Lars Henrik Fugger

Control of hypothalamic orexin neurons by acid and CO2

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Rhîannan H Williams, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England.
  • ,
  • Lise T Jensen
  • Alex Verkhratsky
  • ,
  • Lars Fugger
  • Denis Burdakov

Hypothalamic orexin/hypocretin neurons recently emerged as key orchestrators of brain states and adaptive behaviors. They are critical for normal stimulation of wakefulness and breathing: Orexin loss causes narcolepsy and compromises vital ventilatory adaptations. However, it is unclear how orexin neurons generate appropriate adjustments in their activity during changes in physiological circumstances. Extracellular levels of acid and CO2 are fundamental physicochemical signals controlling wakefulness and breathing, but their effects on the firing of orexin neurons are unknown. Here we show that the spontaneous firing rate of identified orexin neurons is profoundly affected by physiological fluctuations in ambient levels of H+ and CO2. These responses resemble those of known chemosensory neurons both qualitatively (acidification is excitatory, alkalinization is inhibitory) and quantitatively (approximately 100% change in firing rate per 0.1 unit change in pHe). Evoked firing of orexin cells is similarly modified by physiologically relevant changes in pHe: Acidification increases intrinsic excitability, whereas alkalinization depresses it. The effects of pHe involve acid-induced closure of leak-like K+ channels in the orexin cell membrane. These results suggest a new mechanism of how orexin/hypocretin networks generate homeostatically appropriate firing patterns.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue25
Pages (from-to)10685-90
Number of pages6
ISSN0027-8424
DOIs
Publication statusPublished - 19 Jun 2007

    Research areas

  • Acids/pharmacology, Action Potentials/drug effects, Animals, Carbon Dioxide/pharmacology, Hydrogen-Ion Concentration, Hypothalamus/cytology, Intracellular Signaling Peptides and Proteins/metabolism, Mice, Mice, Transgenic, Neurons/drug effects, Neuropeptides/metabolism, Orexins, Patch-Clamp Techniques

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