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

## TL;DR

Orexin helps control the body's response to low oxygen during active times by acting on specific brain pathways.

## Contribution

The study identifies a specific orexin-CRH-nTS pathway mechanism for phase-dependent chemoreflex modulation.

## Key findings

- Silencing CRH-nTS neurons in the active phase reduced the chemoreflex by 50%.
- Ox1R blockade prevented further chemoreflex inhibition during active phase.
- CRH-nTS pathway silencing reduced hypoxia-induced activation of CRH neurons.

## Abstract

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.