Primate hibernation: The past, present, and promise of captive dwarf lemurs.

The dwarf lemurs (Cheirogaleus spp.) of Madagascar are the only obligate hibernators among primates. Despite century-old field accounts of seasonal lethargy, and more recent evidence of hibernation in the western fat-tailed dwarf lemur (Cheirogaleus medius), inducing hibernation in captivity remained elusive for decades. This included the Duke Lemur Center (DLC), which maintains fat-tailed dwarf lemurs and has produced sporadic research on reproduction and metabolism. With cumulative knowledge from the field, a newly robust colony, and better infrastructure, we recently induced hibernation in DLC dwarf lemurs. We describe two follow-up experiments in subsequent years. First, we show that dwarf lemurs under stable cold conditions (13°C) with available food continued to eat daily, expressed shallower and shorter torpor bouts, and had a modified gut microbiome compared to peers without food. Second, we demonstrate that dwarf lemurs under fluctuating temperatures (12-30°C) can passively rewarm daily, which was associated with altered patterns of fat depletion and reduced oxidative stress. Despite the limitations of working with endangered primates, we highlight the promise of studying hibernation in captive dwarf lemurs. Follow-up studies on genomics and epigenetics, metabolism, and endocrinology could have relevance across multidisciplinary fields, from biomedicine to evolutionary biology, and conservation.

Heart rate monitoring reveals differential seasonal energetic trade-offs in male noctule bats.

Understanding how animals meet their daily energy requirements is critical in our rapidly changing world. Small organisms with high metabolic rates can conserve stored energy when food availability is low or increase energy intake when energetic requirements are high, but how they balance this in the wild remains largely unknown. Using miniaturized heart rate transmitters, we continuously quantified energy expenditure, torpor use and foraging behaviour of free-ranging male bats (Nyctalus noctula) in spring and summer. In spring, bats used torpor extensively, characterized by lowered heart rates and consequently low energy expenditures. In contrast, in summer, bats consistently avoided torpor, even though they could have used this low-energy mode. As a consequence, daytime heart rates in summer were three times as high compared with the heart rates in spring. Daily energy use increased by 42% during summer, despite lower thermogenesis costs at higher ambient temperatures. Likely, as a consequence, bats nearly doubled their foraging duration. Overall, our results indicate that summer torpor avoidance, beneficial for sperm production and self-maintenance, comes with a high energetic cost. The ability to identify and monitor such vulnerable energetic life-history stages is particularly important to predict how species will deal with increasing temperatures and changes in their resource landscapes.

Torpor use in the wild by one of the world's largest bats.

Torpor is widespread among bats presumably because most species are small, and torpor greatly reduces their high mass-specific resting energy expenditure, especially in the cold. Torpor has not been recorded in any bat species larger than 50 g, yet in theory could be beneficial even in the world's largest bats (flying-foxes; Pteropus spp.) that are exposed to adverse environmental conditions causing energy bottlenecks. We used temperature telemetry to measure body temperature in wild-living adult male grey-headed flying-foxes (P. poliocephalus; 799 g) during winter in southern Australia. We found that all individuals used torpor while day-roosting, with minimum body temperature reaching 27°C. Torpor was recorded following a period of cool, wet and windy weather, and on a day with the coldest maximum air temperature, suggesting it is an adaptation to reduce energy expenditure during periods of increased thermoregulatory costs and depleted body energy stores. A capacity for torpor among flying-foxes has implications for understanding their distribution, behavioural ecology and life history. Furthermore, our discovery increases the body mass of bats known to use torpor by more than tenfold and extends the documented use of this energy-saving strategy under wild conditions to all bat superfamilies, with implications for the evolutionary maintenance of torpor among bats and other mammals.

Invasive shrubs differentially alter autumnal activity for three common small-mammal species.

