Extended Wakefulness: Compromised Metabolics in and Degeneration of Locus Ceruleus Neurons

Abstract

Modern society enables a shortening of sleep times, yet long-term consequences of extended wakefulness on the brain are largely unknown. Essential for optimal alertness, locus ceruleus neurons (LCns) are metabolically active neurons that fire at increased rates across sustained wakefulness. We hypothesized that wakefulness is a metabolic stressor to LCns and that, with extended wakefulness, adaptive mitochondrial metabolic responses fail and injury ensues. The nicotinamide adenine dinucleotide-dependent deacetylase sirtuin type 3 (SirT3) coordinates mitochondrial energy production and redox homeostasis. We find that brief wakefulness upregulates SirT3 and antioxidants in LCns, protecting metabolic homeostasis. Strikingly, mice lacking SirT3 lose the adaptive antioxidant response and incur oxidative injury in LCns across brief wakefulness. When wakefulness is extended for longer durations in wild-type mice, SirT3 protein declines in LCns, while oxidative stress and acetylation of mitochondrial proteins, including electron transport chain complex I proteins, increase. In parallel with metabolic dyshomeostasis, apoptosis is activated and LCns are lost. This work identifies mitochondrial stress in LCns upon wakefulness, highlights an essential role for SirT3 activation in maintaining metabolic homeostasis in LCns across wakefulness, and demonstrates that extended wakefulness results in reduced SirT3 activity and, ultimately, degeneration of LCns.

Associations of brain lesions at autopsy with polysomnography features before death

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Self-reported sleep duration and cognitive performance in older adults: a systematic review and meta-analysis

“…A recent animal study showed that sleep deprivation can result in neuronal loss in the locus coeruleus [76], which may lead to negative cognitive consequences. This is a candidate mechanism explaining how self-reported short sleep might lead to poorer cognitive function in older adults.…”

Problematic internet use and academic achievement among teacher-trainees in Israeli colleges

“…Sleep deprivation itself has been shown to be negatively correlated with memory function, as well as, in the context of international testing of academic achievement (Diekelmann & Born, 2010;Mullis et al, 2012). The social and cultural changes incurred by technology-associated chrono-disruption should not be overlooked (Ekirch, 2001;Kantermann 2013) and should be an increasing concern with the contribution of technology, and the educational use of technology on disruption of optimal sleep patterns (West et al, 2011) and the effects of this on brain function (Yuan et al, 2011;Yang et al, 2014;Zhang et al, 2014), which undoubtedly impact on academic achievement.…”