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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


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
Issue number39
Publication statusPublished - 2016 Sept 28


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

ASJC Scopus subject areas

  • Neuroscience(all)


Dive into the research topics of 'Hypocretin/orexin peptides alter spike encoding by serotonergic dorsal raphe neurons through two distinct mechanisms that increase the late afterhyperpolarization'. Together they form a unique fingerprint.

Cite this