Acute intermittent hypoxia in neonatal rodent central nervous system facilitates respiratory frequency through the recruitment of hypothalamic areas

Abstract

Moderate and acute intermittent hypoxia (IH) facilitates respiration in adults, mostly by recruiting peripheral chemo-/baroreceptors. As central chemoreceptors are widely expressed in immature brains, we hypothesized that IH modulates respiration at birth through a purely neurogenic mechanism involving the hypothalamus. The central nervous system (CNS) isolated from 0- to 3-day-old rats was perfused with four to eight brief (5 min) bouts of mild-hypoxic/normocapnic modified Krebs solution, intermingled with 5-min normoxic episodes, during continuous electrophysiological recordings from upper cervical ventral roots. An IH protocol did not modify bath pH, but superficial ventrolateral medulla and hypothalamic areas experienced lowered oxygen tension, more severe after the second postnatal day, with a partial recovery after each bout. Single exposures to mild hypoxia were well tolerated, and at birth often triggered a spontaneous epoch of irregular baseline activity (< 1 min) superimposed on respiratory events in both whole CNS preparations and spinal cords. Conversely, IH largely halted breathing activity after the second postnatal day, while at birth IH transiently increased the amplitude of respiratory bursts and stably sped up rhythm only when intact suprapontine structures were present. Rhythm acceleration was not directly correlated to instantaneous changes in tissue oxygen tension. After IH, respiratory frequency remained 260% higher than pre-IH control for up to 60 min. Identical modulatory effects were observed with IH supplied through a HEPES buffer solution. Interestingly, IH increased electrical activity and cFos expression in hypothalamic areas without altering total cell number. These observations cast some light on the mechanisms of IH during development, with important insights about pediatric effects of repeated hypoxic episodes.