The naked mole-rat (Heterocephalus glaber) is a burrowing rodent native to East Africa, famous for its large, protruding teeth, wrinkled naked skin, and many other peculiar physical characteristics. Moreover, naked mole-rats are eusocial mammals and, live in underground colonies. Thanks to natural selection, these animals have adapted their external and internal physiology to these harsh underground environments. Over the last decade, many of the strange physiological characteristics of this organism have been uncovered. In 2014, scientists from University of Cambridge Department of Pharmacology established the Naked Mole-Rat Initiative (NMRI) which brings together experts to identify molecular explanations for the naked mole-rat’s unusual physiology.
Naked Mole-Rats and Their Habitat
The naked-mole rat is eusocial, cold-blooded, cancer-resistant , and can live for over 30 years . An average of 75 to 80 individuals live together in complex underground systems in arid deserts of East Africa. These colonies can be three to five kilometers long . Just like any other well-known example of eusocial species such as ants, bees, and wasps, each colony has a queen, one to three males responsible for reproduction, and sterile workers who are committed to foraging and maintaining the colony. They generally feed on large tubers found underground, which can provide the whole colony with a long-term food source. Their sharp front teeth allow them not only to eat these plant roots but also to dig through the dirt when foraging. In fact, about 25% of a naked mole-rat’s muscle mass is in its jaws. Moreover, these animals also consume their own feces, because eating the once digested food allows greater absorption of nutrients . Just by looking at the basic characteristics of this species, one can see the effect of evolutionary pressure created by the harsh environment.
One of the distinct characteristics of the naked mole-rat’s habitat is low oxygen availability. The rodents exhale high levels of carbon dioxide which accumulate in the underground colonies due to poorly ventilated spaces. While the air humans normally inhale have carbon dioxide levels of less than 0.1%, naked mole-rats are able to live up to 10% carbon dioxide . This extreme carbon-dioxide-rich environment is considered to be the reason for two of the most significant physiological characteristics of the naked mole-rat: acid insensitivity and hypoxia resistance.
Because of their poor vision resulting from their small eyes, naked mole-rats must rely heavily on mechanical and thermal stimuli. However, they fail to perceive acid as a noxious stimulus. When Thomas Park, Ph.D and his colleagues at University of Illinois at Chicago injected the paws of unconscious naked mole-rats with acid and capsaicin, the rodents didn’t show any pain in either tests.. To explore this unusual resistance further, the researchers then used a modified cold sore virus to insert genes for Substance P into the foot of these rodents. Interestingly, the genetically modified mole-rats pulled their foot back to lick it when capsaicin was injected, suggesting that the DNA was able to restore its ability to perceive the burning sensation. However, the mole-rats remained completely insensitive to acids, even with the genes for Substance P, which indicates a major difference in the molecular mechanisms between their response to capsaicin and to acids .
Recently, a study by Dr. Ewan St. John Smith from the University of Cambridge Naked Mole-Rat Initiative (NMRI) identified the molecular basis of this unusual acid-induced nocifensive behavior . In most vertebrates, nociceptors express several ion channels that are modulated by proton concentration to produce depolarization. When this depolarization reaches the activation threshold of voltage-gated sodium channels, an action potential is initiated. The study showed that in naked-mole rats, there is a gene variant in the voltage-gated sodium channel subunit NaV1.7. Although the protons in the acid activate certain ion channels, they simultaneously block NaV1.7 which prevents the generation of an action potential. In other words, the variant enables the inhibitory effect to outweigh the excitatory effect, therefore abolishing acid nociception .
Due to the high-carbon dioxide, low-oxygen environments, the naked-mole rat’s metabolism has evolved to extreme hypoxia. In most mammals, even brief periods of oxygen deprivation can cause irreversible damage to the brain as it requires high levels of aerobic metabolism. This is because oxygen supply is indispensable for ATP production, which is necessary for the various neuronal functions including ion transport and neurotransmitter re-uptake. Without these functions, concentration gradients are significantly altered, leading to excitotoxic levels of neurotransmitters, which can trigger cell damage and death.
The neurons in a naked mole-rat’s brain can maintain synaptic transmission during both chronic and acute episodes of hypoxia. Researchers have studied the acute response of the mole-rat’s brain tissue using hippocampal slices in vitro, measuring oxygen sensitivity of synaptic transmission and using mice as the controls. Slices of the naked mole-rat and mice brains tolerated the replacement of half the oxygen in the provided atmosphere with nitrogen equally well. When the oxygen supply was further reduced, the mouse slice showed a much more rapid and severe decline in function than the mole-rat slice.
Furthermore, researchers decided to explore whether this hypoxia tolerance is resulting from the retention of juvenile characteristics into the adult period. They examined the expression of NMDA receptor subunits in the brains of neonatal and adult naked mole-rats and mice, as these receptors play an important role in hypoxia-induced excitotoxicity. The finding was that the adult naked mole-rat brain retains a significantly higher proportion of GluN2D subunit (66% of neonate) than the adult mouse brain (13% of neonate), suggesting arrested development of hypoxia-tolerant characteristics .
What It Tells Us
Research on these bizarre-looking creatures may seem irrelevant to human applications. Nevertheless, some researchers argue that these findings are beneficial for developing new strategies and targets for a wide variety of conditions including chronic pain. By looking at an animal that naturally lacks the acid-sensing mechanism, researchers can begin identifying what exactly the mechanism is. The Cambridge NMRI is currently working to develop a new therapeutic for particular conditions associated with tissue acidosis, such as rheumatoid arthritis. Moreover, examining how nervous systems have adapted to acute and chronic hypoxia can shed light on therapy for conditions such as stroke and epilepsy .
Photo by Meghan Murphy, Courtesy of Smithsonian’s National Zoological Park
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