Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 25, Pages 10685-10690Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0702676104
Keywords
arousal; hypocretin; hypothalamus; pH; breathing
Categories
Funding
- Medical Research Council [MC_U137881016] Funding Source: Medline
- Medical Research Council [MC_U137881016] Funding Source: researchfish
- MRC [MC_U137881016] Funding Source: UKRI
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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 (approximate to 100% change in firing rate per 0.1 unit change in pH(e)). Evoked firing of orexin cells is similarly modified by physiologically relevant changes in pH(e): Acidification increases intrinsic excitability, whereas alkalinization depresses it. The effects of pH(e) 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.
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