Activation of the hypothalamic paraventricular nucleus by acute intermittent hypoxia: Implications for sympathetic long-term facilitation neuroplasticity

Exp Neurol. 2019 Apr;314:1-8. doi: 10.1016/j.expneurol.2018.12.011. Epub 2018 Dec 31.


Exposure to acute intermittent hypoxia (AIH) induces a progressive increase of sympathetic nerve activity (SNA) that reflects a form of neuroplasticity known as sympathetic long-term facilitation (sLTF). Our recent findings indicate that activity of neurons in the hypothalamic paraventricular nucleus (PVN) contributes to AIH-induced sLTF, but neither the intra-PVN distribution nor the neurochemical identity of AIH responsive neurons has been determined. Here, awake rats were exposed to 10 cycles of AIH and c-Fos immunohistochemistry was performed to identify transcriptionally activated neurons in rostral, middle and caudal planes of the PVN. Effects of graded intensities of AIH were investigated in separate groups of rats (n = 6/group) in which inspired oxygen (O2) was reduced every 6 min from 21% to nadirs of 10%, 8% or 6%. All intensities of AIH failed to increase c-Fos counts in the caudally located lateral parvocellular region of the PVN. c-Fos counts increased in the dorsal parvocellular and central magnocellular regions, but significance was achieved only with AIH to 6% O2 (P < 0.002). By contrast, graded intensities of AIH induced graded c-Fos activation in the stress-related medial parvocellular (MP) region. Focusing on AIH exposure to 8% O2, experiments next investigated the stress-regulatory neuropeptide content of AIH-activated MP neurons. Tissue sections immunostained for corticotropin-releasing hormone (CRH) or arginine vasopressin (AVP) revealed a significantly greater number of neurons stained for CRH than AVP (P < 0.0001), though AIH induced expression of c-Fos in a similar fraction (~14%) of each neurochemical class. Amongst AIH-activated MP neurons, ~30% stained for CRH while only ~2% stained for AVP. Most AIH-activated CRH neurons (~82%) were distributed in the rostral one-half of the PVN. Results indicate that AIH recruits CRH, but not AVP, neurons in rostral to middle levels of the MP region of PVN, and raise the possibility that these CRH neurons may be a substrate for AIH-induced sLTF neuroplasticity.

Keywords: Anxiety; Depression; Hypertension; Neural plasticity; Sympathetic nerve activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine Vasopressin / metabolism
  • Arterial Pressure
  • Cell Count
  • Corticotropin-Releasing Hormone / metabolism
  • Heart Rate
  • Hypoxia / physiopathology*
  • Long-Term Potentiation
  • Male
  • Neuronal Plasticity*
  • Neuropeptides / metabolism
  • Paraventricular Hypothalamic Nucleus / physiopathology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sympathetic Nervous System / physiopathology*


  • Neuropeptides
  • Proto-Oncogene Proteins c-fos
  • Arginine Vasopressin
  • Corticotropin-Releasing Hormone