The future of artificial hibernation medicine:protection of nerves and organs after spinal cord injury

Spinal cord injury is a serious disease of the central nervous system involving irreversible nerve injury and various organ system injuries.At present,no effective clinical treatment exists.As one of the artificial hibernation techniques,mild hypothermia has preliminarily confirmed its clinical effect on spinal cord injury.However,its technical defects and barriers,along with serious clinical side effects,restrict its clinical application for spinal cord injury.Artificial hibernation is a futureoriented disruptive technology for human life support.It involves endogenous hibernation inducers and hibernation-related central neuromodulation that activate particular neurons,reduce the central constant temperature setting point,disrupt the normal constant body temperature,make the body adapt"to the external cold environment,and reduce the physiological resistance to cold stimulation.Thus,studying the artificial hibernation mechanism may help develop new treatment strategies more suitable for clinical use than the cooling method of mild hypothermia technology.This review introduces artificial hibernation technologies,including mild hypothermia technology,hibernation inducers,and hibernation-related central neuromodulation technology.It summarizes the relevant research on hypothermia and hibernation for organ and nerve protection.These studies show that artificial hibernation technologies have therapeutic significance on nerve injury after spinal co rd injury through inflammatory inhibition,immunosuppression,oxidative defense,and possible central protection.It also promotes the repair and protection of res pirato ry and digestive,cardiovascular,locomoto r,urinary,and endocrine systems.This review provides new insights for the clinical treatment of nerve and multiple organ protection after spinal cord injury thanks to artificial hibernation.At present,artificial hibernation technology is not mature,and research fa ces various challenges.Neve rtheless,the effort is wo rthwhile for the future development of medicine.

Application of artificial hibernation technology in acute brain injury

Controlling intracranial pressure,nerve cell regeneration,and microenvironment regulation are the key issues in reducing mortality and disability in acute brain injury.There is currently a lack of effective treatment methods.Hibernation has the characteristics of low temperature,low metabolism,and hibernation rhythm,as well as protective effects on the nervous,cardiovascular,and motor systems.Artificial hibernation technology is a new technology that can effectively treat acute brain injury by altering the body’s metabolism,lowering the body’s core temperature,and allowing the body to enter a state similar to hibernation.This review introduces artificial hibernation technology,including mild hypothermia treatment technology,central nervous system regulation technology,and artificial hibernation-inducer technology.Upon summarizing the relevant research on artificial hibernation technology in acute brain injury,the research results show that artificial hibernation technology has neuroprotective,anti-inflammatory,and oxidative stress-resistance effects,indicating that it has therapeutic significance in acute brain injury.Furthermore,artificial hibernation technology can alleviate the damage of ischemic stroke,traumatic brain injury,cerebral hemorrhage,cerebral infarction,and other diseases,providing new strategies for treating acute brain injury.However,artificial hibernation technology is currently in its infancy and has some complications,such as electrolyte imbalance and coagulation disorders,which limit its use.Further research is needed for its clinical application.

Spontaneous firing in olfactory bulb neurons of Bufo bufo gargarizans in and after hibernation

Microelectrode technique was used to record the spontaneous electrical activities of the neurons in olfactory bulb of the Bufo bufo gargarizans, both in hibernation and after hibemation. This study investigated the electrophysiological characteristics of amphibian olfactory bulb in the period of hibernation and after hibernation and its effects on the start of hibernation and spontaneous awakening. The research showed four forms of spontaneous firings： single spontaneous firing, burst spontaneous firing, irregular spontaneous firing and consecutive single spontaneous firing. The single spontaneous firing includes slow depolarized spontaneous firing and fast depolarized spontaneous firing, and the slow depolarized spontaneous firing occurs only during the hibernation period. In hibernation, the low amplitude and low frequency firing with a longer duration may be relevant to maintaining the tonicity of the central nervous system in toads that are in hibernation, and this kind of firing may also provide an excited basis for their arousal from hibernation. After hibernation, the amplitude and frequency of firing increase, but the firing duration gets shorter. This form of short-term firing, which may be a phenomenon of sensory neurons fast adapting, is one of the neuronal mechanisms for the arousal of hibernating animals.