Seasonal variation in animal activity influences fitness and the intensity of ecological interactions (e.g., competition, predation), yet aspects of global change in the Anthropocene may catalyze shifts in seasonal activity. Invasive plants are components of global change and can modify animal daily activity, but their influence on animal seasonal activity is less understood. We examined how invasive woody shrubs (Autumn olive [Elaeagnus umbellata] and Amur honeysuckle [Lonicera maackii]) affect seasonal activity of three common small-mammal species by coupling experimental shrub removal with autumnal camera trapping for two consecutive years at six paired forest sites (total 12 plots). Eastern chipmunks (Tamias striatus) foraged more, and foraging was observed at least 20 days longer, in shrub-invaded forests. White-footed mice (Peromyscus leucopus) foraged more in invaded than cleared plots in one study year, but P. leucopus autumn activity timing did not differ between shrub-removal treatments. Fox squirrel (Sciurus niger) activity displayed year-specific responses to shrub removal suggesting intraannual cues (e.g., temperature) structure S. niger autumnal activity. Our work highlights how plant invasions can have species-specific effects on seasonal animal activity, may modify the timing of physiological processes (e.g., torpor), and could generate variation in animal-mediated interactions such as seed dispersal or granivory.

Hibernacula of bats in Mexico, the southernmost records of hibernation in North America.

Although Mexico holds the southernmost hibernating bats in North America, information on winter behavior and hibernacula microclimate use of temperate Mexican bats is limited. We studied hibernating bats at high altitudes (>1,000 m a.s.l.) in northern and central Mexico during 5 consecutive winters. Our aims were to document and describe the hibernacula, winter behavior (such as abundance and roost pattern), and microclimates (estimated as adjacent substrate temperature) of cave-hibernating bats in Mexico. We found 78 hibernacula and 6,089 torpid bats of 10 vespertilionid species, increasing by over 50% the number of cave-hibernating bat species and quadrupling the number of hibernacula for Mexico. Hibernacula were at altitudes between 1,049 and 3,633 m a.s.l., located in 3 mountain ranges, mainly in oak and conifer forests. Myotis velifer was the most common species, followed by Corynorhinus townsendii and C. mexicanus. We recorded the adjacent substrate temperatures from 9 species totaling 1,106 torpid bats and found differences in microclimate use among the 3 most common species. In general, abundance of torpid bats in our region of study was similar to those in the western United States, with aggregations of tens to a few hundred individuals per cave, and was lower than in the eastern United States where a cave may hold thousands of individuals. Knowledge of bat hibernation is crucial for developing conservation and management strategies on current conditions while accommodating environmental changes and other threats such as emerging diseases.

Aunque México tiene los murciélagos hibernantes más sureños en Norteamérica, la información sobre el comportamiento invernal y el uso de microclimas en los refugios de hibernación de los murciélagos templados mexicanos es limitada. Estudiamos a los murciélagos hibernantes en altitudes altas (>1000 msnm) en el norte y centro de México durante cinco inviernos consecutivos. Nuestros objetivos fueron documentar y describir las cuevas de hibernación, el comportamiento invernal (como la abundancia y patrón de percha), y el uso de microclimas (estimado como la temperatura del sustrato adyacente), de los murciélagos que hibernan en cuevas en México. Encontramos 78 cuevas de hibernación con 6089 murciélagos en torpor de 10 especies de vespertiliónidos, incrementando en más del 50% el número de especies de murciélagos que hibernan en cuevas y cuadriplicando el número de cuevas de hibernación para México. Las cuevas de hibernación estuvieron en elevaciones entre 1049 y 3633 msnm, localizadas en tres cadenas montañosas, principalmente en bosques de encinos y coníferas. Myotis velifer fue la especie más común, seguida por Corynorhinus townsendii y C. mexicanus. Reportamos las temperaturas del sustrato adyacente de 1106 murciélagos en torpor de nueve especies y encontramos diferencias en el uso de microclimas entre las tres especies más comunes. Aquí proveemos información relevante para especies de murciélagos templados en la ocurrencia más sureña de hibernación de murciélagos en Norteamérica. En general, la abundancia de murciélagos en torpor que encontramos fue similar a las del oeste de Estados Unidos, con agregaciones de decenas y algunos cientos de individuos por cueva; y fue menor que las del este de Estados Unidos, donde las cuevas pueden albergar miles de murciélagos. El conocimiento de la hibernación de murciélagos es crucial para el desarrollo de estrategias de conservación y manejo adecuadas en la actualidad y mientras se adaptan a los cambios ambientales y a otras amenazas tales como las enfermedades emergentes.

