Interactions Between Postnatal Sustained Hypoxia and Intermittent Hypoxia in the Adulthood to Alter Brainstem Structures and Respiratory Function

Abstract

Neural plasticity is defined as a persistent change in the morphology and/or function based on prior experiences. Plasticity is well evident when the triggering experience occurs early in life, but in the case of respiratory control plasticity, it also can be triggered in adult life. We have combined a 10 days postnatal hypoxic (PH) (0-10 days of age;11% O(2)) and a 15 days intermittent hypoxia (IH) exposures in the adulthood (90-105 days of age; 5% O(2), 40 s/20% O(2), 80 s; 8 h/day) to test if early PH interacts with IH of the adulthood to generate detrimental plastic changes. After recording of ventilatory parameters, the brains were studied immunocytochemically for localization of the organization pattern of non-phosphorylated subunit of neurofilament H (NFH) and tyrosine hydroxylase (TH) expression in the nucleus tractus solitarius (Sol) and caudal (CVL) and rostral ventrolateral reticular (RVL) nuclei, areas related to central cardio-respiratory regulation. In comparison to control, PH male rats (but not females) at 1 month of age hyperventilated at rest, in response to moderate hypoxia (12% O(2)) and 5% CO(2), the effect being due to increased tidal volume. At 3.5 months sex differences in ventilation disappeared and it was indistinguishable between control and PH. IH tended to decrease ventilation in both control (C) and PH animals. PH augmented PENH values in air and in hypoxic conditions when compared with C group. IH in both groups, tended to decrease the PENH value, being statistically different in PH+IH. Results also show an increment of disorganization of NFH-positive labeled structures at the level of Sol and CVL/RVL nuclei in PH, IH and HP+HI groups. PH rats showed differences in the number of TH-positive neurons at the level of CVL/RVL nuclei, which was increased in the PH and PH+IH groups with respect to C one. In conclusion, PH alters the central morpho-physiological organization and the catecholaminergic components of cardio-respiratory nuclei, whose effects were enhanced after a period of IH in the adulthood.

Hypoxia Modulates the Adenosinergic Neural Network

“…Adaptive responses have evolved in different animal species to guarantee a sufficient supply of O 2 to tissues and to facilitate the survival of cells under transient or sustained conditions of limited O 2 availability. Although hypoxia is often related to a pathological condition, it is of great importance to recognize that variations in Pa O 2 can be part of normal situations that require strenuous physiological responses, for example, during hypoventilation training or intense physical exercise [4,5,16,21,[25][26][27][28]. It has to be also taken into account the condition of hypercapnia that results from an excess of Pa CO 2 , which results in acidification of blood and tissues.…”

“…and initiates respiratory and autonomic reflex adjustments during hypoxic and hypercapnic. Activation of either the hypoxic or hypercapnic chemoreflex elicits both hyperventilation and sympathetic activation [4,5,16,[25][26][27][28]. However, the hypoxic insult is a fundamental drive to increase respiratory rate.…”

“…Nevertheless, these chronic intermittent hypoxia (CIH) laboratory protocols vary greatly between researches in lifespan of hypoxic exposure periods, numbers of hypoxic episodes per day and the total number of days of exposure. In any case, and in spite of the lack of a uniform definition, most of the recent data suggest that animals exposed to CIH would present multiple long-term pathophysiological consequences that are similar to those observed in clinic and, for that, it would be a good animal model to study different respiratory pathologies [4,5,16,21,[25][26][27][28].…”

“…Since the condition in which the whole body (or a region) was exposed to variations in arterial O 2 concentrations can be part of the normal physiology, a mild and non-damaging intermittent hypoxia (IH) is used intentionally, for example, during altitude training to develop an athletic performance adaptation at both the systemic and cellular level [4,5,16,21,[26][27][28]. However, hypoxia is a deprivation of adequate O 2 supply at the tissue level and, often, a pathological condition with very serious consequences of preterm birth in the neonate, for example.…”

“…These syndromes have been linked to deficits in neurons related with the respiratory control in the pre-Bötzinger complex, pontine raphe and adjacent areas. Obviously, an understanding of how the response to hypoxia is organized and when or why the system become maladapted and could induce cell damage is extremely important for knowing how to fight against the diseases in the future [4,5,16,21,[26][27][28].…”