Colloquium Keynote:

The Hypothalamic Hypocretin/Orexin System as a Target for Treatment of Sleep Disorders and Addiction

Dr. Thomas Kilduff, PhD

Director, Center for Neuroscience, SRI International

ABSTRACT: The neuropeptidergic hypocretin/orexin (Hcrt) system, identified independently by two groups in 1998, has since been established as a central regulator of energy balance, sleep-wake states, and arousal stability. Hcrt-producing neurons in the lateral hypothalamus have been shown to integrate circadian, metabolic, and environmental signals to promote wakefulness and suppress REM sleep, thereby playing a critical role in the regulation of sleep-wake cycles. Hcrt signaling also is involved in hedonic/motivational functions and goal-directed behaviors, as these neurons heavily innervate the limbic system. Accordingly, disruption of this system has been implicated in sleep disorders including Narcolepsy Type 1 (NT1), insomnia, and hypersomnia, as well as substance use disorders. Growing evidence also suggests a role for the Hcrt system in neurodegenerative diseases, neurodevelopmental disorders, and psychiatric conditions. Advances in neuroimaging, electrophysiology, genetics, and pharmacology - particularly the development of orexin receptor agonists and antagonists - have furthered understanding how the Hcrt system interacts with sleep architecture, motivational drive and reward-related processes, and the interplay between sleep and substance use disorders. The discovery that NT1 was due to loss of Hcrt neurons was crucial in understanding not only the neuropathology underlying this disorder but also provided a critical clue regarding the role of this system in the maintenance of wakefulness. In this presentation, I will discuss the physiological consequences of partial vs. complete degeneration of the Hcrt neurons and the relevance for the more prevalent Narcolepsy Type 2 (NT2) and other disorders of hypersomnolence.

BIO: Thomas Kilduff, PhD, is an expert in the neurobiology of sleep and wakefulness, sleep disorders, and the biological clock. Kilduff was co-first author on the paper that originally described hypocretin/orexin (Hcrt), a neuropeptide system that stimulates arousal and is involved in wakefulness regulation. Dysfunction of the Hcrt system results in narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and a sudden loss of muscle tone known as cataplexy. In addition to basic research on sleep, his group conducts in vitro and in vivo pharmacology studies related to the development of new medications for the treatment of sleep disorders. Government agencies, private foundations, and pharmaceutical companies have supported this research. Kilduff has authored or co-authored more than 200 published abstracts, scientific articles, and book chapters. Kilduff was previously a senior research scientist at Stanford University’s Center for Sleep and Circadian Neurobiology. He has been elected to the board of directors of the Sleep Research Society (SRS) and served as secretary/treasurer for both the SRS and SRS Foundation. He received his Ph.D. in biological sciences from Stanford University. In 2010, Kilduff was named a Fellow of the American Association for the Advancement of Science (AAAS). Kilduff was named an SRI Fellow in 2010 and a Distinguished Scientist by the SRS in 2017. View Dr. Kilduff’s publications via PubMed or Google Scholar.