Naked Mole-rat Brain Research Articles

CACNA1B protects naked mole-rat hippocampal neuron from apoptosis via altering the subcellular localization of Nrf2 after 60Co irradiation.

Although radiotherapy is the most effective treatment modality for brain tumors, it always injures the central nervous system, leading to potential sequelae such as cognitive dysfunction. Radiation induces molecular, cellular, and functional changes in neuronal and glial cells. The hippocampus plays a critical role in learning and memory; therefore, concerns about radiation-induced injury are widespread. Multiple studies have focused on this complex problem, but the results have not been fully elucidated. Naked mole rat brains were irradiated with 60Co at a dose of 10 Gy. On 7 days, 14 days, and 28 days after irradiation, hippocampi in the control groups were obtained for next-generation sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were subsequently performed. Venn diagrams revealed 580 differentially expressed genes (DEGs) that were common at different times after irradiation. GO and KEGG analyses revealed that the 580 common DEGs were enriched in molecular transducer activity. In particular, CACNA1B mediated regulatory effects after irradiation. CACNA1B expression increased significantly after irradiation. Downregulation of CACNA1B led to a reduction in apoptosis and reactive oxygen species levels in hippocampal neurons. This was due to the interaction between CACNA1B and Nrf2, which disturbed the normal nuclear localization of Nrf2. In addition, CACNA1B downregulation led to a decrease in the cognitive functions of naked mole rats. These findings reveal the pivotal role of CACNA1B in regulating radiation-induced brain injury and will lead to the development of a novel strategy to prevent brain injury after irradiation.

Sources of Reactive Oxygen Species in Normoxic and Hypoxic Naked Mole-Rat Brain

Oxygen availability dictates the rate of reactive oxygen species production from various cellular sources; excessive ROS accumulation can be cytotoxic. Mitochondria are usually the primary contributors to basal reactive oxygen species generation in the brain; however, xanthine oxidoreductase and nicotinamide adenine dinucleotide phosphate oxidase can also produce considerable reactive oxygen species during hypoxia/reoxygenation. In the brains of most mammals, cellular death accompanies hypoxia-mediated surges in reactive oxygen species production, but this is avoided in the cortex of hypoxia-tolerant naked mole-rats (Heterocephalus glaber). However, the contributions of various reactive oxygen species generators towards total reactive oxygen species homeostasis in naked mole-rat brain is unknown. We hypothesized that mitochondria remain the primary reactive oxygen species generators in naked mole-rat cortex and predicted that pharmacological inhibition of mitochondrial complex I would induce greater fluctuations in superoxide (O2•-) and hydrogen peroxide (H2O2) than inhibition of xanthine oxidoreductase or nicotinamide adenine dinucleotide phosphate oxidase. To test this, we used fluorescence microscopy to measure H2O2 and O2•- production from cortical slices during normoxia and hypoxia while pharmacologically inhibiting mitochondrial complex I, xanthine oxidoreductase, or nicotinamide adenine dinucleotide phosphate oxidase. Unexpectedly, we found xanthine oxidoreductase inhibition induced the greatest increase in O2•- during normoxia and hypoxia (~100% and 70%, respectively). Hypoxic inhibition of nicotinamide adenine dinucleotide phosphate oxidase induced the greatest decrease in H2O2 by ~35% below baseline. Finally, although inhibition of mitochondrial complex I during hypoxia yielded significant fluctuations in O2•- and H2O2, these changes were considerably smaller than fluctuations induced by inhibiting xanthine oxidoreductase or nicotinamide adenine dinucleotide phosphate oxidase. Together, and unlike in other rodent brain, our results suggest that xanthine oxidoreductase is the primary contributor to reactive oxygen species production in naked mole-rat cortex.

Enhanced mitochondrial buffering prevents Ca2+ overload in naked mole-rat brain.