On a Hibernation Plankton-Nutrient Chemostat Model with Delayed Response in Growth

In this paper, a hibernation plankton-nutrient chemostat model with delayed response in growth is considered. By using the stroboscopic map and the theorem of impulsive delay differential equation, a plankton-extinction boundary periodic solution is obtained. The sufficient conditions on the permanence and globally attractive of the chemostat system are also obtained. Our main results reveal that the delayed response in growth plays an important role on the dynamical behaviors of system.

Release of myocardial noradrenaline during acute hibernation in the isolated rat heart

Objective： To explore the release of myocardial noradrenaline during acute hibernation. Methods： The hearts were gained from rats and set up as modified Langendorf preparations beating isometrically. They were perfused with modified Krebs-Henseleit buffer under controlled pressure. Mechanical measurements and coronary effluent were recorded simultaneously at 30min intervals for 150min. Lactate dehydrogenase in coronary effluent was assayed at the beginning, 60min and 120min low-flow ischemia. Noradrenaline in coronary effluent was determined at the beginning of low-flow and 120min of low-flow ischemia and also in control, during hibernation and after 30min reperfusion during stimulation, myocardial noradrenaline response on tyramine was investigated in absence or presence of desipramine after 30min reperfusion. Results： In the control, there was nosignificant chant in noradrenaline overflow during 120min perfusion; In the acute myocardial hibernation group, there was also nosignificant difference in noradrenaline overflow between the beginning and 120min low-flow ischemia. The electrical field stimulation-induced overflow of noradrenaline during hibernation myocardium was significantly less than preischemia or after reperfusion, but there was nosignificant difference between preischemia and reperfusion group. Tyramine induced significant noradrenaline release in absence of desipramine after 30min reperfusion, but this increase in noradrenaline release had nosignificant in the presence of desipramine. These studies indicated that there was not significant spontaneous noadrenaline overflow during acute myocardial hibernation in isolated rat hearts, the stimulation-induced noradrenaline overflow decreased during hibernation and restored to the level of preischemia after reperfusion, myocardial noradrenaline response to tyramine remained after 30min reperfusion. Conclusion： Myocardial noradrenaline overflow may not contribute to the development of acute myocardial hibernation and the function of sympathetic nerve may also maintain in hibernation as myocardium does during acute myocardial hibernation, reperfusion of myocardium may contribute to restoring the function of sympathetic nerve.

Physiological responses in vitamin C system during hibernation in juvenile Chinese soft-shelled turtle Pelodiscus sinensis

Vitamin C (Vc) is an important antioxidant that helps turtles tolerating stressful environment. This work quantified changes in tissue Vc levels during winter hibernation in the soft-shelled turtle Pelodiscus sinensis , to reveal the stress response pattern of tissue Vc during hibernation and contribute basic data for turtle culture. We sampled juvenile soft-shelled turtles at pre-hibernation (17.0°C mud temperature;MT), during hibernation (5.8°C MT) and after arousal (20.1°C MT) in the field. The transcript levels of the gene encoding L-gulonolactone oxidase (GLO), the key enzyme for Vc synthesis, decreased significantly during hibernation. However, GLO activity did not match the GLO transcription patterns and remained stable during hibernation, and showed temperature-dependent kinetic characteristics. Vitamin C levels in the brain, liver, kidney, and spleen (but not muscle) all decreased significantly during hibernation, but recovered to pre-hibernation levels or even higher levels after arousal. The soft-shelled turtle endured 5 months of hibernation with no significant oxidative damage in most tissues, except in the spleen. Splenic Vc was nearly exhausted during hibernation, accompanied by a significantly elevated malonaldehyde (MDA) level. Although the high level of oxidative damage quickly decreased after arousal, the potential tissue damage in the spleen during hibernation might account for the weakened immune capacity of turtles after hibernation.

Mammalian hibernation:a unique model for medical research

Hibernation is an adaptive behavior for some small animals to survive cold winter.Hibernating mammals usually down-regulate their body temperature from~37℃to only a few degrees.During the evolution,mammalian hibernators have inherited unique strategies to survive extreme conditions that may lead to disease or death in humans and other non-hibernators.Hibernating mammals can not only tolerant deep hypothermia,hypoxia and anoxia,but also protect them against osteoporosis,muscle atrophy,heart arrhythmia and ischemia-reperfusion injury.Finding the molecular and regulatory mechanisms underlying these adaptations will provide novel ideas for treating related human diseases.