Hibernation nest site selection but not overwinter activity is associated with microclimatic conditions in a hibernating mammal.

Fine-scale variation in microclimates between habitats may impact energy consumption for the organisms that inhabit them. This may be particularly important for sedentary species or those unable to change habitats for long periods, such as hibernators. Low ambient temperatures were traditionally thought key to microclimatic selection for hibernation locations, but recent research suggests that other factors may contribute or exceed ambient temperature in importance. We aimed to characterise microclimates at hibernacula of wild hibernating hazel dormice Muscardinus avellanarius, and test how these microclimates differ to those at locations without hibernacula using a microclimatic modelling approach. Dormice hibernated in areas with warmer soil temperatures and lower variability in humidity and relative shortwave radiation. These results add to the growing body of evidence that low ambient temperatures may not be the primary driver of hibernation microclimate selection, although temperature is still likely to play an important role. We also found that ambient temperatures measured at the microclimatic level were substantially buffered compared to point samples taken at the nearest weather station (∼1.6 km away), highlighting the importance of considering microclimates in wildlife conservation in the face of future environmental change.

Predation can shape the cascade interplay between heterothermy, exploration and maintenance metabolism under high food availability.

Maintenance metabolism as the minimum energy expenditure needed to maintain homeothermy (a high and stable body temperature, T b), reflects the magnitude of metabolic machinery and the associated costs of self-maintenance in endotherms (organisms able to produce heat endogenously). Therefore, it can interact with most, if not all, organismal functions, including the behavior-fitness linkage. Many endothermic animals can avoid the costs of maintaining homeothermy and temporally reduce T b and metabolism by entering heterothermic states like torpor, the most effective energy-saving strategy. Variations in BMR, behavior, and torpor use are considered to be shaped by food resources, but those conclusions are based on research studying these traits in isolation. We tested the effect of ecological contexts (food availability and predation risk) on the interplay between the maintenance costs of homeothermy, heterothermy, and exploration in a wild mammal-the yellow-necked mouse. We measured maintenance metabolism as basal metabolic rate (BMR) using respirometry, distance moved (exploration) in the open-field test, and variation in T b (heterothermy) during short-term fasting in animals captured at different locations of known natural food availability and predator presence, and with or without supplementary food resources. We found that in winter, heterothermy and exploration (but not BMR) negatively correlated with natural food availability (determined in autumn). Supplementary feeding increased mouse density, predation risk and finally had a positive effect on heterothermy (but not on BMR or exploration). The path analysis testing plausible causal relationships between the studied traits indicated that elevated predation risk increased heterothermy, which in turn negatively affected exploration, which positively correlated with BMR. Our study indicates that adaptive heterothermy is a compensation strategy for balancing the energy budget in endothermic animals experiencing low natural food availability. This study also suggests that under environmental challenges like increased predation risk, the use of an effective energy-saving strategy predicts behavioral expression better than self-maintenance costs under homeothermy.

Regional Intraspecific Differences of Thermal Biology in a Marsupial Hibernator.