Deleterious Ca2+ accumulation is central to hypoxic cell death in the brain of most mammals. Conversely, hypoxia-mediated increases in cytosolic Ca2+ are retarded in hypoxia-tolerant naked mole-rat brain. We hypothesized that naked mole-rat brain mitochondria have an enhanced capacity to buffer exogenous Ca2+ and examined Ca2+ handling in naked mole-rat cortical tissue. We report that naked mole-rat brain mitochondria buffer >2-fold more exogenous Ca2+ than mouse brain mitochondria, and that the half-maximal inhibitory concentration (IC50 ) at which Ca2+ inhibits aerobic oxidative phosphorylation is >2-fold higher in naked mole-rat brain. The primary driving force of Ca2+ uptake is the mitochondrial membrane potential (Δψm ), and the IC50 at which Ca2+ decreases Δψm is ∼4-fold higher in naked mole-rat than mouse brain. The ability of naked mole-rat brain mitochondria to safely retain large volumes of Ca2+ may be due to ultrastructural differences that support the uptake and physical storage of Ca2+ in mitochondria. Specifically, and relative to mouse brain, naked mole-rat brain mitochondria are larger and have higher crista density and increased physical interactions between adjacent mitochondrial membranes, all of which are associated with improved energetic homeostasis and Ca2+ management. We propose that excessive Ca2+ influx into naked mole-rat brain is buffered by physical storage in large mitochondria, which would reduce deleterious Ca2+ overload and may thus contribute to the hypoxia and ischaemia-tolerance of naked mole-rat brain. KEY POINTS: Unregulated Ca2+ influx is a hallmark of hypoxic brain death; however, hypoxia-mediated Ca2+ influx into naked mole-rat brain is markedly reduced relative to mice. This is important because naked mole-rat brain is robustly tolerant against in vitro hypoxia, and because Ca2+ is a key driver of hypoxic cell death in brain. We show that in hypoxic naked mole-rat brain, oxidative capacity and mitochondrial membrane integrity are better preserved following exogenous Ca2+ stress. This is due to mitochondrial buffering of exogenous Ca2+ and is driven by a mitochondrial membrane potential-dependant mechanism. The unique ultrastructure of naked mole-rat brain mitochondria, as a large physical storage space, may support increased Ca2+ buffering and thus hypoxia-tolerance.

Is NADPH Critical to Maintain Redox Homeostasis in Hypoxia-Tolerant Naked Mole-Rat Brain?

Nicotinamide adenine dinucleotide phosphate (NADPH) is a ubiquitous electron donor and a key reducing agent in numerous biochemical reactions. Among other important cellular roles, NADPH activity is central to the maintenance of redox homeostasis in eukaryotic cells. NADPH increases markedly during acute in vivo hypoxia in the brain of naked mole-rats, which are among the most hypoxia-tolerant mammals, and which do not exhibit imbalances in redox homeostasis or increased reactive oxygen species (ROS)-mediated damage during bouts of hypoxia-reoxygenation in brain. Conversely, NADPH does not increase in the brain of hypoxia-intolerant mice, which are prone to deleterious ROS bursts during perturbations in oxygen availability. Although the importance of NADPH in mediating ROS homeostasis has been demonstrated in the brain of other mammals, little is known about the source of NADPH changes in hypoxic naked mole-rat brain, nor about the mechanisms via which NADPH may provide neuroprotection in this species. Elucidating the underlying mechanisms that support the remarkably stable ROS profile in naked mole-rat brain may provide insight into novel mechanisms to ameliorate the deleterious impact of ROS bursts in the brains of hypoxia-intolerant mammals, such as occur during stroke and other diseases. In this review, we discuss what is known regarding the management of ROS and NADPH in naked mole-rat brain, examine potential cellular sources of NADPH that may underlie the large hypoxic increase in this molecule during acute hypoxic exposure, and propose experiments to advance our understanding of the role NADPH has in maintaining naked mole-rat brain redox balance. (First online: December 28, 2022)

Acute pH alterations do not impact cardiac mitochondrial respiration in naked mole-rats or mice

Energetically demanding conditions such as hypoxia and exercise favour anaerobic metabolism (glycolysis), which leads to acidification of the cellular milieu from ATP hydrolysis and accumulation of the anaerobic end-product, lactate. Cellular acidification may damage mitochondrial proteins and/or alter the H+ gradient across the mitochondrial inner membrane, which may in turn impact mitochondrial respiration and thus aerobic ATP production. Naked mole-rats are among the most hypoxia-tolerant mammals, and putatively experience intermittent environmental and systemic hypoxia while resting and exercising in their underground burrows. Previous studies in naked mole-rat brain, heart, and skeletal muscle mitochondria have demonstrated adaptations that favour improved efficiency in hypoxic conditions; however, the impact of cellular acidification on mitochondrial function has not been explored. We hypothesized that, relative to hypoxia-intolerant mice, naked mole-rat cardiac mitochondrial respiration is less sensitive to cellular pH changes. To test this, we used high-resolution respirometry to measure mitochondrial respiration by permeabilized cardiac muscle fibres from naked mole-rats and mice exposed in vitro to a pH range from 6.6 to 7.6. Surprisingly, we found that acute pH changes do not impact cardiac mitochondrial respiration or compromise mitochondrial integrity in either species. Our results suggest that acute alterations of cellular pH have minimal impact on cardiac mitochondrial respiration.

