling, gene expression and may cause changes in dendritic structure in neurons. Genome wide studies have shown that acute sleep deprivation alters gene transcription, although the pool of genes affected varies between brain regions. More recently, advances in research have drawn attention to differences in gene regulation between the level of the transcriptome compared with the pool of mRNA associated with ribosomes for protein translation following sleep deprivation. Thus, in addition to transcriptional changes, sleep deprivation also affects downstream processes to alter protein translation. In this review, we focus on the multiple levels through which acute sleep deprivation impacts gene regulation, highlighting potential post-transcriptional and translational processes that may be affected by sleep deprivation. Understanding the multiple levels of gene regulation impacted by sleep deprivation is essential for future development of therapeutics that may mitigate the effects of sleep loss.

Keywords: gene expression; hippocampus; memory; ribosome; sleep deprivation; translation.

Figure 1.. Overview of the impacts of sleep deprivation on hippocampus dependent memory and examples of molecular pathways that are affected.

Figure 2.. Post-transcriptional processes impacted by sleep deprivation.

Sleep deprivation affects mRNA splicing, polyadenylation, and miRNA mediated degradation. Sleep deprivation also decreases mTOR signaling resulting in 4EBP mediated inhibition of translation.

Figure 3.. Prediction analysis of miRNAs associated with downregulation of gene expression after sleep deprivation.

Analysis of genes down regulated in the translatome, but not the transcriptome, revealed predicted 3’ UTR binding sites for two miRNAs, miR-7045–3p and miR-6971–5p.

Figure 4.. Comparative analysis of the translatome in hippocampal excitatory neurons after sleep deprivation and long-term potentiation.

a) Comparison of differentially expressed genes after 3 hours of sleep deprivation and 5 hours of sleep deprivation. b) Comparison of differentially expressed genes in the translatome after 5 hours of sleep deprivation with changes observed after LTP in the hippocampus. Genes highlighted in yellow have opposite directions of regulation between sleep deprivation and LTP.