While the mammalian brain is considered to be highly sensitive to low oxygen (hypoxia), not all animals at all life stages are equally vulnerable to hypoxic stress. In fact, some mammals are highly adapted to low oxygen conditions. Diving marine mammals and high altitude species, for example,share such similar traits as high hemoglobin and myoglobin concentrations that increase the body's oxygen carrying capacity. Fetal mammals are also adapted to low oxygen conditions; fetal hemoglobins in general bind oxygen more strongly than adult hemoglobin, and the fetal brain at the cellular level withstands hypoxia better than the adult brain.
Compared with lowland species, fetal life for high-altitude animals like llamas is particularly challenging. Fetal llamas exhibit several adaptations to deal with the double blow of a low oxygen environment in utero and their mother's low oxygen montane environment. These include hemoglobin that can strip oxygen from the maternal circulation, lower cardiac output and organ perfusion, and increased oxygen extraction efficiency.
This led Roberto Reyes' group at the Universidad de Chile at Santiago and their collaborators to question if a fetal llama can decrease its brain's energy demands as oxygen supply decreases. This hypometabolism is a well-studied phenomenon in true facultative anaerobes such as the freshwater turtle Trachemys and the Crucian carp, which can withstand days to months without oxygen. By decreasing energy demand to match reduced energy supply, facultative anaerobes ensure that no energy imbalance occurs and their brain survives, albeit at a reduced activity level.
To see if fetal llamas show hypometabolism when their mother's arterial oxygen levels plummet, Reyes' group looked for decreased fetal llama brain temperature, Na+ and K+ channel density, and Na+/K+-ATPase activity in the fetal brain. The team induced fetal hypoxemia (low blood oxygen) for 24 h by reducing the inspired oxygen fraction of pregnant llama mothers to ∼12 mmHg. They succeeded in lowering maternal arterial oxygen from an average of 92.5 to 66.4 torr and fetal blood oxygen from ∼18 torr to 12 torr, with no change in arterial CO2, pH or heart rate. During the 24 h hypoxemia, the investigators found that fetal brain temperatures declined an average of 0.56°C, with no change in core body temperature. This temperature decrease was accompanied by a 51% decrease in activity of the Na+/K+ pump and a 44%decrease in the protein content of the voltage-gated Na+ channel NaV1.1 in the fetal llamas' brains, all tell-tale signs that the llamas had depressed their brains' metabolism. Interestingly, when the team examined the fetal brains for degradation of poly ADP-ribose polymerase (PARP), an indicator of cell death, they found no evidence for increased PARP proteolysis. Apparently, fetal llama brains can cope with 24 h hypoxemia without suffering increased cell death.
The fetal llama brain, then, is evidently able to utilize some of the same mechanisms as well-studied facultative anaerobes to decrease brain metabolism in times of energy crisis. By decreasing temperature, ion leak and ion pumping, llama babies reduce the energy requirements of their brains and can give hypoxia the proverbial `cold shoulder'!