A novel neuroinflammation-responsive hydrogel based on mimicking naked mole rat brain microenvironment retards neurovascular dysfunction and cognitive decline in Alzheimer’s disease

Neuroinflammation is one of the major processes that trigger neuropathological amyloid-β (Aβ) deposition and contribute to Alzheimer’s disease (AD) progression. Naked mole rats, which are the longest living rodents and exhibit negligible senescence, have a special brain microenvironment characterized by high-molecular-mass hyaluronan (HMM-HA) and high levels of neuregulin 1 (NRG1), which are related to resistance to neuroinflammation and Aβ deposition, leading to protection from AD. Thus, mimicking the unique brain microenvironment of the naked mole rat as a strategy for AD treatment is of critical interest. Here, naked mole rat HMM-HA and NRG1 were used to establish an injectable neuroinflammation-responsive triglycerol monostearate (TM)-HA-NRG1 hydrogel to alter the brain microenvironment in the early to late stages of AD. Intracerebroventricular (ICV) delivery of the hydrogel resulted in significant mitigation of Aβ plaque formation and complement C1q deposition in the hippocampus. Interestingly, we found that C1q deposition on pericytes was probably associated with capillary dysfunction. Furthermore, continuous intervention obviously reduced C1q deposition on pericytes and improved the oxygen supply to the brain. Importantly, in 16-month-old AD mice, cognitive decline was significantly ameliorated after TM-HA-NRG1 hydrogel treatment. Thus, the work reported here provides a potential early intervention strategy for retarding later AD progression.

Metabolomic Analysis of Carbohydrate and Amino Acid Changes Induced by Hypoxia in Naked Mole-Rat Brain and Liver.

Hypoxia poses a major physiological challenge for mammals and has significant impacts on cellular and systemic metabolism. As with many other small rodents, naked mole-rats (NMRs; Heterocephalus glaber), who are among the most hypoxia-tolerant mammals, respond to hypoxia by supressing energy demand (i.e., through a reduction in metabolic rate mediated by a variety of cell- and tissue-level strategies), and altering metabolic fuel use to rely primarily on carbohydrates. However, little is known regarding specific metabolite changes that underlie these responses. We hypothesized that NMR tissues utilize multiple strategies in responding to acute hypoxia, including the modulation of signalling pathways to reduce anabolism and reprogram carbohydrate metabolism. To address this question, we evaluated changes of 64 metabolites in NMR brain and liver following in vivo hypoxia exposure (7% O2, 4 h). We also examined changes in matched tissues from similarly treated hypoxia-intolerant mice. We report that, following exposure to in vivo hypoxia: (1) phenylalanine, tyrosine and tryptophan anabolism are supressed both in NMR brain and liver; (2) carbohydrate metabolism is reprogramed in NMR brain and liver, but in a divergent manner; (3) redox state is significantly altered in NMR brain; and (4) the AMP/ATP ratio is elevated in liver. Overall, our results suggest that hypoxia induces significant metabolic remodelling in NMR brain and liver via alterations of multiple metabolic pathways.

Isolation and characterization of neural stem/progenitor cells in the subventricular zone of the naked mole-rat brain

BackgroundThe naked mole-rat (NMR) is the longest-lived rodent with a maximum lifespan of more than 37 years and shows a negligible senescence phenotype, suggesting that tissue stem cells of NMRs are highly capable of maintaining homeostasis. However, the properties of NMR tissue stem cells, including neural stem cells (NSCs), are largely unclear.MethodsNeural stem/progenitor cells (NS/PCs) were isolated from the subventricular zone of the neonate NMR brain (NMR-NS/PCs) and cultured in neurosphere and adherent culture conditions. Expression of NSC markers and markers of neurons, astrocytes, and oligodendrocytes was analyzed by immunocytochemistry. In adherent culture conditions, the proliferation rate and cell cycle of NMR-NS/PCs were assessed and compared with those of NS/PCs from mice (mouse-NS/PCs). The DNA damage response to γ-irradiation was analyzed by immunocytochemistry and reverse transcription-quantitative PCR.ResultsNMR-NS/PCs expressed several NSC markers and differentiated into neurons, astrocytes, and oligodendrocytes. NMR-NS/PCs proliferated markedly slower than mouse-NS/PCs, and a higher percentage of NMR-NS/PCs than mouse-NS/PCs was in G0/G1 phase. Notably, upon γ-irradiation, NMR-NS/PCs exhibited a faster initiation of the DNA damage response and were less prone to dying than mouse-NS/PCs.ConclusionsNMR-NS/PCs were successfully isolated and cultured. The slow proliferation of NMR-NS/PCs and their resistance to DNA damage may help to prevent stem cell exhaustion in the brain during the long lifespan of NMRs. Our findings provide novel insights into the mechanism underlying delayed aging of NMRs. Further analysis of NMR tissue stem cells may lead to the development of new strategies that can prevent aging in humans.