AbstractDuring periods of torpor, hibernators can reduce metabolic rate (MR) and body temperature (Tb) substantially. However, to avoid physiological dysfunction at low temperatures, they defend Tb at a critical minimum, often between ~0°C and 10°C via an increase in MR. Because thermoregulation during torpor requires extra energy, individuals with lower Tb's and thus minimal MR during torpor should be selected in colder climates. Such inter- and intraspecific variations occur in some placental mammals, but for the evolutionary separate marsupials, available information is scarce. Marsupial eastern pygmy possums (Cercartetus nanus; ~22 g body mass), widely distributed along the Australian southeastern coast including subtropical to alpine areas, were used to test the hypothesis that the defended Tb of torpid individuals is related to the climate of their habitat. Possums were captured from five regions, 1,515 km apart, with midwinter (July) minimum environmental temperatures (min Tenv's) ranging from -3.9°C to 6.6°C. Captive possums in deep torpor were slowly cooled with ambient temperature (Ta), while their MR was measured to determine the minimum torpor metabolic rate (TMR), the Ta at which their MR increased for thermoregulation (min Ta), and the corresponding minimum Tb (min Tb). Partial least squares regression analysis revealed that Ta and Tenv were the strongest explanatory variables for the min Tb. The min Tb and Ta were also correlated with latitude but not elevation of the capture sites. However, the best correlations were observed between the min Tenv and the min Tb and Ta for individuals experiencing min Tenv>0°C; these individuals thermoconformed to min Ta's between -0.8°C and 3.7°C, and their min Tb ranged from 0.5°C to 6.0°C and was 0.5°C-2.6°C below the min Tenv at the capture site. In contrast, individuals experiencing a min Tenv of -3.9°C regulated Tb at 0.6°C±0.2°C or 4.5°C above the Tenv. The minimum TMR of all possums did not differ with Ta and thus did not differ among populations and was 2.6% of the basal MR. These data provide new evidence that thermal variables of marsupials are subject to regional intraspecific variation. It suggests that min Tb is a function of the min Tenv but only above 0°C, perhaps because the Tb-Ta differential for torpid possums in the wild, at a min Tenv of -3.9°C, remains small enough to be compensated by a small increase in MR and does not require the physiological capability for a reduction of Tb below 0°C.

Torpor induces reversible tau hyperphosphorylation and accumulation in mice expressing human tau.

Tau protein hyperphosphorylation and aggregation are key pathological events in neurodegenerative tauopathies such as Alzheimer's disease. Interestingly, seasonal hibernators show extensive tau hyperphosphorylation during torpor, i.e., the hypothermic and hypometabolic state of hibernation, which is completely reversed during arousal. Torpor-associated mechanisms that reverse tau hyperphosphorylation may be of therapeutic relevance, however, it is currently not known to what extent they apply to human tau. Here we addressed this issue using daily torpor in wildtype mice that express mouse tau (mtau) and in mice that lack mtau expression and instead express human tau (htau). AT8, AT100 and Ser396 immunoblotting and immunohistochemistry were used to assess tau (hyper)phosphorylation at clinically relevant phosphorylation sites. We found that torpor robustly and reversibly increases the levels of phosphorylated tau in both mtau and htau mice. Immunohistochemistry revealed four brain areas that show prominent tau phosphorylation: the hippocampus, posterior parietal cortex, piriform cortex and cortical amygdala. Whereas wildtype mice primarily showed increased levels of diffusely organized hyperphosphorylated tau during torpor, htau mice contained clear somato-dendritic accumulations of AT8 reactivity resembling tau pre-tangles as observed in the Alzheimer brain. Interestingly, AT8-positive accumulations disappeared upon arousal, and tau phosphorylation levels at 24 h after arousal were lower than observed at baseline, suggesting a beneficial effect of torpor-arousal cycles on preexisting hyperphosphorylated tau. In conclusion, daily torpor in mice offers a quick and standardized method to study tau phosphorylation, accumulation and clearance in mouse models relevant for neurodegeneration, as well as opportunities to discover new targets for the treatment of human tauopathies.

Identification of hypothermia-inducing neurons in the preoptic area and activation of them by isoflurane anesthesia and central injection of adenosine.

