Neonatal stress augments the hypoxic chemoreflex of adult male rats by increasing AMPA receptor-mediated modulation

Exp Physiol. 2013 Aug;98(8):1312-24. doi: 10.1113/expphysiol.2013.072090. Epub 2013 Apr 19.


Neonatal stress disrupts the developmental trajectory of homeostatic systems. Adult (8- to 10-week-old) male rats exposed to maternal separation (a form of neonatal stress) display several traits reported in patients suffering from sleep-disordered breathing, including an augmented hypoxic chemoreflex. To understand the mechanisms behind this effect, we tested the hypothesis that neonatal stress augments glutamatergic neurotransmission in three regions involved in respiratory regulation, namely the nucleus of the solitary tract, the paraventricular nucleus of the hypothalamus and the phrenic motor nucleus. Maternal separation was performed for 3 h day(-1) from postnatal day 3 to 12. Control pups were undisturbed. Adult rats were instrumented for intracerebroventricular injection of the AMPA/kainate receptor antagonist CNQX (0-4.3 μm). Using plethysmography, ventilatory activity was measured at rest in awake animals during normoxia (fractional inspired O2 = 0.21) and during acute hypoxia (fractional inspired O2 = 0.12; 20 min). Following vehicle injection, the hypoxic ventilatory response of stressed rats was 35% greater than that of controls. Microinjection of CNQX attenuated the hypoxic ventilatory response, but the effect observed in stressed rats was greater than that in control animals. Autoradiography experiments showed that neonatal stress augments expression of AMPA receptors within the paraventricular nucleus of the hypothalamus and the phrenic motor nucleus. Quantification of brain-derived neurotrophic factor showed that neonatal stress augments brain-derived neurotrophic factor expression only within the paraventricular nucleus. We conclude that neonatal stress augments the hypoxic chemoreflex by increasing the efficacy of glutamatergic synaptic inputs projecting onto key respiratory structures, especially the paraventricular nucleus of the hypothalamus. These data provide new insight into the aetiology of sleep-disordered breathing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Female
  • Hypothalamus / metabolism
  • Hypothalamus / physiopathology
  • Hypoxia / metabolism
  • Hypoxia / physiopathology*
  • Male
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Paraventricular Hypothalamic Nucleus / physiopathology
  • Phrenic Nerve / metabolism
  • Phrenic Nerve / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism*
  • Reflex / physiology*
  • Respiration
  • Sleep Apnea Syndromes / metabolism
  • Sleep Apnea Syndromes / physiopathology*
  • Solitary Nucleus / metabolism
  • Solitary Nucleus / physiopathology
  • Stress, Physiological / physiology*
  • Synaptic Transmission / physiology*


  • Receptors, AMPA