UCSF

Sleep is critical for the survival of all animals and serves many vital functions throughout the body, including brain development, cognition, immune function, and metabolic control. Indeed, sleep disorders such as insomnia can have devastating consequences on human health. Additionally, emerging evidence suggests a complex, bi-causal relationship between sleep disturbances and neuropsychiatric disorders. Despite the importance of proper sleep-wake regulation, it remains unclear how exactly the brain controls sleep-wake transitions. Historically, the focus on sleep regulation has focused exclusively on neurons, but astrocytes, the largest class of non-neuronal cells in the brain, are also positioned to play a critical role. The primary focus of this dissertation is to explore the complex role of cortical astrocytes in sleep regulation. First, we present a novel tool that allows for the accurate quantification of astrocyte calcium dynamics (Chapter 2), an essential step in studying astrocyte physiology in the context of sleep. Next, we demonstrate, for the first time, that astrocytes play a causal role in regulating distinct features of sleep through different GPCR pathways (Chapter 3). Lastly, we begin to explore the mechanistic pathways by which astrocytes regulate sleep. We explore the neuromodulator histamine as a candidate endogenous ligand for astrocytic control of sleep (Chapter 4) and we investigate astrocytic regulation of extracellular glutamate and GABA, putative functional astrocyte outputs of Gi-GPCR signaling (Chapter 5). Together, we present evidence that cortical astrocytes are a vital part of the sleep regulatory system, bringing us closer to understanding this critical behavior.