Project Summary Sleep and metabolic disorders are often comorbid, but how they interact is poorly understood. The salt inducible kinase SIK3 was identified (first in C. elegans and 8 years later in flies and mice) as a sleep drive regulator. Our findings suggest that SIKs connect sleep and metabolic regulation. In the prior funding cycle, we demonstrated hierarchical somatic/neural interactions regulating both sleep and energy homeostasis. We have shown that the sleep and energy-regulating roles of KIN-29/SIK occur by inhibiting the class 2 histone deacetylase HDA-4 (HDAC4) in 12 pairs of glutamatergic neurons. Illuminating the mechanism by which KIN- 29 signals in glutamatergic neurons during high sleep drive will be the goal of aim 1. We will study the role of CREB and CREB-regulated transcription coactivator 1 (CRTC1) in glutamatergic neurons. In aim 2, we will test the hypothesis that reactive oxygen species promote sleep. In aim 3 we will test the hypothesis that NAD+ precursors promote sleep and are reduced in kin-29 mutants. Finally, in aim 4, we will identify genes whose expression is regulated by the KIN-29--|HDA-4 signaling module. Such genes will be candidates for mediating sleep-promoting signaling by glutamatergic neurons. At the completion of these aims, we will have an improved understanding of the genetic and metabolic regulation of sleep. Data collected in aim 4 will motivate additional genetic hypotheses that will be tested in future research.