Na+/K+-ATPase activity is regionally regulated by acute hypoxia in naked mole-rat brain

Matching ATP supply and demand is key to neuronal hypoxia-tolerance and failure to achieve this balance leads to excitotoxic cell death in most adult mammalian brains. Ion pumping is the most energy-demanding process in the brain and some hypoxia-tolerant vertebrates coordinately down-regulate ion movement across neuronal membranes to reduce the workload of energy-expensive ion pumps, and particularly the Na+/K+-ATPase. Naked mole-rats are among the most hypoxia-tolerant mammals and achieve a hypometabolic state while maintaining brain [ATP] during severe hypoxia; however, whether ionic homeostasis is plastic in naked mole-rat brain is unknown. To examine this question, we exposed animals to 4 h of normoxia or moderate or severe hypoxia (11 or 3% O2, respectively) and measured changes in brain Na+/K+-ATPase activity. We found that 1) whole body metabolic rate decreased ∼25 and 75% in moderate and severe hypoxia, respectively, and 2) Na+/K+-ATPase activity decreased ∼50% in forebrain but increased 2-fold in cerebellum and was unchanged in brainstem. These results indicate that naked mole-rats acutely modulate brain energy demand in a region-specific manner to prioritize energy usage by the cerebellum. This may support exploration, navigation, and escape behaviours, while also enabling ATP savings when encountering hypoxia in nature.

Hypoxic naked mole-rat brains use microRNA to coordinate hypometabolic fuels and neuroprotective defenses.

Naked mole-rats are among the mammalian champions of hypoxia tolerance. They evolved adaptations centered around reducing metabolic rate to overcome the challenges experienced in their underground burrows. In this study, we used next-generation sequencing to investigate one of the factors likely supporting hypoxia tolerance in naked mole-rat brains, posttranscriptional microRNAs (miRNAs). Of the 212 conserved miRNAs identified using small RNA sequencing, 18 displayed significant differential expression during hypoxia. Bioinformatic enrichment revealed that hypoxia-mediated miRNAs were suppressing energy expensive processes including de novo protein translation and cellular proliferation. This suppression occurred alongside the activation of neuroprotective and neuroinflammatory pathways, and the induction of central signal transduction pathways including HIF-1α and NFκB via miR-335, miR-101, and miR-155. MiRNAs also coordinated anaerobic glycolytic fuel sources, where hypoxia-upregulated miR-365 likely suppressed protein levels of ketohexokinase, the enzyme responsible for catalyzing the first committed step of fructose catabolism. This was further supported by a hypoxia-mediated reduction in glucose transporter 5 proteins that import fructose into the cell. Yet, messenger RNA and protein levels of lactate dehydrogenase, which converts pyruvate to lactate in the absence of oxygen, were elevated during hypoxia. Together, this demonstrated the induction of anaerobic glycolysis despite a lack of reliance on fructose as the primary fuel source, suggesting that hypoxic brains are metabolically different than anoxic naked mole-rat brains that were previously found to shift to fructose-based glycolysis. Our findings contribute to the growing body of oxygen-responsive miRNAs "OxymiRs" that facilitate natural miRNA-mediated mechanisms for successful hypoxic exposures.

Naked mole rat brain mitochondria electron transport system flux and H+ leak are reduced during acute hypoxia.

