Project Summary/Abstract Sex differences in daily sleep amount, sleep fragmentation, and basal slow wave activity (SWA) are largely driven by gonadal hormones. However, sex differences in the mid-active phase sleep amount and the ability to recover from sleep loss are largely insensitive to gonadal hormones, and are regulated in part by sex chromosomes. Preliminary data in this application show that a key determinant of sex differences in active phase sleep amount is the presence or absence of the Sry gene of the Y chromosome, which encodes the testis-determining factor. This study will use two mouse lines with altered sex chromosomes to elucidate the origin of sex differences in sleep and in order to determine the respective roles of Sry gene and chromosome complement on sleep regulatory mechanisms. The first specific aim will test the hypothesis that Sry gene establishes sex differences in sleep homeostasis during development by observing sleep-wake patterns in the EMG of neonatal, prepubertal mice, and EEG/EMG of adult mice with altered sex chromosomes and hormones. The second specific aim will test the hypothesis that X chromosome dosage drives sex differences in the ability to recover from sleep loss. During each of these studies, active-phase sleep amount in mice will be used as a biomarker for sleep homeostasis. These experiments are important and required to understand the role of the sleep homeostat in regulating sleep and how it is established. They are the first comprehensive analysis of sex differences in a juvenile mammalian species and the first to examine the specific effects of either X or Y chromosome dosage on sleep. The overarching goal of these experiments is to identify the specific mechanisms through which sex chromosomes and sex-linked genes are able to regulate sleep. These studies will uncover the origins of sex differences in the homeostatic ability to recover from sleep loss. These findings will likely lead to improved therapies for sleep disorders that exhibit sex differences in incidence and severity, particularly those more prevalent in women.