Postnatal development of metabolic rate during normoxia and acute hypoxia in rats: implication for a sensitive period

Abstract

Liu Q, Fehring C, Lowry TF, Wong-Riley MTT. Postnatal development of metabolic rate during normoxia and acute hypoxia in rats: implication for a sensitive period. J Appl Physiol 106: 1212-1222, 2009. First published December 31, 2008 doi:10.1152/japplphysiol.90949.2008.-Previously, we reported that the hypoxic ventilatory response (HVR) in rats was weakest at postnatal day (P) P13, concomitant with neurochemical changes in respiratory nuclei. A major determinant of minute ventilation (V E) is reportedly the metabolic rate [O2 consumption (V O2) and CO2 production (V CO2)]. The present study aimed at testing our hypothesis that daily metabolic rates changed in parallel with ventilation during development and that a weak HVR at P13 was attributable mainly to an inadequate metabolic rate in hypoxia. Ventilation and metabolic rates were monitored daily in P0 -P21 rats. We found that 1) ventilation and metabolic rates were not always correlated, and V E/V O2 and V E/V CO2 ratios were not constant during development; 2) metabolic rate and V E/V O2 and V E/V CO2 ratios at P0 -P1 were significantly different from the remaining first postnatal week in normoxia and hypoxia; 3) at P13, metabolic rates and V E/V O2 and V E/V CO2 ratios abruptly increased in normoxia and were compromised in acute hypoxia, unlike more stable trends during the remaining second and third postnatal weeks; and 4) the respiratory quotient (V CO2/V O2) was quite stable in normoxia and fluctuated slightly in hypoxia from P0 to P21. Thus our data revealed heretofore unsuspected metabolic adjustments at P0 -P1 and P13. At P0 -P1, ventilation and metabolic rates were uncorrelated, whereas at P13, they were closely correlated under normoxia and hypoxia. The findings further strengthened the existence of a critical period of respiratory development around P13, when multiple physiological and neurochemical adjustments occur simultaneously. carbon dioxide production; critical period; oxygen consumption; respiratory quotient; ventilation PREVIOUSLY, WE CONDUCTED DETAILED, day-to-day studies of various brain stem respiratory nuclei of the rat and found that neurotransmitters and receptors underwent distinct developmental changes. Significantly, at or around postnatal day (P) 12, the expression of excitatory neurotransmitter glutamate and its N-methyl-D-aspartate receptors dropped precipitously, whereas the expression of inhibitory neurotransmitter ␥-aminobutyric acid (GABA), GABA B receptors, and glycine receptors rose sharply (27,30, 61). Concomitantly, there was a sudden fall in cytochrome oxidase activity (27,28, 61), a sensitive indicator of metabolic capacity and neuronal activity (60). We hypothesized that at and around P12 is a sensitive period in the postnatal development of the rat's respiratory control network, when a transient dominance of inhibitory over excitatory neurotransmission renders the animals less capable of overcoming exogenous respiratory stressors. Our subsequent ventilatory studies revealed striking changes in normoxic ventilation ...

Abrupt changes in pentobarbital sensitivity in preBötzinger complex region, hypoglossal motor nucleus, nucleus tractus solitarius, and cortex during rat transitional period (P10–P15)

“…Another surprising finding from this study was that abrupt increases or decreases in pentobarbital resistance that we observed occurred mainly at P14, rather than at P11–P12 as elegantly demonstrated repeatedly by Wong-Riley and colleagues (Gao et al , 2011; Liu et al, 2006, 2009; Liu and Wong-Riley, 2002, 2004, 2005, 2006, 2010; Wong-Riley and Liu, 2008, Wong-Riley et al, 2013). We speculate that the abrupt changes in the medulla at P11–P12 may initiate a cascade of events that lead to further changes in the next two days that may compromise breathing.…”

“…During acute hypoxia, the ventilatory response is weakest in P13 animals, and is significantly lower from P12–P14 compared to the rest of the first three postnatal weeks (Liu et al, 2006). At P13, the combination of relatively low metabolism, and low ratios of ventilation/O 2 consumption and ventilation/CO 2 production are hypothesized to be unique for the entire first 21 postnatal days and put the rats at risk during a severe, prolonged bout of hypoxia (Liu et al, 2009). Likewise, in a different laboratory, P12–13 male rats were found to have lower ventilation during hypercapnia (Holley et al, 2012).…”

“…Although “critical period” was used by Wong-Riley and colleagues in their seminal studies of development (Gao et al , 2011; Liu et al, 2006, 2009; Liu and Wong-Riley, 2002, 2004, 2005, 2006, 2010; Wong-Riley and Liu, 2008, Wong-Riley et al, 2013), we prefer to use the term “transitional period” because “critical period” is more often used in neuroscience to define a specific developmental period whereby a perturbation ( e.g. , sensory deprivation) causes long-lasting changes in neural function ( e.g.…”

“…With respect to GABA A Rs, subunit composition switches from including predominately alpha-3 subunits (immature phenotype) to alpha-1 subunits (mature phenotype) on postnatal day 12 in preBötC and NTS neurons, (Liu and Wong-Riley, 2004; 2006). Functionally, these changes may contribute to decreased neuronal excitability, and potentially cause the blunted hypoxic and hypercapnic ventilatory responses in found in P12–P15 rats (Holley et al , 2012; Liu et al , 2006, 2009; Wong-Riley and Liu, 2008). Taken together, these studies suggest that neuronal inhibition is relatively high during the second postnatal week.…”

Younger rats are more susceptible to the lethal effects of sarin than adult rats: 24 h LC50for whole-body (10 and 60 min) exposures

“…These neurochemical changes are closely followed by significant increases in ventilation (Liu et al, 2006) and metabolic rate (Liu et al, 2009) at PND 13, which require too much energy to maintain under hypoxic conditions. This weakened hypoxic ventilatory response may explain why PND 14 rats were the most susceptible to the lethal effects associated with whole-body exposure to sarin.…”