| An estimated 50-70 million people in the United States have a sleep disorder. In addition, countless others in modern society receive insufficient or inadequate sleep, resulting in incalculable health, cognitive, and economic costs. Chronic sleep loss is associated with an increased prevalence for nearly every major chronic disease, including obesity, diabetes, hypertension, and heart attacks. Despite this, much is unknown about the mechanisms regulating sleep and wakefulness. Even less is known about the processes that drive sleep following prolonged wakefulness, limiting treatment options and targets for the health and cognitive impacts of sleep deprivation. The neuropeptide Cortistatin is a sleep-promoting peptide expressed in inhibitory interneurons of the neocortex, and may play a unique and integral role in regulating sleep drive following extended wakefulness. Infusion of the Cortistatin peptide drives animals to sleep and augments the low frequency cortical activity associated with slow wave sleep. Importantly, deletion of the receptor for the brain-derived neurotrophic factor (BDNF), an important growth factor in sleep regulation and neuronal plasticity, specifically in Cortistatin- expressing interneurons but not in other cortical interneuron subtypes, results in severe hyperexcitability, seizures, and premature death. Cortistatin, therefore, may be in an integral signaling molecule at the nexus of sleep regulation, memory consolidation, and synaptic plasticity. This proposal aims to use the latest genetic tools and experimental techniques, including in vivo fiber photometry, optogenetics, chemogenetics, and newly developed optical constructs to investigate the hypothesis that the neuropeptide Cortistatin is a critical regulator of sleep and cognitive function. Findings from this proposal may lead to fundamental insight into the mechanisms driving sleep, as well as provide a potential novel therapeutic target for sleep disorders and cognitive impairment resulting from insufficient sleep.
| Sleep problems and sleep deprivation are extremely common in modern society. The cellular mechanisms mediating sleep/wake regulation, as well as those that drive sleep following prolonged wakefulness are not well known, limiting treatment options and therapeutic potential. The cortically-restricted neuropeptide, Cortistatin, is active during wakefulness, yet its activation subsequently drives sleep, suggesting that Cortistatin may play an integral role in the homeostatic regulation of sleep.
