title: Mechanism for Hypocretin-mediated sleep-to-wake transitions.
abstract: Current models of sleep/wake regulation posit that Hypocretin (Hcrt)-expressing neurons in the lateral hypothalamus promote and stabilize wakefulness by projecting to subcortical arousal centers. However, the critical downstream effectors of Hcrt neurons are unknown. Here we use optogenetic, pharmacological, and computational tools to investigate the functional connectivity between Hcrt neurons and downstream noradrenergic neurons in the locus coeruleus (LC) during nonrapid eye movement (NREM) sleep. We found that photoinhibiting LC neurons during Hcrt stimulation blocked Hcrt-mediated sleep-to-wake transitions. In contrast, when LC neurons were optically stimulated to increase membrane excitability, concomitant photostimulation of Hcrt neurons significantly increased the probability of sleep-to-wake transitions compared with Hcrt stimulation alone. We also built a conductance-based computational model of Hcrt-LC circuitry that recapitulates our behavioral results using LC neurons as the main effectors of Hcrt signaling. These results establish the Hcrt-LC connection as a critical integrator-effector circuit that regulates NREM sleep/wake behavior during the inactive period. This coupling of distinct neuronal systems can be generalized to other hypothalamic integrator nuclei with downstream effector/output populations in the brain.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Carter
authors.forename: Julia
authors.initials: J
authors.lastname: Brill
authors.forename: Patricia
authors.initials: P
authors.lastname: Bonnavion
authors.forename: John R
authors.initials: JR
authors.lastname: Huguenard
authors.forename: Ramon
authors.initials: R
authors.lastname: Huerta
authors.forename: Luis
authors.initials: L
authors.lastname: de Lecea
mesh_terms: D059331:Adrenergic Neurons / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008125:Locus Coeruleus / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D010775:Photic Stimulation; D015398:Signal Transduction / Q000502:physiology*; D012895:Sleep, REM / Q000502:physiology*; D014851:Wakefulness / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins