Project Summary Evolutionary medicine leverages the power of naturally occurring phenotypic differences derived through adaptation to investigate genetic mechanisms underlying diseases, including neurological disorders. The Mexican cavefish exhibits a dramatic evolution of sleep loss compared to ancestral surface fish of the same species, providing a unique and powerful model to identify genetic factors regulating sleep. The proposed experiments will implement genetic technology in Mexican cavefish to identify novel regulators of naturally occurring insomnia-like phenotypes in cavefish. This proposal will also apply a newly developed neuroanatomical brain atlas and whole-brain calcium imaging to determine how novel sleep genes impact brain structure and function. These experiments will provide critical insight into the mechanistic basis of sleep regulation and identify naturally occurring genetic variants that contribute to sleep regulation. Further, the genetic tools and methodology established in these studies will provide valuable resources that can be applied to address questions beyond the scope in this proposal, including diseases such as eye-degeneration, obesity, hyperphagia and aggression that are commonly studied in this system.