Hibernation and torpor are not passive responses caused by external temperature drops and fasting but are active brain functions that lower body temperature. A population of neurons in the preoptic area was recently identified as such active torpor-regulating neurons. We hypothesized that the other hypothermia-inducing maneuvers would also activate these neurons. To test our hypothesis, we first refined the previous observations, examined the brain regions explicitly activated during the falling phase of body temperature using c-Fos expression, and confirmed the preoptic area. Next, we observed long-lasting hypothermia by reactivating torpor-tagged Gq-expressing neurons using the activity tagging and DREADD systems. Finally, we found that about 40-60% of torpor-tagged neurons were activated by succeeding isoflurane anesthesia and by icv administration of an adenosine A1 agonist. Isoflurane-induced and central adenosine-induced hypothermia is, at least in part, an active process mediated by the torpor-regulating neurons in the preoptic area.

Mitochondrial microRNA profiles are altered in thirteen-lined ground squirrels (Ictidomys tridecemlineatus) during hibernation.

Thirteen-lined ground squirrels (TLGSs) are obligate hibernators that cycle between torpor (low metabolic rate and body temperature) and interbout euthermia (IBE; typical euthermic body temperature and metabolism) from late autumn to spring. Many physiological changes occur throughout hibernation, including a reduction in liver mitochondrial metabolism during torpor, which is reversed during arousal to interbout euthermia. Nuclear-encoded microRNA (miRNA, small posttranscriptional regulator molecules) differ in abundance throughout TLGS hibernation and have been shown to regulate mitochondrial gene expression in mammalian cell culture (where they are referred to as mitomiRs). This study characterized differences in mitomiR profiles from TLGS liver mitochondria isolated during summer, torpor, and IBE, and predicted their mitochondrial targets. Using small RNA sequencing, differentially abundant mitomiRs were identified between hibernation states, and using quantitative PCR analysis, we quantified the expression of predicted mitochondrial mRNA targets. Most differences in mitomiR abundances were seasonal (i.e., between summer and winter) with only one mitomiR differentially abundant between IBE and torpor. Multiple factor analysis (MFA) revealed three clusters divided by hibernation states, where clustering was predominantly driven by mitomiR abundances. Nine of these differentially abundant mitomiRs had predicted mitochondrial RNA targets, including subunits of electron transfer system complexes I and IV, 12S rRNA, and two tRNAs. Overall, mitomiRs were predicted to suppress the expression of their mitochondrial targets and may have some involvement in regulating protein translation in mitochondria. This study found differences in mitomiR abundances between seasons and hibernation states of TLGS and suggests potential mechanisms for regulating the mitochondrial electron transfer system.NEW & NOTEWORTHY During the hibernation season, thirteen-lined ground squirrels periodically increase metabolism remarkably between torpor and interbout euthermia (IBE). This process involves rapid reactivation of mitochondrial respiration. We predicted that mitochondrial microRNA (mitomiRs) might be altered during this response. We found that the abundance of 38 liver mitomiRs differs based on hibernation state (summer, IBE, and torpor). Small RNA sequencing identified mitomiR profiles, including some mitomiRs that are predicted to bind to mitochondrial RNAs.

Ultrasonic vocalisation rate tracks the diurnal pattern of activity in winter phenotype Djungarian hamsters (Phodopus sungorus).

Vocalisations are increasingly being recognised as an important aspect of normal rodent behaviour yet little is known of how they interact with other spontaneous behaviours such as sleep and torpor, particularly in a social setting. We obtained chronic recordings of the vocal behaviour of adult male and female Djungarian hamsters (Phodopus sungorus) housed under short photoperiod (8 h light, 16 h dark, square wave transitions), in different social contexts. The animals were kept in isolation or in same-sex sibling pairs, separated by a grid which allowed non-physical social interaction. On approximately 20% of days hamsters spontaneously entered torpor, a state of metabolic depression that coincides with the rest phase of many small mammal species in response to actual or predicted energy shortages. Animals produced ultrasonic vocalisations (USVs) with a peak frequency of 57 kHz in both social and asocial conditions and there was a high degree of variability in vocalisation rate between subjects. Vocalisation rate was correlated with locomotor activity across the 24-h light cycle, occurring more frequently during the dark period when the hamsters were more active and peaking around light transitions. Solitary-housed animals did not vocalise whilst torpid and animals remained in torpor despite overlapping with vocalisations in social-housing. Besides a minor decrease in peak USV frequency when isolated hamsters were re-paired with their siblings, changing social contexts did not influence vocalisation behaviour or structure. In rare instances, temporally overlapping USVs occurred when animals were socially-housed and were grouped in such a way that could indicate coordination. We did not observe broadband calls (BBCs) contemporaneous with USVs in this paradigm, corroborating their correlation with physical aggression which was absent from our experiment. Overall, we find little evidence to suggest a direct social function of hamster USVs. We conclude that understanding the effects of vocalisations on spontaneous behaviours, such as sleep and torpor, will inform experimental design of future studies, especially where the role of social interactions is investigated.