Mitochondrial respiration and ATP production are compromised by hypoxia. Naked mole rats (NMRs) are among the most hypoxia-tolerant mammals and reduce metabolic rate in hypoxic environments; however, little is known regarding mitochondrial function during in vivo hypoxia exposure in this species. To address this knowledge gap, we asked whether the function of NMR brain mitochondria exhibits metabolic plasticity during acute hypoxia. Respirometry was utilized to assess whole-animal oxygen consumption rates and high-resolution respirometry was utilized to assess electron transport system (ETS) function in saponin-permeabilized NMR brain. We found that NMR whole-animal oxygen consumption rate reversibly decreased by ∼85% in acute hypoxia (4 h at 3% O2). Similarly, relative to untreated controls, permeabilized brain respiratory flux through the ETS was decreased by ∼90% in acutely hypoxic animals. Relative to carbonyl cyanide p-trifluoro-methoxyphenylhydrazone-uncoupled total ETS flux, this functional decrease was observed equally across all components of the ETS except for complex IV (cytochrome c oxidase), at which flux was further reduced, supporting a regulatory role for this enzyme during acute hypoxia. The maximum enzymatic capacities of ETS complexes I-V were not altered by acute hypoxia; however, the mitochondrial H+ gradient decreased in step with the decrease in ETS respiration. Taken together, our results indicate that NMR brain ETS flux and H+ leak are reduced in a balanced and regulated fashion during acute hypoxia. Changes in NMR mitochondrial metabolic plasticity mirror whole-animal metabolic responses to hypoxia.

Extended Postnatal Brain Development in the Longest-Lived Rodent: Prolonged Maintenance of Neotenous Traits in the Naked Mole-Rat Brain.

The naked mole-rat (NMR) is the longest-lived rodent with a maximum lifespan >31 years. Intriguingly, fully-grown naked mole-rats (NMRs) exhibit many traits typical of neonatal rodents. However, little is known about NMR growth and maturation, and we question whether sustained neotenous features when compared to mice, reflect an extended developmental period, commensurate with their exceptionally long life. We tracked development from birth to 3 years of age in the slowest maturing organ, the brain, by measuring mass, neural stem cell proliferation, axonal, and dendritic maturation, synaptogenesis and myelination. NMR brain maturation was compared to data from similar sized rodents, mice, and to that of long-lived mammals, humans, and non-human primates. We found that at birth, NMR brains are significantly more developed than mice, and rather are more similar to those of newborn primates, with clearly laminated hippocampi and myelinated white matter tracts. Despite this more mature brain at birth than mice, postnatal NMR brain maturation occurs at a far slower rate than mice, taking four-times longer than required for mice to fully complete brain development. At 4 months of age, NMR brains reach 90% of adult size with stable neuronal cytostructural protein expression whereas myelin protein expression does not plateau until 9 months of age in NMRs, and synaptic protein expression continues to change throughout the first 3 years of life. Intriguingly, NMR axonal composition is more similar to humans than mice whereby NMRs maintain expression of three-repeat (3R) tau even after brain growth is complete; mice experience an abrupt downregulation of 3R tau by postnatal day 8 which continues to diminish through 6 weeks of age. We have identified key ages in NMR cerebral development and suggest that the long-lived NMR may provide neurobiologists an exceptional model to study brain developmental processes that are compressed in common short-lived laboratory animal models.

Protracted brain development in a rodent model of extreme longevity.

Extreme longevity requires the continuous and large-scale adaptation of organ systems to delay senescence. Naked mole rats are the longest-living rodents, whose nervous system likely undergoes life-long adaptive reorganization. Nevertheless, neither the cellular organization of their cerebral cortex nor indices of structural neuronal plasticity along extreme time-scales have been established. We find that adult neurogenesis and neuronal migration are not unusual in naked mole rat brains. Instead, we show the prolonged expression of structural plasticity markers, many recognized as being developmentally controlled, and multi-year-long postnatal neuromorphogenesis and spatial synapse refinement in hippocampal and olfactory structures of the naked mole rat brain. Neurophysiological studies on identified hippocampal neurons demonstrated that morphological differentiation is disconnected from the control of excitability in all neuronal contingents regardless of their ability to self-renew. Overall, we conclude that naked mole rats show an extremely protracted period of brain maturation that may permit plasticity and resilience to neurodegenerative processes over their decades-long life span. This conclusion is consistent with the hypothesis that naked mole rats are neotenous, with retention of juvenile characteristics to permit survival in a hypoxic environment, with extreme longevity a consequence of greatly retarded development.

Blunted neuronal calcium response to hypoxia in naked mole-rat hippocampus.

