Epidermal Growth Factor Signaling Promotes Sleep through a Combined Series and Parallel Neural Circuit.

Sleep requires sleep-active neurons that depolarize to inhibit wake circuits. Sleep-active neurons are under the control of homeostatic mechanisms that determine sleep need. However, little is known about the molecular and circuit mechanisms that translate sleep need into the depolarization of sleep-active neurons. During many stages and conditions in C. elegans, sleep requires a sleep-active neuron called RIS. Here, we defined the transcriptome of RIS and discovered that genes of the epidermal growth factor receptor (EGFR) signaling pathway are expressed in RIS. Because of cellular stress, EGFR directly activates RIS. Activation of EGFR signaling in the ALA neuron has previously been suggested to promote sleep independently of RIS. Unexpectedly, we found that ALA activation promotes RIS depolarization. Our results suggest that ALA is a drowsiness neuron with two separable functions: (1) it inhibits specific behaviors, such as feeding, independently of RIS, (2) and it activates RIS. Whereas ALA plays a strong role in surviving cellular stress, surprisingly, RIS does not. In summary, EGFR signaling can depolarize RIS by an indirect mechanism through activation of the ALA neuron that acts upstream of the sleep-active RIS neuron and through a direct mechanism using EGFR signaling in RIS. ALA-dependent drowsiness, rather than RIS-dependent sleep bouts, appears to be important for increasing survival after cellular stress, suggesting that different types of behavioral inhibition play different roles in restoring health. VIDEO ABSTRACT.

Hepatic Ketogenesis Induced by Middle Cerebral Artery Occlusion in Mice.

BACKGROUND: Ketone bodies are known to substitute for glucose as brain fuel when glucose availability is low. Ketogenic diets have been described as neuroprotective. Similar data have been reported for triheptanoin, a fatty oil and anaplerotic compound. In this study, we monitored the changes of energy metabolites in liver, blood, and brain after transient brain ischemia to test for ketone body formation induced by experimental stroke. METHODS AND RESULTS: Mice were fed a standard carbohydrate-rich diet or 2 fat-rich diets, 1 enriched in triheptanoin and 1 in soybean oil. Stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by reperfusion. Mice were sacrificed, and blood plasma and liver and brain homogenates were obtained. In 1 experiment, microdialysis was performed. Metabolites (eg glucose, ß-hydroxybutyrate, citrate, succinate) were determined by gas chromatography-mass spectrometry. After 90 minutes of brain ischemia, ß-hydroxybutyrate levels were dramatically increased in liver, blood, and brain microdialysate and brain homogenate, but only in mice fed fat-rich diets. Glucose levels were changed in the opposite manner in blood and brain. Reperfusion decreased ß-hydroxybutyrate and increased glucose within 60 minutes. Stroke-induced ketogenesis was blocked by propranolol, a ß-receptor antagonist. Citrate and succinate were moderately increased by fat-rich diets and unchanged after stroke. CONCLUSIONS: We conclude that brain ischemia induces the formation of ß-hydroxybutyrate (ketogenesis) in the liver and the consumption of ß-hydroxybutyrate in the brain. This effect seems to be mediated by ß-adrenergic receptors.