No Escaping the Rat Race: Simulated Night Shift Work Alters the Time-of-Day Variation in BMAL1 Translational Activity in the Prefrontal Cortex

Abstract

Millions of people worldwide work during the night, resulting in disturbed circadian rhythms and sleep loss. This may cause deficits in cognitive functions, impaired alertness and increased risk of errors and accidents. Disturbed circadian rhythmicity resulting from night shift work could impair brain function and cognition through disrupted synthesis of proteins involved in synaptic plasticity and neuronal function. Recently, the circadian transcription factor brain-and-muscle arnt-like protein 1 (BMAL1) has been identified as a promoter of mRNA translation initiation, the most highly regulated step in protein synthesis, through binding to the mRNA “cap”. In this study we investigated the effects of simulated shift work on protein synthesis markers. Male rats (n = 40) were exposed to forced activity, either in their rest phase (simulated night shift work) or in their active phase (simulated day shift work) for 3 days. Following the third work shift, experimental animals and time-matched undisturbed controls were euthanized (rest work at ZT12; active work at ZT0). Tissue lysates from two brain regions (prefrontal cortex, PFC and hippocampus) implicated in cognition and sleep loss, were analyzed with m7GTP (cap) pull-down to examine time-of-day variation and effects of simulated shift work on cap-bound protein translation. The results show time-of-day variation of protein synthesis markers in PFC, with increased protein synthesis at ZT12. In the hippocampus there was little difference between ZT0 and ZT12. Active phase work did not induce statistically significant changes in protein synthesis markers at ZT0 compared to time-matched undisturbed controls. Rest work, however, resulted in distinct brain-region specific changes of protein synthesis markers compared to time-matched controls at ZT12. While no changes were observed in the hippocampus, phosphorylation of cap-bound BMAL1 and its regulator S6 kinase beta-1 (S6K1) was significantly reduced in the PFC, together with significant reduction in the synaptic plasticity associated protein activity-regulatedcytoskeleton-associated protein (Arc). Our results indicate considerable time-of-day and brain-region specific variation in cap-dependent translation initiation. We concludethat simulated night shift work in rats disrupts the pathways regulating the circadian component of the translation of mRNA in the PFC, and that this may partly explain impaired waking function during night shift work.

Cognitive function and brain plasticity in a rat model of shift work: role of daily rhythms, sleep and glucocorticoids

“…Taken together, these results replicate our previous findings that simulated night shift work impairs regulation of cap-dependent initiation of translation as well as expression of the synaptic plasticity regulator Arc 11 .…”

“…The present study strengthens this notion. We replicate previous findings from our lab showing that the regulation of capbound translational regulators (eIF4E and BMAL1) is impaired in the prefrontal cortex following rest work, as compared to undisturbed time-matched controls 11 . We show that expression of the translational regulators p-BMAL1 and p-eIF4E within the PFC are predicted by changes in daily rhythmicity during simulated shift work.…”

“…Very few studies examine the interaction between circadian rhythms and sleep on cognitive performance, although some biochemical pathways implicated in memory performance and consolidation have been shown to be altered by both sleep and circadian rhythms. These for example include the cAMP/MAPK/ CREB transcriptional pathway 38 , but more recently also the cap-dependent translation initiation pathway 11,16,39,40 . www.nature.com/scientificreports/ Daily rhythm, sleep drive and serum corticosterone predict markers of cortical regulation of translation after simulated shift work.…”

“…www.nature.com/scientificreports/ Daily rhythm, sleep drive and serum corticosterone predict markers of cortical regulation of translation after simulated shift work. We have previously suggested that impairments to eIF4F complex assembly after rest work may in part underlie the cognitive deficits observed on the night shift 11 . The present study strengthens this notion.…”

Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology

“…Reduced amplitude of ion rhythms, or their temporal misalignment with sympathetic stimulation, will attenuate cardiomyocytes' intrinsic capacity to facilitate increased heart rate at this time. We propose that dysregulation of cardiac ion or protein rhythms, during shift work or aging, renders the heart less competent to satisfy increased output demand in the early morning, contributing to the increased frequency of adverse events at this time [58][59][60][61][62][63] .…”