Orexin facilitates the peripheral chemoreflex in the active phase via corticotropin-releasing hormone neurons that project to the nucleus of the solitary tract.

Projections from the paraventricular nucleus (PVN) of the hypothalamus to the nucleus of the solitary tract (nTS) facilitate the peripheral chemoreflex. A significant proportion of this projection is composed of corticotropin-releasing hormone (CRH) neurons. Orexin neurons in the perifornical hypothalamus augment the peripheral chemoreflex, project to the PVN, and facilitate the hypoxia-induced activation of nTS-projecting CRH neurons. We hypothesized that nTS-projecting CRH neurons are necessary for the full reflex, and that orexin facilitates the reflex via the CRH-nTS pathway. We chemogenetically silenced or activated nTS-projecting CRH neurons during normoxia and acute hypoxia. For each rat, reflex strength was tested in both inactive and active phases as the activity of orexin neurons is phase dependent. Testing was done following vehicle, Compound 21 (1 mg/kg) to activate Gi- or Gq-DREADDs, and after systemic Ox1R blockade (SB-334867; 1 mg/kg). We performed immunohistochemistry to assess how chemogenetic manipulation of nTS-projecting CRH neurons influenced their activation by hypoxia (via cFos). Activating the CRH-nTS pathway had no effect on the chemoreflex in either phase. Silencing the pathway in the active phase, but not inactive phase, reduced the strength of the reflex by ∼50% and prevented further inhibition by Ox1R blockade, suggesting orexin acts via Ox1R on CRH neurons. Pathway silencing reduced the proportion of nTS-projecting CRH neurons activated by hypoxia, consistent with the effects of pathway silencing on the reflex. These data suggest that orexin augments the peripheral chemoreflex in the active phase via the CRH-nTS pathway.