Hypoxia activates a neuropeptidergic pathway from the paraventricular nucleus of the hypothalamus to the nucleus tractus solitarii

Am J Physiol Regul Integr Comp Physiol. 2018 Dec 1;315(6):R1167-R1182. doi: 10.1152/ajpregu.00244.2018. Epub 2018 Sep 19.


The paraventricular nucleus of the hypothalamus (PVN) contributes to both autonomic and neuroendocrine function. PVN lesion or inhibition blunts cardiorespiratory responses to peripheral chemoreflex activation, suggesting that the PVN is required for full expression of these effects. However, the role of efferent projections to cardiorespiratory nuclei and the neurotransmitters/neuromodulators that are involved is unclear. The PVN sends dense projections to the nucleus tractus solitarii (nTS), a region that displays neuronal activation following hypoxia. We hypothesized that acute hypoxia activates nTS-projecting PVN neurons. Using a combination of retrograde tracing and immunohistochemistry, we determined whether hypoxia activates PVN neurons that project to the nTS and examined the phenotype of these neurons. Conscious rats underwent 2 h normoxia (21% O2, n = 5) or hypoxia (10% O2, n = 6). Hypoxia significantly increased Fos immunoreactivity in nTS-projecting neurons, primarily in the caudal PVN. The majority of activated nTS-projecting neurons contained corticotropin-releasing hormone (CRH). In the nTS, fibers expressing the CRH receptor corticotropin-releasing factor receptor 2 (CRFR2) were colocalized with oxytocin (OT) fibers and were closely associated with hypoxia-activated nTS neurons. A separate group of animals that received a microinjection of adeno-associated virus type 2-hSyn-green fluorescent protein (GFP) into the PVN exhibited GFP-expressing fibers in the nTS; a proportion of these fibers displayed OT immunoreactivity. Thus, nTS CRFR2s appear to be located on the fibers of PVN OT neurons that project to the nTS. Taken together, our findings suggest that PVN CRH projections to the nTS may modulate nTS neuronal activation, possibly via OTergic mechanisms, and thus contribute to chemoreflex cardiorespiratory responses.

Keywords: chemoreflex; corticotropin-releasing factor receptor 2; corticotropin-releasing hormone; oxytocin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Corticotropin-Releasing Hormone / metabolism
  • Hypothalamus / metabolism*
  • Hypoxia / metabolism*
  • Hypoxia / physiopathology
  • Male
  • Neurons / metabolism
  • Oxytocin / metabolism*
  • Paraventricular Hypothalamic Nucleus / metabolism*
  • Paraventricular Hypothalamic Nucleus / physiopathology
  • Rats, Sprague-Dawley
  • Solitary Nucleus / drug effects
  • Solitary Nucleus / metabolism


  • Oxytocin
  • Corticotropin-Releasing Hormone