Coreleased Orexin and Glutamate Evoke Nonredundant Spike Outputs and Computations in Histamine Neurons

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→HANOHR2 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. [Display omitted] •Natural orexin release generates unique signatures of brain activity•Unlike classical transmitter glutamate, orexin release produces enduring communication•Orexin transmission requires a distinct neural firing code•Orexin transmission is necessary for brain histamine neurons to integrate inputs Stable wakefulness requires brain orexin/hypocretin neurons, whose loss causes narcoleptic instability of consciousness. These neurons produce several neuroexcitatory transmitters, such as orexins and glutamate. The logic of this is unclear, because it seems energetically wasteful to make several transmitters serving the same function of excitation. Schöne et al. found, however, that when naturally coreleased, orexin and glutamate each create unique signatures of brain activity, which are mutually independent and useful for different but complementary purposes. This may offer insights into why orexins are indispensable for stable consciousness.