Changes in microRNA expression related to ischemia-reperfusion injury in the kidney of the thirteen-lined ground squirrel during torpor.

During the hibernation season, the thirteen-lined ground squirrel undergoes cyclical torpor and arousal periods. The decrease and restoration of metabolic rate and oxygen delivery during torpor and arousal, respectively, may cause reperfusion-ischemia injury in the kidneys. In order to maintain the structural integrity of the kidneys necessary for renal function resumption during arousal, the thirteen-lined ground squirrel has developed adaptive methods to prevent and repair kidney injury. In this present study, computational methods were used to clean and analyze sequenced kidney RNA samples. Significantly differentially expressed microRNAs and enriched gene sets were also determined. From the gene set analysis, the results showed an increase in ubiquitin-related processes and p53 signaling pathways which suggested the occurrence of kidney damage during torpor. There was also an observed increase in cell cycle processes and the anchoring junction cellular compartment which may lend to the prevention of kidney injury. From the differentially expressed microRNAs, miR-27a (log2FC = 1.639; p-value = 0.023), miR-129 (log2FC = 2.516; p-value = 0.023), miR-let-7b (log2FC = 2.360; p-value = 0.025), miR-let-7c (log2FC = 2.291; p-value = 0.037) and miR-let-7i (log2FC = 1.564; p-value = 0.039) were found to be significantly upregulated. These biochemical adaptations may allow the thirteen-lined ground squirrel to maintain kidney structure and function during hibernation.

Cold resistance of mammalian hibernators ∼ a matter of ferroptosis?

Most mammals adapt thermal physiology around 37°C and large deviations from their range, as observed in severe hypothermia and hyperthermia, resulting in organ dysfunction and individual death. A prominent exception is mammalian hibernation. Mammalian hibernators resist the long-term duration of severe low body temperature that is lethal to non-hibernators, including humans and mice. This cold resistance is supported, at least in part, by intrinsic cellular properties, since primary or immortalized cells from several hibernator species can survive longer than those from non-hibernators when cultured at cold temperatures. Recent studies have suggested that cold-induced cell death fulfills the hallmarks of ferroptosis, a type of necrotic cell death that accompanies extensive lipid peroxidation by iron-ion-mediated reactions. In this review, we summarize the current knowledge of cold resistance of mammalian hibernators at the cellular and molecular levels to organ and systemic levels and discuss key pathways that confer cold resistance in mammals.

Hippocampal neuroimmune response in mice undergoing serial daily torpor induced by calorie restriction.

Hibernating animals demonstrate a remarkable ability to withstand extreme physiological brain changes without triggering adverse neuroinflammatory responses. While hibernators may offer valuable insights into the neuroprotective mechanisms inherent to hibernation, studies using such species are constrained by the limited availability of molecular tools. Laboratory mice may serve as an alternative, entering states of hypometabolism and hypothermia similar to the torpor observed in hibernation when faced with energy shortage. Notably, prolonged calorie restriction (CR) induces serial daily torpor patterns in mice, comparable to species that utilize daily hibernation. Here, we examined the neuroinflammatory response in the hippocampus of male C57BL/6 mice undergoing serial daily torpor induced by a 30% CR for 4 weeks. During daily torpor episodes, CR mice exhibited transient increases in TNF-α mRNA expression, which normalized upon arousal. Concurrently, the CA1 region of the hippocampus showed persistent morphological changes in microglia, characterized by reduced cell branching, decreased cell complexity and altered shape. Importantly, these morphological changes were not accompanied by evident signs of astrogliosis or oxidative stress, typically associated with detrimental neuroinflammation. Collectively, the adaptive nature of the brain's inflammatory response to CR-induced torpor in mice parallels observations in hibernators, highlighting its value for studying the mechanisms of brain resilience during torpor. Such insights could pave the way for novel therapeutic interventions in stroke and neurodegenerative disorders in humans.