Naked mole-rats are highly social and strictly subterranean rodents that live in large communal colonies in sealed and chronically oxygen-depleted burrows. Brain slices from naked mole-rats show extreme tolerance to hypoxia compared to slices from other mammals, as indicated by maintenance of synaptic transmission under more hypoxic conditions and three fold longer latency to anoxic depolarization. A key factor in determining whether or not the cellular response to hypoxia is reversible or leads to cell death may be the elevation of intracellular calcium concentration. In the present study, we used fluorescent imaging techniques to measure relative intracellular calcium changes in CA1 pyramidal cells of hippocampal slices during hypoxia. We found that calcium accumulation during hypoxia was significantly and substantially attenuated in slices from naked mole-rats compared to slices from laboratory mice. This was the case for both neonatal (postnatal day 6) and older (postnatal day 20) age groups. Furthermore, while both species demonstrated more calcium accumulation at older ages, the older naked mole-rats showed a smaller calcium accumulation response than even the younger mice. A blunted intracellular calcium response to hypoxia may contribute to the extreme hypoxia tolerance of naked mole-rat neurons. The results are discussed in terms of a general hypothesis that a very prolonged or arrested developmental process may allow adult naked mole-rat brain to retain the hypoxia tolerance normally only seen in neonatal mammals.

Buried Alive! Arrested Development and Hypoxia Tolerance in the Naked Mole-Rat

Event Abstract Back to Event Buried Alive! Arrested Development and Hypoxia Tolerance in the Naked Mole-Rat John Larson1*, Bethany L. Peterson2, Madeline Romano1 and Thomas J. Park2 1 University of Illinois at Chicago, Psychiatry, United States 2 University of Illinois at Chicago, Biological Sciences, United States Naked mole-rats are highly social subterranean rodents that live in large communal colonies in sealed and chronically oxygen-depleted burrows. In addition to systemic factors such as reduced metabolic rate, hypothermia, and high-affinity hemoglobin, we found that brain slices from adult naked mole-rats are also remarkably resistant to hypoxia. We hypothesized that extreme brain resistance to hypoxia may reflect an arrested state of brain development in which the well-known tolerance of neonatal brain tissue to hypoxia is retained into the adult state. Hippocampal slices from adult naked mole-rats manifest extreme tolerance to hypoxia in at least three ways, compared to other mammal species: synaptic transmission is maintained under more hypoxic conditions; anoxic depolarization time is delayed three times longer after total oxygen deprivation, and slices recover electrophysiological responsiveness after much longer period of anoxia. Since hypoxia tolerance is a characteristic of neonatal brains generally, we examined naked mole-rat brains for other neonatal characteristics potentially related to hypoxia tolerance. NMDA receptors in many brain areas show developmental changes in which GluN2B and GluN2D subunits decrease with maturation while GluN2A and GluN2C increase in abundance. We found that adult naked mole-rat brain retains more GluN2D into adulthood than do mice. GluN2D has also been linked to hypoxia tolerance in neonatal mice and rats, since channels containing this subunit exhibit decreased openings under low-oxygen conditions. A key factor in determining whether or not the cellular response to hypoxia is reversible or leads to cell death is the elevation of intracellular calcium concentration. Using calcium imaging methods, we found that calcium accumulation during hypoxia was significantly and substantially attenuated in slices from naked mole-rats compared to slices from laboratory mice. Both species demonstrated more calcium accumulation at older ages; however, the older naked mole-rats showed a smaller calcium response than even the neonatal mice. Finally, we measured the ATP content of hippocampal slices from adult mice and naked mole-rats before and during an episode of anoxia. Naked mole-rat slices had considerably higher resting levels of ATP than did mouse slices. These results are also consistent with the arrested development hypothesis since ATP levels in mouse are higher in the early postnatal period than in adulthood. During anoxia, ATP levels declined similarly in slices from mice and naked mole-rats. In summary, adult naked mole-rat brain exhibits a remarkable tolerance to hypoxia. Considering that brain is an important consumer of oxygen, we suggest that evolution in a chronically hypoxic environment may have resulted in an adaptation involving arrested brain development such that adult naked mole-rat brain maintains neonatal hypoxia tolerance into adulthood. Keywords: Anoxia, ATP, Calcium, fossorial, Hippocampus, NMDA Conference: Tenth International Congress of Neuroethology, College Park. Maryland USA, United States, 5 Aug - 10 Aug, 2012. Presentation Type: Invited Symposium (only for people who have been invited to a particular symposium) Topic: Cellular Properties Citation: Larson J, Peterson BL, Romano M and Park TJ (2012). Buried Alive! Arrested Development and Hypoxia Tolerance in the Naked Mole-Rat. Conference Abstract: Tenth International Congress of Neuroethology. doi: 10.3389/conf.fnbeh.2012.27.00047 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Apr 2012; Published Online: 07 Jul 2012. * Correspondence: Prof. John Larson, University of Illinois at Chicago, Psychiatry, Chicago, IL, 60612, United States, jrlarson@uic.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers John Larson Bethany L Peterson Madeline Romano Thomas J Park Google John Larson Bethany L Peterson Madeline Romano Thomas J Park Google Scholar John Larson Bethany L Peterson Madeline Romano Thomas J Park PubMed John Larson Bethany L Peterson Madeline Romano Thomas J Park Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Blunted Neuronal Calcium Response to Hypoxia in Naked Mole-Rat Hippocampus

