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Objective: It is now emerging that central chemoreceptors (CCR) may be widely distributed in the brain, but little is known about specific structure and mechanism of CCR. Because the firing rate of hypothalamic orexin neurons is affected by acid and CO2, we hypothesize that orexin neurons may act as CCR. Methods:Electrophysiology was performed to observe the influence of local acidification in the lateral hypothalamus (LH)on breathing in SD rats. Double immunofluorescence was confirmed the expression of acid-sensing ion channels(ASICs) on orexin neurons. The effect of orexin neurons on respiratory regulation was verified by destruction of orexin neurons via orexin-SAP. Results: Local acidification (pH=6.5) in the LH increased the amplitude of phrenic nerve discharge and respiratory drive by 70% and 40% compared with pH=7.4. Orexin-A immunoreactive cells co-expressed with ASIC1 in the LH. Expression of orexin-A neurons was significant loss accompanied by pulmonary function deteriorated and local acidification of the LH no longer stimulated breathing in orexin-SAP rats. Conclusion: The study provides new evidence that hypothalamic orexin neurons are CCR, which regulate breathing via ASICs.