Intersections of Sleep and Coma: Neural Pathways of Alpha-2 Adrenergic Hypnosis

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Disorders of sleep or arousal will affect up to a third of all Americans at some point in their lives, with upwards of 50 million of those experiencing chronic issues. To understand and treat these disorders, we must first understand the neural circuits and networks responsible for arousal and sleep. We propose to study the hypnotic action of α2 adrenergic agonists, which activate endogenous sleep-active circuits and produce a hypnosis that appears similar to slow-wave sleep. Our data corroborates earlier behavioral studies showing the neuronal population(s) producing α2 agonist hypnosis lies in the rostral pons in a region that includes the locus coeruleus. However, adrenergic neurons of the locus coeruleus alone do not appear to be sufficient. The proposed investigation will determine the role of adrenergic and rostral pontine neurons in hypnotic actions of α2 adrenergic agonists through addressing these questions: Can discrete and localized actions of α2 agonists targeting the rostral pons produce and maintain hypnosis? Previously published together with our preliminary data support the idea that local delivery of α2 agonists to pons including the locus coeruleus is sufficient for hypnosis. We will use novel α2 adrenergic agonist photolabels to locally modulate neuronal activity and rigorously test this hypothesis. Are adrenergic neurons of the locus coeruleus necessary for α2-mediated hypnosis? We will perform adrenergic-specific knockouts of α2A adrenergic receptors in the rostral pons, looking for resistance to α2 adrenergic agonist hypnosis. We will also optogenetically drive adrenergic neurons of the rostral pons to determine if their activity can reverse α2 mediated hypnosis. Is the neuronal firing pattern in the rostral pons around the LC under α2-agonist hypnosis primarily dependent on local or systemic effects? Can changing adrenergic neuron activity reverse α2-agonist hypnosis? We will record unit-activity in the rostral pons with α2 agonist administration in wild-type and adrenergic α2A receptor knockout mice. Using optogenetics and α2 photolabels, we will mechanistically dissect local presynaptic vs. systemic circuit effects of α2 agonists. At the completion of this project, we will have determined the contribution of adrenergic neurons of the rostral pons to α2 mediated hypnosis. This will give insight into the neural circuits common to sleep and anesthesia—a door to future therapies for disorders of sleep and arousal. The proposed project will also build upon the PI's base knowledge of anesthetic pharmacology, as well as providing expertise in new areas of neuroscience and genetics. The strong, multi-disciplinary mentoring team, equally intellectually diverse collaborators, a clear career development plan, and the phenomenal support of a department that deeply values research at a world-class institution will ensure that the PI not only achieves the scientific goals of this proposal, but is prepared for a successful career investigating sleep and anesthetic hypnosis.