Event Abstract Back to Event Blunted Neuronal Calcium Response to Hypoxia in Naked Mole-Rat Hippocampus Bethany Peterson1, Thomas Park1* and John Larson2 1 University of Illinois at Chicago, Biological Sciences, United States 2 University of Illinois at Chicago, Psychiatry, United States Naked mole-rats are highly social subterranean rodents that live in large communal colonies in sealed and chronically oxygen-depleted burrows. Brain slices from naked mole-rats show extreme tolerance to hypoxia compared to slices from other mammals, as indicated by maintenance of synaptic transmission under more hypoxic conditions, and three-fold longer latency to anoxic depolarization. A key factor in determining whether or not the cellular response to hypoxia is reversible or leads to cell death is the elevation of intracellular calcium concentration. In the present study, we used fluorescent imaging techniques to measure intracellular calcium accumulation in CA1 pyramidal cells of hippocampal slices during hypoxia. We found that calcium accumulation during hypoxia was significantly and substantially attenuated in slices from naked mole-rats compared to slices from laboratory mice. This was the case for both neonatal (P6) and older (P20) age groups. Furthermore, while both species demonstrated more calcium accumulation at older ages, the older naked mole-rats showed a smaller calcium response than even the neonatal mice. The attenuation of the calcium response in naked mole-rat hippocampus appears to be specifically related to hypoxia tolerance since the calcium response to potassium depolarization was much more similar for naked mole-rats and mice (no significant difference at P20). The data suggest that blunted intracellular calcium response to hypoxia contributes to the extreme hypoxia tolerance of naked mole-rat neurons. The results are discussed in terms of a general hypothesis that a very prolonged or arrested developmental process may allow adult naked mole-rat brain to retain the hypoxia tolerance normally only seen in neonatal mammals. Keywords: Calcium, hypoxia, mole-rat, NMDA Conference: Tenth International Congress of Neuroethology, College Park. Maryland USA, United States, 5 Aug - 10 Aug, 2012. Presentation Type: Poster (but consider for student poster award) Topic: Cellular Properties Citation: Peterson B, Park T and Larson J (2012). Blunted Neuronal Calcium Response to Hypoxia in Naked Mole-Rat Hippocampus. Conference Abstract: Tenth International Congress of Neuroethology. doi: 10.3389/conf.fnbeh.2012.27.00094 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 20 Apr 2012; Published Online: 07 Jul 2012. * Correspondence: Prof. Thomas Park, University of Illinois at Chicago, Biological Sciences, Chicago, IL, 60607, United States, tpark@uic.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Bethany Peterson Thomas Park John Larson Google Bethany Peterson Thomas Park John Larson Google Scholar Bethany Peterson Thomas Park John Larson PubMed Bethany Peterson Thomas Park John Larson Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Adult naked mole-rat brain retains the NMDA receptor subunit GluN2D associated with hypoxia tolerance in neonatal mammals

