Alterations in brain energetics and related processes during spontaneous sleep-wake and prolonged wakefulness
Final Report Abstract
Sleep is one of the most pervasive biological phenomena, but one whose function remains elusive. Although many theories of function, indirect evidence, and even common sense suggest sleep is needed for an increase in brain energy levels that are depleted during prior wakefulness. Therefore the aim of the funded research was to further evaluate the metabolic pathways in the mammalian brain involved in sleep regulation and sleep function. Our results show that ATP levels are maintained at a steadystate levels during spontaneous waking but the levels exhibit a surge in the initial hours of sleep in brain regions with predominantly wake-active neuronal activity, a surge abolished by preventing sleep, whereas in “sleep-active” brain regions preventing sleep does not change ATP levels. The increase in ATP positively correlates with the intensity of non-rapid eye movement (NREM) EEG-delta activity (0.5– 4.5 Hz), a marker of homeostatic sleep pressure. This ATP–delta correlation was also confirmed by pharmacologically induced sleep using adenosine perfusion into the basal forebrain or ketamine-xylazine anesthesia that allowed us to provoke a uniform state with pure delta oscillations. Furthermore, the changes in ATP exhibit reciprocity with the phosphorylated state of the cellular energy sensor, phosphorylated AMP-activated protein kinase (P-AMPK), thus supporting the induction of anabolic processes during sleep. Our results recast the long-lasting sleep and energy restoration hypothesis. Instead of speaking of energy “restoration,” we restate the hypothesis as “sleep is for an energy surge,” a surge that permits energy-consuming anabolic processes, such as protein and fatty acid synthesis, to occur. Our findings received major attention from the scientific and nonscientific community. In a next set of experiments, we investigated the relationship between sleep, brain energy levels and food intake, since ATP and AMPK were shown to be important in the regulation of food intake and body weight. We observed that sleep deprivation resulted in a significant decrease in ATP concentrations and associated food intake in the “neuronal hunger center” lateral hypothalamus, whereas no significant change was observed in control regions. These findings indicate a strong overall correlation between ATP concentrations in the lateral hypothalamus and individual food intake suggest a sleep–wake dependent neuronal control of food intake and body weight. Finally we investigated the effects of 4weeks orally applied creatine-supplementation on brain ATP concentrations and accompanied sleep-wake behavior. Creatine supplementation results in increased wake time and reduced NREM-sleep behavior. Also, reductions in brain ATP and extracellular adenosine concentrations were observed after creatine diet, indicating that changes in cellular brain metabolism induced by a high-energy diet affect sleep-wake behavior significantly, presumably by changes in cellular nucleotide and nucleoside metabolism. Overall, the results of the described studies provide fundamental evidence for a direct relationship between sleep-wake associated changes in neuronal activity and brain energy metabolism and possible implications on food intake and body weight. We believe that our findings brought significant and critical data-based insights to bear on the long-standing conundrum about the relationship of sleep and brain energy.
Publications
- (2009) Energy restorative function of sleep: Evidence from changing levels of ATP and the activation of AMP-activated protein kinase in rat brain. Association of Professional Sleep Societies, Seattle, WA, June 7-11, 2009. Scientific Program, Page 144
Dworak M, Kim T, Nipa F, Kalinchuk AV, McCarley RW, Basheer R
- (2010) Ketamine-Xylazine induced inhibition of neuronal activity increases brain energy charge in sleep-wakerelated brain regions. SLEEP, Volume 33, Abstract Supplement, 2010
Dworak M, Kim T, McCarley RW, Basheer R
- (2010) Sleep and brain energy levels: ATP changes during sleep. J Neurosci 30: 9007-9016
Dworak M, McCarley RW, Kim T, Kalinchuk AV, Basheer R
- (2011) Replies to Commentaries on ATP Changes During Sleep. SLEEP 34(7):841-3
Dworak M, McCarley RW, Kim T, Kalinchuk AV, Basheer R
- (2011) Sleep, brain energy levels, and food intake Relationship between hypothalamic ATP concentrations, food intake, and body weight during sleep–wake and sleep deprivation in rats Somnology 15: 111-117
Dworak M, McCarley RW, Kim T, Basheer R
