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Cell Rep. 2014 May 8;7(3):697-704. doi: 10.1016/j.celrep.2014.03.055. Epub 2014 Apr 24.

Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons.

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Division of Neurophysiology, MRC National Institute for Medical Research, London NW7 1AA, UK.
Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan; International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Neurology Department, Bern University Hospital, 3010 Bern, Switzerland; Department of Psychiatry, McGill University, Montreal, QC H3A 0G4, Canada.
Division of Neurophysiology, MRC National Institute for Medical Research, London NW7 1AA, UK; MRC Centre for Developmental Neurobiology, King's College London, London WC2R 2LS, UK. Electronic address:


Stable wakefulness requires orexin/hypocretin neurons (OHNs) and OHR2 receptors. OHNs sense diverse environmental cues and control arousal accordingly. For unknown reasons, OHNs contain multiple excitatory transmitters, including OH peptides and glutamate. To analyze their cotransmission within computational frameworks for control, we optogenetically stimulated OHNs and examined resulting outputs (spike patterns) in a downstream arousal regulator, the histamine neurons (HANs). OHR2s were essential for sustained HAN outputs. OHR2-dependent HAN output increased linearly during constant OHN input, suggesting that the OHN→HAN(OHR2) module may function as an integral controller. OHN stimulation evoked OHR2-dependent slow postsynaptic currents, similar to midnanomolar OH concentrations. Conversely, glutamate-dependent output transiently communicated OHN input onset, peaking rapidly then decaying alongside OHN→HAN glutamate currents. Blocking glutamate-driven spiking did not affect OH-driven spiking and vice versa, suggesting isolation (low cross-modulation) of outputs. Therefore, in arousal regulators, cotransmitters may translate distinct features of OHN activity into parallel, nonredundant control signals for downstream effectors.

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