Adult naked mole-rats show a number of systemic adaptations to a crowded underground habitat that is low in oxygen and high in carbon dioxide. Remarkably, brain slice tissue from adult naked mole-rats also is extremely tolerant to oxygen deprivation as indicated by maintenance of synaptic transmission under hypoxic conditions as well as by a delayed neuronal depolarization during anoxia. These characteristics resemble hypoxia tolerance in brain slices from neonates in a variety of mammal species. An important component of neonatal tolerance to hypoxia involves the subunit composition of NMDA receptors. Neonates have a high proportion of NMDA receptors with GluN2D subunits which are protective because they retard calcium entry into neurons during hypoxic episodes. Therefore, we hypothesized that adult naked mole-rats retain a protective, neonatal-like, NMDA receptor subunit profile. We used immunoblotting to assess age-related changes in NMDA receptor subunits in naked mole-rats and mice. The results show that adult naked mole-rat brain retains a much greater proportion of the hypoxia-protective GluN2D subunit compared to adult mice. However, age-related changes in other subunits (GluN2A and GluN2B) from the neonatal period to adulthood were comparable in mice and naked mole-rats. Hence, adult naked mole-rat brain only retains the neonatal NMDA receptor subunit that is associated with hypoxia tolerance.

Comments on Point:Counterpoint: High altitude is/is not for the birds!

TO THE EDITOR: The debate between Scott et al. (6) and Llanos et al. (4) highlights the remarkable ability of birds and mammals to adapt and survive at high altitudes and cope with reduced oxygen (O2) availability. Scott and colleagues (6) make a compelling argument that birds are far superior to mammals at adapting and thriving in hypoxic environments, both at rest and during exercise. While their argument is supported by comparisons between birds and terrestrial mammals, it ignores marine mammals. Marine mammals such as seals are routinely exposed to and tolerate long bouts of hypoxia during breath-hold diving. For example, elephant seals may dive to depths of nearly 1,600 m and occasionally remain submerged for 2 h (3). Moreover, marine mammals can be exposed to partial pressures of arterial oxygen (PaO2) as low as 12 mmHg during free dives (5), which is less than the 20 mmHg observed in the bar-headed goose (6). Interestingly, a PaO2 of 12 mmHg observed in elephant seals corresponds to arterial saturations and O2 content of only 8% and 2.7 ml O2/dl (5). Thus marine mammals such as the elephant seal demonstrate a remarkable hypoxia tolerance. The integration of several key physiological adaptations including 1) substantially greater myoglobin concentrations compared to other mammals, 2) reductions in metabolism, 3) a greater reliance on aerobic metabolism (i.e., less lactate production), 4) a host of dramatic acute cardiovascular adjustments; and 5) an increased intrinsic cerebral hypoxia tolerance allow marine mammals to thrive in hypoxic environments and enable long deep dives (1–3).

Expression pattern of cadherins in the naked mole rat (Heterocephalus glaber) suggests innate cortical diversification of the cerebrum

The cerebral cortex is an indispensable region for higher cognitive function that is remarkably diverse among mammalian species. Although previous research has shown that the cortical area map in the mammalian cerebral cortex is formed by innate and activity-dependent mechanisms, it remains unknown how these mechanisms contribute to the evolution and diversification of the functional cortical areas in various species. The naked mole rat (Heterocephalus glaber) is a subterranean, eusocial rodent. Physiological and anatomical studies have revealed that the visual system is regressed and the somatosensory system is enlarged. To examine whether species differences in cortical area development are caused by intrinsic factors or environmental factors, we performed comparative gene expression analysis of neonatal naked mole rat and mouse brains. The expression domain of cadherin-6, a somatosensory marker, was expanded caudally and shifted dorsally in the cortex, whereas the expression domain of cadherin-8, a visual marker, was reduced caudally in the neonatal naked mole rat cortex. The expression domain of cadherin-8 was also reduced in other visual areas, such as the lateral geniculate nucleus and superior colliculus. Immunohistochemical analysis of thalamocortical fibers further suggested that somatosensory input did not affect cortical gene expression in the neonatal naked mole rat brain. These results suggest that the development of the somatosensory system and the regression of the visual system in the naked mole rat cortex are due to intrinsic genetic mechanisms as well as sensory input-dependent mechanisms. Intrinsic genetic mechanisms thus appear to contribute to species diversity in cortical area formation.

Extreme hypoxia tolerance of naked mole-rat brain

Mammalian brains have extremely high levels of aerobic metabolism and typically suffer irreversible damage after brief periods of oxygen deprivation such as occur during stroke or cardiac arrest. Here we report that brain tissue from naked mole-rats, rodents that live in a chronically low-oxygen environment, is remarkably resistant to hypoxia: naked mole-rat neurons maintain synaptic transmission much longer than mouse neurons and can recover from periods of anoxia exceeding 30 min. We suggest that brain tolerance to hypoxia may result from slowed or arrested brain development in these extremely long-lived animals.