Project Summary / Abstract Sleep disorders and obesity are inextricably linked – poor sleep quality and short sleep duration increase the risk of developing obesity, while obesity is an independent risk factor for chronic sleep disruption (CSD) and excessive daytime sleepiness (EDS). Despite a clear bidirectional and pernicious association between obesity and sleep disorders, the neural substrates mediating this association remain largely unknown. Our research program seeks to identify critical neural circuit linking metabolic alterations to CSD and EDS. Our long-term goal is to delineate the neural circuits underlying metabolic regulation of sleep-wake behavior. We have recently found that adipocyte-derived metabolic hormone, leptin, promotes wakefulness and chemogenetic activation of a subset of GABAergic neurons in the lateral hypothalamic area (LHA) expressing leptin receptor (LepR) completely disrupts sleep in mice. The overall objective of this research proposal is to clarify how leptin acts on key hypothalamic neurons to affect normal sleep-wake cycle. Build upon strong preliminary data, the central hypothesis is that circulating leptin acts on a subset of LHA LepR-expressing GABAergic neurons to affect sleep-wake behavior through their projections to the ventral tegmental area (VTA) and/or preoptic area (POA) and thereby contribute to CSD and EDS commonly associated with obesity. We will test our hypothesis by pursuing following two specific aims: 1) determine if the LHA is a key site mediating the action of leptin on sleep-wake regulation and 2) determine if leptin engages LHAVTA and/or LHAPOA circuits to regulate sleep-wake behavior. Advanced neuroscience techniques will be employed to answer these questions, including Cre/loxP technology, optogenetics/chemogenetics, in vivo fiber photometry, and electrophysiology coupled with chronic wireless recording of EEG/EMG in freely moving animals. The proposed research is significant because it is expected to not only advance and our understanding of hypothalamic regulation of sleep-wake behavior but also shed light on largely unknown mechanisms that connect metabolic disorders to sleep-wake regulation. The proposed research is also innovative because it utilizes a combination of state-of- art neuroscience techniques coupled with sophisticated physiological measurements to address an important yet largely under-investigated question – what are the underlying neural circuits mediating CSD and EDS in obesity? Such knowledge may ultimately lead to the development of a novel strategy to effectively manage sleep problems associated with obesity in human patients.