title: Direct and indirect excitation of laterodorsal tegmental neurons by Hypocretin/Orexin peptides: implications for wakefulness and narcolepsy.
abstract: Compelling evidence links the recently discovered hypothalamic peptides Hypocretin/Orexin (Hcrt/Orx) to rapid eye movement sleep (REM) control and the sleep disorder narcolepsy, yet how they influence sleep-related systems is not well understood. We investigated the action of Hcrt/Orx on mesopontine cholinergic (MPCh) neurons of the laterodorsal tegmental nucleus (LDT), a target group whose function is altered in canine narcolepsy and appears pivotal for normal REM and wakefulness. Extracellular recordings from mouse brainstem slices revealed that Hcrt/Orx evoked prolonged firing of LDT neurons. Whole-cell recordings revealed that Hcrt/Orx had actions on both presynaptic neurons and at postsynaptic sites. Hcrt/Orx produced an increase in frequency and amplitude of spontaneous EPSCs without equivalent effect on IPSCs, by triggering action potentials and enhancing spike-evoked synaptic transmission in glutamatergic afferents. Postsynaptically, Hcrt/Orx produced an inward current and an increase in membrane current noise, which were accompanied by a conductance increase. These persisted in TTX, ionotropic glutamate receptor antagonists, and low extracellular calcium. Both presynaptic and postsynaptic actions were specific because they were not mimicked by an Hcrt/Orx fragment, and both actions were observed for cholinergic and noncholinergic LDT neurons. Finally, extracellular recordings during postsynaptic potential blockade demonstrated that postsynaptic actions of Hcrt/Orx alone could evoke prolonged firing. In the context of other recent work, our findings suggest that Hcrt/Orx neurons may coordinate the activity of the entire reticular activating system during waking. Moreover, these findings address specific hypotheses regarding the cellular mechanisms underlying REM disregulation in narcolepsy.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York 10595, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Burlet
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Tyler
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Leonard
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D000068797:Orexins; D018408:Patch-Clamp Techniques; D012154:Reticular Formation / Q000502:physiology; D012895:Sleep, REM / Q000502:physiology; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013681:Tegmentum Mesencephali / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D014851:Wakefulness / Q000187:drug effects* / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D013779:Tetrodotoxin; D019001:Nitric Oxide Synthase; D002118:Calcium