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Neurobiology of Sleep and Wakefulness
SRI takes an integrated approach to understand the systems that control sleep and wakefulness.
A central goal in neuroscience is to understand the neural circuits that underlie behavior, how these circuits are altered across arousal states, and how they go awry in pathological conditions. Researchers at SRI’s Center for Neuroscience use an integrated approach that includes behavioral, pharmacological, electrophysiological and neuroanatomical assessments to understand the systems that control sleep and wakefulness.
The Center is engaged in two related projects for the National Institutes of Health. They are briefly described below.
Functional Connectivity of the Hypocretin/Orexin System
The hypocretin/orexin (Hcrt) system is a neuropeptide system involved in behavioral arousal, metabolism, addiction, stress-induced analgesia (SIA), and neuroendocrine function. Hcrt deficiency results in the sleep disorder narcolepsy. Given the functional significance of the Hcrt system, identification of the inputs that control it and its pathways are of clinical relevance.
SRI researchers are striving to further understand the Hcrt system. Using state-of-the-art techniques called optogenetics to activate or inhibit Hcrt neurons with light, they aim to uncover how Hcrt cells interact with the daily time-keeping system and sleep homeostatic mechanisms. As part of this work, novel models of Hcrt hypofunction and conditional Hcrt ablation will be developed that may be useful to understand the metabolic pathologies associated with narcolepsy and other sleep disorders.
The project described was supported by Award Number 1R01NS077408-01A1 from the National Institute of Neurological Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.
TAAR1 and the Control of Wakefulness
Trace amines—amino acid metabolites previously considered to be ‘false neurotransmitters’—have been shown to act as ligands (binding molecules) produced in the human body for TAAR1, a receptor that modulates brain activity with the neurotransmitters dopamine, serotonin, and glutamate. In papers published in Molecular Psychiatry and Biological Psychiatry with scientists from F. Hoffmann-LaRoche, SRI researchers describe novel, brain-penetrable TAAR1 agonists with pro-cognitive, antidepressant- and antipsychotic-like properties, suggesting TAAR1 as a novel target for the treatment of neuropathological disorders.
SRI researchers have also shown that TAAR1 partial agonism increases wakefulness and decreases NREM and REM sleep, suggesting this novel receptor may activate an endogenous wake-promoting system. By testing these new TAAR1 compounds in systems with targeted disruptions of known wake-promoting neurotransmitters, SRI researchers hope to uncover which pathways are relevant to TAAR1 mediated arousal. Other work will determine if TAAR1 signaling plays a role in the wake-promoting effects of caffeine and therapeutics for sleepiness such as modafinil (Provigil®).
These studies are expected to advance our understanding of the interaction of TAAR1 with wakefulness-promoting systems in the brain and will likely impact the development of drug therapies directed toward this novel target for the treatment of sleep/wake and other neural disorders.
The project described was supported by Award Number 1R01NS082876-01 from the National Institute of Neurological Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.