On the immunological limitations of hibernation and synthetic torpor as a supporting technique for astronauts’ radioprotection in deep space missions

Although human hibernation has been introduced as an effective technique in space exploration,there are concerns regarding the intrinsic risks of the approach(i.e.,synthetic torpor)and other factors involved in this procedure.Besides concerns about the brain changes and the state of consciousness during hibernation,an"Achilles heel"of the hibernation is the negative impact of torpor on factors such as the number of circulating leukocytes,complement levels,response to lipopolysaccharides,phagocytotic capacity,cytokine production,lymphocyte proliferation,and antibody production.Moreover,increased virulence of bacteria in deep space can significantly increase the risk of infection.The increased infection risk during long-term space missions with the combined effects of radiation and microgravity affect the astronauts’immune system.With these additional immune system stressors,torpor-induced extraimmunosuppression can be potentially life threatening for astronauts.

Juvenile survival curves in a solitary ground squirrel with a prolonged hibernation:effects of individual characteristics,environment,and maternal investment

Juvenile survival is a key life-history influence on population dynamics and adaptive evolution.We analyzed the effects of individual chara-cteristics,early environment,and maternal investment on juvenile survival in a large solitary hibernating rodent-yellow ground squirrel Spermophilus fulvus using Cox mixed-effects models.Only 48%of weaned pups survived to dispersal and 17%survived to hibernation.Early life expectancy was primarily determined by individual characteristics and,to a lesser extent,by the early environment.The strongest and pos-itive predictor of juvenile survival was body mass which crucially affected mortality immediately after weaning.Males suffered higher mortality than females after the onset of dispersal;however,the overall difference between sexes was partly masked by high rates of mortality in the first days after emergence in both sexes.Later emerged juveniles had lower life expectancy than the earliest pups.The overall effect of local juvenile density was positive.Prolonged lactation did not enhance juvenile survival:Pups nursed longer survived shorter than the young nursed for a shorter period.Our findings support the hypothesis that females of S.fulvus cannot effectively regulate maternal expenditures to mitigate the effects of unfavorable conditions on their offspring.The strategy to deal with seasonal time constraints on life history in female S.fulvus suggests an early termination of maternal care at the cost of juvenile quality and survival.This female reproductive strategy corresponds to a"fast-solitary"life of folivorous desert-dwelling S.fulvus and other solitary ground squirrels with prolonged hibernation.

Surviving winter on the Qinghai-Xizang Plateau:Extensive reversible protein phosphorylation plays a dominant role in regulating hypometabolism in hibernating Nanorana parkeri

Changes in protein abundance and reversible protein phosphorylation(RPP)play important roles in regulating hypometabolism but have never been documented in overwintering frogs at high altitudes.To test the hypothesis that protein abundance and phosphorylation change in response to winter hibernation,we conducted a comprehensive and quantitative proteomic and phosphoproteomic analysis of the liver of the Xizang plateau frog,Nanorana parkeri,living on the Qinghai-Xizang Plateau.In total,5170 proteins and 5695 phosphorylation sites in 1938 proteins were quantified.Based on proteomic analysis,674 differentially expressed proteins(438 up-regulated,236 down-regulated)were screened in hibernating N.parkeri versus summer individuals.Functional enrichment analysis revealed that higher expressed proteins in winter were significantly enriched in immune-related signaling pathways,whereas lower expressed proteins were mainly involved in metabolic processes.A total of 4251 modified sites(4147 up-regulated,104 down-regulated)belonging to 1638 phosphoproteins(1555 up-regulated,83 down-regulated)were significantly changed in the liver.During hibernation,RPP regulated a diverse array of proteins involved in multiple functions,including metabolic enzymatic activity,ion transport,protein turnover,signal transduction,and alternative splicing.These changes contribute to enhancing protection,suppressing energy-consuming processes,and inducing metabolic depression.Moreover,the activities of phosphofructokinase,glutamate dehydrogenase,and ATPase were all significantly lower in winter compared to summer.In conclusion,our results support the hypothesis and demonstrate the importance of RPP as a regulatory mechanism when animals transition into a hypometabolic state.

