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 ?2 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 ?2 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 ?2 adrenergic agonists through addressing these questions: Can discrete and localized actions of ?2 agonists targeting the rostral pons produce and maintain hypnosis? Previously published together with our preliminary data support the idea that local delivery of ?2 agonists to pons including the locus coeruleus is sufficient for hypnosis. We will use novel ?2 adrenergic agonist photolabels to locally modulate neuronal activity and rigorously test this hypothesis. Are adrenergic neurons of the locus coeruleus necessary for ?2-mediated hypnosis? We will perform adrenergic-specific knockouts of ?2A adrenergic receptors in the rostral pons, looking for resistance to ?2 adrenergic agonist hypnosis. We will also optogenetically drive adrenergic neurons of the rostral pons to determine if their activity can reverse ?2 mediated hypnosis. Is the neuronal firing pattern in the rostral pons around the LC under ?2-agonist hypnosis primarily dependent on local or systemic effects? Can changing adrenergic neuron activity reverse ?2-agonist hypnosis? We will record unit-activity in the rostral pons with ?2 agonist administration in wild-type and adrenergic ?2A receptor knockout mice. Using optogenetics and ?2 photolabels, we will mechanistically dissect local presynaptic vs. systemic circuit effects of ?2 agonists. At the completion of this project, we will have determined the contribution of adrenergic neurons of the rostral pons to ?2 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.
One third of Americans will suffer from a sleep disorder in their lifetime, and the cost of such disorders exceeds 30 billion dollars annually. In order to address this public health need, this proposal will investigate the brain pathways common to sleep and sleep-like hypnosis, in the hope that understanding these neural circuits will inform new treatments for disorders of sleep and arousal.
|McKinstry-Wu, Andrew R; Kelz, Max B (2018) Optoanesthesia: Use of Anesthetic Photolabels In Vivo. Methods Enzymol 603:171-180|
|McKinstry-Wu, Andrew; Carspecken, Charles W; Proekt, Alex et al. (2018) Xenon Anesthesia and CT: Noninvasive Measures of Brain Anesthetic Concentration. Methods Enzymol 602:289-298|