No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

Abstract

Many vertebrates are challenged by either chronic or acute episodes of low oxygen availability in their natural environments. Brain function is especially vulnerable to the effects of hypoxia and can be irreversibly impaired by even brief periods of low oxygen supply. This review describes recent research on physiological mechanisms that have evolved in certain vertebrate species to cope with brain hypoxia. Four model systems are considered: freshwater turtles that can survive for months trapped in frozen-over lakes, arctic ground squirrels that respire at extremely low rates during winter hibernation, seals and whales that undertake breath-hold dives lasting minutes to hours, and naked mole-rats that live in crowded burrows completely underground for their entire lives. These species exhibit remarkable specializations of brain physiology that adapt them for acute or chronic episodes of hypoxia. These specializations may be reactive in nature, involving modifications to the catastrophic sequelae of oxygen deprivation that occur in non-tolerant species, or preparatory in nature, preventing the activation of those sequelae altogether. Better understanding of the mechanisms used by these hypoxiatolerant vertebrates will increase appreciation of how nervous systems are adapted for life in specific ecological niches as well as inform advances in therapy for neurological conditions such as stroke and epilepsy.KEY WORDS: Arctic ground squirrel, Cetacean, Hypoxia, Naked mole-rat, Seal, Turtle IntroductionEnvironmental conditions vary enormously for vertebrates, both with respect to the extreme conditions tolerated by a given species at different times and with respect to average living conditions tolerated by different species. Temperature is perhaps the most obvious example: from the poles to the equator, average ambient temperatures vary widely and have been accompanied by physiological adaptations appropriate to resident species; seasonal variations in temperature and resource variability can induce dramatic changes in physiological and/or behavioral patterns including migration and hibernation. Oxygen levels also vary widely, with animals adapted to sea level, high-altitude, underground and aquatic habitats. Oxygen levels can also change dramatically on a shorter-term basis, as can occur in tidal pools or in breath-hold divers. Approximately 20% of the oxygen consumed by the human body is used by the brain. The greater part of this oxygen is used to produce the ATP required to maintain the membrane potentials necessary for electrical signaling with synaptic and action potentials (Harris et al., 2012). In many vertebrates, including adult humans, interruption of the oxygen supply to the brain for more than a few minutes leads to irreversible neurological damage, including neuronal death. Without oxidative phosphorylation, ATP-dependent neuronal processes including ion transport and neurotransmitter reuptake decline sharply. Without pumping, ion gradients fail and neurons depolarize, releasing excessive levels...

Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism

“…First, various hibernating animal species developed mechanisms to cope with oxygen starvation, i.e. by depressing oxidative metabolism (often by lowering oxygen consumption by more than 50-fold) and by reducing protein synthesis and other energy-consuming processes (Fraisl et al, 2009; Larson et al, 2014). Second, in the mammalian brain, hypometabolism has been implicated in ischemic preconditioning by eliciting a hibernation-like phenomenon (Bernaudin et al, 2002; Dirnagl et al, 2003; Stenzel-Poore et al, 2003), even tough a direct contribution to neuroprotection in acute ischemic events remains outstanding.…”

Metabolic Flexibility: Hibernation, Torpor, and Estivation

“…For brain, a key to such resistance may be the blunting of excitotoxicity that normally occurs in ischemia (reviewed in ref. 171). Macromolecular damage by reactive oxygen species is also thought to cause damage during reperfusion.…”

High altitude cachexia: Adaptation instead of deterioration? (Comment on DOI 10.1002/bies.201400042)

“…From an evolutionary perspective, humans carry an ancient genetic heritage of many mechanisms, shared with other life forms, to cope with harsh environmental challenges [4]. For example, hypometabolism in conditions of hypoxia is frequent across phylogeny, though humans are an exception because of their near loss of this capacity, which is limited to deep meditative states, the reduction of thermogenesis during starvation and the human newborns' hypometabolic response to hypoxia [5].…”

“…Another example is the diving reflex that humans share with diving mammals such as the seal. Cardiovascular and metabolic adjustments enable seals to dive in apnoea for a staggering 2 h, during which arterial blood O 2 tension drops to 12-20 mmHg, lower than "the critical arterial O 2 tension" of 25-40 mmHg, at which impairments from limitations in ATP production are first seen in brains of non-diving mammals [4]. To be sure, human diving performance is less extreme, but it shares several of the underlying mechanisms [6].…”

“…Enzymatic adjustments enhance the potential for lipid catabolism by all organs including the brain, which can switch to a strong reliance on ketone bodies as fuel during hibernation [5]. The naked mole rat, which lives underground, to extraordinary ages, continuously exposed to hypercapnic hypoxia, is another interesting animal that copes extremely well with hypoxia [4].…”