Zinc acts as an evolutionarily conserved sleep driver

Abstract

Sleep is essential physiology conserved across diverse species, yet how sleep mechanisms have evolved during evolution remains elusive. Here we employ a phylogenetic approach to elucidate the conserved role of zinc homeostasis in sleep regulation. Transcriptome analyses in the cnidarian Hydra vulgaris revealed differential expression of zinc transporter genes following pharmacological sleep manipulations. Subsequent behavioral assessments using transgenic Drosophila models demonstrated that depletion of specific zinc transporters in neurons (Zip48C and ZnT33D) or glia (Zip42C.2, Catsup, and ZnT86D) promoted sleep. Dietary zinc supplementation similarly induced sleep in both Hydra and Drosophila, validating the relevance of zinc homeostasis to sleep regulation. Notably, Drosophila mutants of the dopamine transporter, among other mutants of distinct sleep-regulatory pathways, displayed resistance to the zinc-feeding effects. Moreover, zinc-induced sleep drive required dopamine receptor Dop1R1 but not Dop2R, implicating a dedicated dopaminergic pathway. We propose that zinc-dependent sleep likely originated from ancestral species. Additionally, our findings provide a mechanistic basis for dietary zinc supplements to increase human sleep quality.