Comparative transcriptomic evidence of physiological changes and potential relationships in vertebrates under different dormancy states

Dormancy represents a fascinating adaptive strategy for organisms to survive in unforgiving environments.After a period of dormancy,organisms often exhibit exceptional resilience.This period is typically divided into hibernation and aestivation based on seasonal patterns.However,the mechanisms by which organisms adapt to their environments during dormancy,as well as the potential relationships between different states of dormancy,deserve further exploration.Here,we selected Perccottus glenii and Protopterus annectens as the primary subjects to study hibernation and aestivation,respectively.Based on histological and transcriptomic analysis of multiple organs,we discovered that dormancy involved a coordinated functional response across organs.Enrichment analyses revealed noteworthy disparities between the two dormant species in their responses to extreme temperatures.Notably,similarities in gene expression patterns pertaining to energy metabolism,neural activity,and biosynthesis were noted during hibernation,suggesting a potential correlation between hibernation and aestivation.To further explore the relationship between these two phenomena,we analyzed other dormancy-capable species using data from publicly available databases.This comparative analysis revealed that most orthologous genes involved in metabolism,cell proliferation,and neural function exhibited consistent expression patterns during dormancy,indicating that the observed similarity between hibernation and aestivation may be attributable to convergent evolution.In conclusion,this study enhances our comprehension of the dormancy phenomenon and offers new insights into the molecular mechanisms underpinning vertebrate dormancy.

Blood hibernation： a novel strategy to inhibit systemic inflammation and coagulation induced by cardiopulmonary bypass

Background Inflammation and coagulation are two intimately cross-linked defense mechanisms of most, if not all organisms to injuries. During cardiopulmonary bypass （CPB）, these two processes are activated and interact with each other through several common pathways, which may result in subsequent organ dysfunction. In the present study, we hypothesized that the addition of nitric oxide, prostaglandin E1 （PGE1）, and aprotinin to the systemic circulation, hereby referred to as blood hibernation, would attenuate the inflammation and coagulation induced by CPB. Methods Thirty adult mongrel dogs were equally divided into five groups, anesthetized and placed on hypothermic CPB （32℃）. Each group received respectively the following treatments： （1） inhalation of 40 ppm nitric oxide; （2） intravenous infusion of 20 ng.kgl.min1 of PGE1; （3） 80 000 kallikrein inhibitor units （KIU）/kg of aprotinin; （4） the combination of all three agents （blood hibernation group）; and （5） no treatment （control group） during CPB. Activation of leukocyte, platelet, endothelial cell, and formation of thrombin were assessed after CPB. Results As compared with the other four groups, leukocyte counts were higher, while plasma elastase, interleukin-8, CD11b mRNA expression, myeloperoxidase activities and lung tissue leukocyte counts were lower in the blood hibernation group （P 〈0.05 versus other four groups after CPB）. Plasma prothrombin fragment （PTF）1＋2, and platelet activation factors were lower, while platelet counts were higher in the blood hibernation group （P 〈0.05 versus other four groups at 6 and 12 hours after CPB）. Electron microscopy showed endothelial pseudopods protrusion, with cell adherence in all four groups except the blood hibernation group where endothelial cells remained intact. Conclusion Blood hibernation, effected by the addition of nitric oxide, PGE1 and aprotinin to the circulating blood during extra-corporeal circulation, was observed to attenuate the inflammation and coagulation induced by cardiopulmonary bypass, most likely by inhibiting the important common intermediates between the two cross-linked processes.