Physiological and behavioural adaptations by big brown bats hibernating in dry rock crevices.

Winter energy stores are finite and factors influencing patterns of activity are important for overwintering energetics and survival. Hibernation patterns (e.g., torpor bout duration and arousal frequency) often depend on microclimate, with more stable hibernacula associated with greater energy savings than less stable hibernacula. We monitored hibernation patterns of individual big brown bats (Eptesicus fuscus; Palisot de Beauvois, 1796) overwintering in rock-crevices that are smaller, drier, and less thermally stable than most known cave hibernacula. While such conditions would be predicted to increase arousal frequency in many hibernators, we did not find support for this. We found that bats were insensitive to changes in hibernacula microclimate (temperature and humidity) while torpid. We also found that the probability of arousal from torpor remained under circadian influence, likely because throughout the winter during arousals, bats commonly exit their hibernacula. We calculated that individuals spend most of their energy on maintaining a torpid body temperature a few degrees above the range of ambient temperatures during steady-state torpor, rather than during arousals as is typical of other small mammalian hibernators. Flight appears to be an important winter activity that may expedite the benefits of euthermic periods and allow for short, physiologically effective arousals. Overall, we found that big brown bats in rock crevices exhibit different hibernation patterns than conspecifics hibernating in buildings and caves.

Comparing Hypothermic and Thermal Neutral Conditions to Induce Metabolic Suppression.

Suppressing metabolism in astronauts could decrease CO2 production. It is unknown whether active cooling is required to suppress metabolism in sedated patients. We hypothesized that hypothermia would have an additive effect with dexmedetomidine on suppressing metabolism. This is a randomized crossover trial of healthy subjects receiving sedation with dexmedetomidine and exposure to a cold (20°C) or thermal neutral (31°C) environment for 3 hours. We measured heart rate, blood pressure, core temperature, resting oxygen consumption (VO2), resting carbon dioxide production (VCO2), and resting energy expenditure (REE) at baseline and each hour of exposure to either environment. We also evaluated components of the Defense Automated Neurobehavioral Assessment (DANA) Brief to evaluate the effect of metabolic suppression on cognition. Six subjects completed the study. Heart rate and core temperature were lower during the cold (56 bpm) condition than the thermal neutral condition (67 bpm). VO2, VCO2, and REE decreased between baseline and the 3-hour measurement in the cold condition (Δ = 0.9 mL/min, 56.94 mL/min, 487.9 Kcal/D, respectively). DANA simple response time increased between baseline and start of recovery in both conditions (20°C 136.9 cognitive efficiency [CE] and 31°C 87.83 CE). DANA procedural reaction time increased between baseline and start of recovery in the cold condition (220.6 CE) but not in the thermal neutral condition. DANA Go/No-Go time increased between baseline and start of recovery in both conditions (20°C 222.1 CE and 31°C 122.3 CE). Sedation and cold environments are required for metabolic suppression. Subjects experienced decrements in cognitive performance in both conditions. A significant recovery period may be required after metabolic suppression before completing mission critical tasks.

Activation of GFRAL+ neurons induces hypothermia and glucoregulatory responses associated with nausea and torpor.

