Hypocretin/orexin peptides alter spike encoding by serotonergic dorsal raphe neurons through two distinct mechanisms that increase the late afterhyperpolarization

Masaru Ishibashi, Iryna Gumenchuk, Kenichi Miyazaki, Takafumi Inoue, William N. Ross, Christopher S. Leonard

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    Abstract

    Orexins (hypocretins) are neuropeptides that regulate multiple homeostatic processes, including reward and arousal, in part by exciting serotonergic dorsal raphe neurons, the major source of forebrain serotonin. Here, using mouse brain slices, we found that, instead of simply depolarizing these neurons, orexin-A altered the spike encoding process by increasing the postspike afterhyperpolarization (AHP) via two distinct mechanisms. This orexin-enhanced AHP (oeAHP) was mediated by both OX1 and OX2 receptors, required Ca2+ influx, reversed near EK, and decayed with two components, the faster of which resulted from enhanced SK channel activation, whereas the slower component decayed like a slow AHP (sAHP), but was not blocked by UCL2077, an antagonist of sAHPs in some neurons. Intracellular phospholipase C inhibition (U73122) blocked the entire oeAHP, but neither component was sensitive to PKC inhibition or altered PKA signaling, unlike classical sAHPs. The enhanced SK current did not depend on IP3-mediated Ca2+ release but resulted from A-current inhibition and the resultant spike broadening, which increased Ca2+ influx and Ca2+-induced-Ca2+ release, whereas the slower component was insensitive to these factors. Functionally, the oeAHP slowed and stabilized orexin-induced firing compared with firing produced by a virtual orexin conductance lacking the oeAHP. The oeAHP also reduced steady-state firing rate and firing fidelity in response to stimulation, without affecting the initial rate or fidelity. Collectively, these findings reveal a new orexin action in serotonergic raphe neurons and suggest that, when orexin is released during arousal and reward, it enhances the spike encoding of phasic over tonic inputs, such as those related to sensory, motor, and reward events.

    Original languageEnglish
    Pages (from-to)10097-10115
    Number of pages19
    JournalJournal of Neuroscience
    Volume36
    Issue number39
    DOIs
    Publication statusPublished - 2016 Sep 28

    Fingerprint

    Orexin Receptors
    Reward
    Arousal
    Neurons
    Peptides
    Serotonergic Neurons
    Type C Phospholipases
    Prosencephalon
    Neuropeptides
    Serotonin
    Brain
    Orexins
    Dorsal Raphe Nucleus
    Inhibition (Psychology)

    Keywords

    • Arousal
    • Narcolepsy
    • Reward
    • SK channels
    • Slow AHP
    • Spike frequency adaptation

    ASJC Scopus subject areas

    • Neuroscience(all)

    Cite this

    Hypocretin/orexin peptides alter spike encoding by serotonergic dorsal raphe neurons through two distinct mechanisms that increase the late afterhyperpolarization. / Ishibashi, Masaru; Gumenchuk, Iryna; Miyazaki, Kenichi; Inoue, Takafumi; Ross, William N.; Leonard, Christopher S.

    In: Journal of Neuroscience, Vol. 36, No. 39, 28.09.2016, p. 10097-10115.

    Research output: Contribution to journalArticle

    Ishibashi, Masaru ; Gumenchuk, Iryna ; Miyazaki, Kenichi ; Inoue, Takafumi ; Ross, William N. ; Leonard, Christopher S. / Hypocretin/orexin peptides alter spike encoding by serotonergic dorsal raphe neurons through two distinct mechanisms that increase the late afterhyperpolarization. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 39. pp. 10097-10115.
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