Changes in components of energy regulation in mouse cortex with increases in wakefulness

Abstract

Study Objectives: Increases in ATP production machinery have been described in brain after 3 h of sleep deprivation. Whether this is sustained with longer durations of extended wakefulness is unknown. We hypothesized that energy depletion could be a mechanism leading to difficulty maintaining wakefulness and assessed changes in components of the electron transport chain. Design: Protein levels of key subunits of complexes IV and V of the electron transport chain (COXI, COXIV, ATP5B) and uncoupling protein 2 (UCP2) in isolated mitochondria by Westerns in mouse cerebral cortex after 3 and 12 h of sleep deprivation were compared to that in control mice. Activity of complex IV enzyme and relevant transcription factors - Nrf1, Nrf2 (Gabp), and phosphorylation of AMP-dependent kinase (AMPK) - were also assessed. Participants: 8-10 week old C57BL/6J male mice (n = 91). Interventions: 3, 6, and 12 h of sleep deprivation. Measurements and Results: After both 3 and 12 h of sleep deprivation, complex IV proteins and enzyme activity were significantly increased. The complex V catalytic subunit was significantly increased after 12 h of sleep deprivation only. Increased levels of UCP2 protein after 12 h of sleep deprivation suggests that there might be alterations in the ATP/AMP ratio as wakefulness is extended. That phosphorylation of AMPK is increased after 6 h of sleep deprivation supports this assertion. The increase in Nrf1 and Nrf2 (Gabp) mRNA after 6 h of sleep deprivation provides a mechanism by which there is up-regulation of key proteins. Conclusions: There are complex dynamic changes in brain energy regulation with extended wakefulness.