CREB promotes starvation-induced sleep loss by regulating octopamine production in Drosophila.

Starvation induces robust food-seeking behavior in animals as a fundamental survival response. In Drosophila, biogenic amine octopamine (OA) plays a critical role in starvation-induced locomotor hyperactivity and awakeness, while the underlying signaling cascade remains not fully understood. Here, we demonstrated that the conserved transcription factor cAMP-Responsible Element Binding Protein (CREB), activated during starvation through the SIK2-CRTC pathway, contributes to starvation-induced sleep reduction. Mechanistically, we found that tyramine β-hydroxylase, the rate-limiting enzyme for OA synthesis, is upregulated by starvation in a CREB-dependent manner. Selective silencing of CREB in OA-producing neurons ameliorated OA-induced sleep suppression, and CREB loss-of-function mutations can partially rescue sleep fragmentation in a Drosophila model of Huntington's disease. Collectively, these findings reveal a novel regulatory role for CREB in sleep homeostasis through the transcriptional control of OA biosynthesis.