title: Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits.
abstract: The lateral hypothalamus (LH) is a key regulator of multiple vital behaviors. The firing of brain-wide-projecting LH neurons releases neuropeptides promoting wakefulness (orexin/hypocretin; OH), or sleep (melanin-concentrating hormone; MCH). OH neurons, which coexpress glutamate and dynorphin, have been proposed to excite their neighbors, including MCH neurons, suggesting that LH may sometimes coengage its antagonistic outputs. However, it remains unclear if, when, and how OH actions promote temporal separation of the sleep and wake signals, a process that fails in narcolepsy caused by OH loss. To explore this directly, we paired optogenetic stimulation of OH cells (at rates that promoted awakening in vivo) with electrical monitoring of MCH cells in mouse brain slices. Membrane potential recordings showed that OH cell firing inhibited action potential firing in most MCH neurons, an effect that required GABAA but not dynorphin receptors. Membrane current analysis showed that OH cell firing increased the frequency of fast GABAergic currents in MCH cells, an effect blocked by antagonists of OH but not dynorphin or glutamate receptors, and mimicked by bath-applied OH peptide. In turn, neural network imaging with a calcium indicator genetically targeted to MCH neurons showed that excitation by bath-applied OH peptides occurs in a minority of MCH cells. Collectively, our data provide functional microcircuit evidence that intra-LH feedforward loops may facilitate appropriate switching between sleep and wake signals, potentially preventing sleep disorders.
authors: Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, United Kingdom, denis.burdakov@kcl.ac.uk ja451@cam.ac.uk.
authors: John
authors: http://orcid.org/0000-0003-4819-0563
authors: J
authors: Apergis-Schoute
authors: Division of Neurophysiology, MRC National Institute for Medical Research, London NW7 1AA, United Kingdom.
authors: Panagiota
authors: P
authors: Iordanidou
authors: Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, United Kingdom.
authors: Cedric
authors: C
authors: Faure
authors: Department of Psychiatry, McGill University, Montreal, QC H3A 0G4, Canada, and.
authors: Sonia
authors: S
authors: Jego
authors: Division of Neurophysiology, MRC National Institute for Medical Research, London NW7 1AA, United Kingdom.
authors: Cornelia
authors: C
authors: Schöne
authors: Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, United Kingdom.
authors: Teemu
authors: T
authors: Aitta-Aho
authors: Neurology Department, Bern University Hospital, 3010 Bern, Switzerland, Department of Psychiatry, McGill University, Montreal, QC H3A 0G4, Canada, and.
authors: Antoine
authors: A
authors: Adamantidis
authors: Division of Neurophysiology, MRC National Institute for Medical Research, London NW7 1AA, United Kingdom, MRC Centre for Developmental Neurobiology, King's College London, London WC2R 2LS, United Kingdom denis.burdakov@kcl.ac.uk ja451@cam.ac.uk.
authors: Denis
authors: D
authors: Burdakov
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D000075402:Channelrhodopsins; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007026:Hypothalamic Area, Lateral / Q000166:cytology / Q000378:metabolism; D007028:Hypothalamic Hormones / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008543:Melanins / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009415:Nerve Net / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D062308:Optogenetics; D000068797:Orexins; D018408:Patch-Clamp Techniques; D010907:Pituitary Hormones / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014161:Transduction, Genetic; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000097573:Red Fluorescent Protein
chemical_list: D002118:Calcium; D000075402:Channelrhodopsins; D018691:Excitatory Amino Acid Antagonists; D007028:Hypothalamic Hormones; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008239:Lysine; D008543:Melanins; D009479:Neuropeptides; D000068797:Orexins; D010907:Pituitary Hormones; D005680:gamma-Aminobutyric Acid; D000097573:Red Fluorescent Protein; C000596233:Hcrt protein, mouse; C019463:melanin-concentrating hormone; C013411:biocytin
keywords: GABA; hypocretin; hypothalamus; melanin-concentrating hormone; optogenetics; orexin