GFRAL-expressing neurons actuate aversion and nausea, are targets for obesity treatment, and may mediate metformin effects by long-term GDF15-GFRAL agonism. Whether GFRAL+ neurons acutely regulate glucose and energy homeostasis is, however, underexplored. Here, we report that cell-specific activation of GFRAL+ neurons using a variety of techniques causes a torpor-like state, including hypothermia, the release of stress hormones, a shift from glucose to lipid oxidation, and impaired insulin sensitivity, glucose tolerance, and skeletal muscle glucose uptake but augmented glucose uptake in visceral fat. Metabolomic analysis of blood and transcriptomics of muscle and fat indicate alterations in ketogenesis, insulin signaling, adipose tissue differentiation and mitogenesis, and energy fluxes. Our findings indicate that acute GFRAL+ neuron activation induces endocrine and gluco- and thermoregulatory responses associated with nausea and torpor. While chronic activation of GFRAL signaling promotes weight loss in obesity, these results show that acute activation of GFRAL+ neurons causes hypothermia and hyperglycemia.

Telomere dynamics during hibernation in a tropical primate.

Hibernation is a widespread metabolic strategy among mammals for surviving periods of food scarcity. During hibernation, animals naturally alternate between metabolically depressed torpor bouts and energetically expensive arousals without ill effects. As a result, hibernators are promising models for investigating mechanisms that buffer against cellular stress, including telomere protection and restoration. In non-hibernators, telomeres, the protective structural ends of chromosomes, shorten with age and metabolic stress. In temperate hibernators, however, telomere shortening and elongation can occur in response to changing environmental conditions and associated metabolic state. We investigate telomere dynamics in a tropical hibernating primate, the fat-tailed dwarf lemur (Cheirogaleus medius). In captivity, these lemurs can hibernate when maintained under cold temperatures (11-15 °C) with limited food provisioning. We study telomere dynamics in eight fat-tailed dwarf lemurs at the Duke Lemur Center, USA, from samples collected before, during, and after the hibernation season and assayed via qPCR. Contrary to our predictions, we found that telomeres were maintained or even lengthened during hibernation, but shortened immediately thereafter. During hibernation, telomere lengthening was negatively correlated with time in euthermia. Although preliminary in scope, our findings suggest that there may be a preemptive, compensatory mechanism to maintain telomere integrity in dwarf lemurs during hibernation. Nevertheless, telomere shortening immediately afterward may broadly result in similar outcomes across seasons. Future studies could profitably investigate the mechanisms that offset telomere shortening within and outside of the hibernation season and whether those mechanisms are modulated by energy surplus or crises.

Neural control of fluid homeostasis is engaged below 10°C in hibernation.

Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) hibernate for several months each winter without access to water,1 but the mechanisms that maintain fluid homeostasis during hibernation are poorly understood. In torpor, when body temperature (TB) reaches 4°C, squirrels decrease metabolism, slow heart rate, and reduce plasma levels of the antidiuretic hormones arginine vasopressin (AVP) and oxytocin (OXT).1 Squirrels spontaneously undergo interbout arousal (IBA) every 2 weeks, temporarily recovering an active-like metabolism and a TB of 37°C for up to 48 h.1,2 Despite the low levels of AVP and OXT during torpor, profound increases in blood pressure and heart rate during the torpor-IBA transition are not associated with massive fluid loss, suggesting the existence of a mechanism that protects against diuresis at a low TB. Here, we demonstrate that the antidiuretic hormone release pathway is activated by hypothalamic supraoptic nucleus (SON) neurons early in the torpor-arousal transition. SON neuron activity, dense-core vesicle release from the posterior pituitary, and plasma hormone levels all begin to increase before TB reaches 10°C. In vivo fiber photometry of SON neurons from hibernating squirrels, together with RNA sequencing and c-FOS immunohistochemistry, confirms that SON is electrically, transcriptionally, and translationally active to monitor blood osmolality throughout the dynamic torpor-arousal transition. Our work emphasizes the importance of the antidiuretic pathway during the torpor-arousal transition and reveals that the neurophysiological mechanism that coordinates the hormonal response to retain fluid is active at an extremely low TB, which is prohibitive for these processes in non-hibernators.