Phenotypic changes in the metabolic profile and adiponectin activity during seasonal fattening and hibernation in female Daurian ground squirrels(Spermophilus dauricus)

Seasonal hibernation has provided an opportunity to study animals’phenotypic plasticity in adaptation to changing environment.In the present study focusing on the female Daurian ground squirrel(Spermophilus dauricus)-a well demonstrated seasonal hibernator-we examined their behavioral,morphological,and metabolic changes during fattening,hibernation,and emergence.Our data indicated high levels of food intake,fat deposition,and body mass increases during fattening compared to hibernation.The levels of serum glucose and triglycerides were also higher during fattening than during hibernation and emergence.Interestingly,although squirrels showed signs of obesity and elevated triglycerides in serum during fattening,triglyceride levels in the liver and skeletal muscles remained unchanged.Our data also indicated that adiponectin levels in serum and cerebrospinal fluid were different between fattening and hibernation.Levels of adiponectin receptor 1 in the skeletal muscle remained low during fattening but peaked in late hibernation.In contrast,adiponectin receptor 2 in the liver showed a steady increase during fattening,which was followed by a significant decrease at early hibernation.Our data indicate that adiponectin may play an important role in preventing heterotopic fat accumulation in a receptor-and organ-specific manner,as well as in facilitating the switch from glucose metabolism to lipid metabolism during fattening and hibernation in female Daurian ground squirrels.

Wound healing during hibernation by black bears (Ursus americanus) in the wild: elicitation of reduced scar formation

Even mildly hypothermic body or limb temperatures can retard healing processes in mammals.Despite this,we observed that hibernating American black bears(Ursus americanus Pallas,1780)elicit profound abilities in mounting inflammatory responses to infection and/or foreign bodies.In addition,they resolve injuries during hibernation while maintaining mildly hypothermic states(30–35°C)and without eating,drinking,urinating or defecating.We describe experimental studies on free-ranging bears that document their abilities to completely resolve cutaneous cuts and punctures incurred during or prior to hibernation.We induced small,full-thickness cutaneous wounds(biopsies or incisions)during early denning,and re-biopsied sites 2–3 months later(near the end of denning).Routine histological methods were used to characterize these skin samples.All biopsied sites with respect to secondary intention(open circular biopsies)and primary intention(sutured sites)healed,with evidence of initial eschar(scab)formation,completeness of healed epidermis and dermal layers,dyskeratosis(inclusion cysts),and abilities to produce hair follicles.These healing abilities of hibernating black bears are a clear survival advantage to animals injured before or during denning.Bears are known to have elevated levels of hibernation induction trigger(delta-opioid receptor agonist)and ursodeoxycholic acid(major bile acid within plasma,mostly conjugated with taurine)during hibernation,which may relate to these wound-healing abilities.Further research as to the underlying mechanisms of wound healing during hibernation could have applications in human medicine.Unique approaches may be found to improve healing for malnourished,hypothermic,diabetic and elderly patients or to reduce scarring associated with burns and traumatic injuries.

Hibernation with rhythmicity:the circadian clock and hormonal adaptations of the hibernating Asiatic toads(Bufo gargarizans)

Hibernation is one of the fundamental strategies in response to cold environmental temperatures.During hibernation,the endocrine and circadian systems ensure minimal expenditure of energy for survival.The circadian rhythms of key hormones,melatonin(MT),corticosterone(CORT),triiodothyronine(T3),and thyroxine(T4),and the underlying molecular regulatory mechanisms of hibernation have been well determined in mammals but not in ectotherms.Here,a terrestrial hibernating species,Asiatic toad(Bufo gargarizans),was employed to investigate the plasma CORT,MT,T3,and T4;and the retina,brain,and liver mRNA expression of the core clock genes,including circadian locomotor output cycles kaput(Clock),brain and muscle ARNT-like 1(Bmal1),cryptochrome(Cry)1 and 2,and period(Per)1 and 2,at 7-time points over a 24-h period under acute cold(1 day at 4℃),and hibernation(45 days at 4℃).Our results showed that the circadian rhythms of the core clock genes were rather unaffected by acute cold exposure in the retina,unlike the brain and liver.In contrast,during hibernation,the liver clock genes displayed significant circadian oscillations,while those in the retina and brain stopped ticking.Furthermore,plasma CORT expressed circadian oscillations in both groups,and T3 in acute cold exposure group,whereas T4 and MT did not.Our results reveal that the plasma CORT and the liver sustain rhythmicity when the brain was not,indicating that the liver clock along with the adrenal clock synergistically maintains the metabolic requirements to ensure basic survival in hibernating Asiatic toads.

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