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PubMed1982

Role of the testis in regulating the duration of hibernation in the Turkish hamster, Mesocricetus brandti.

The effect of castration on hibernation was studied in male Turkish hamsters (Mesocricetus brandti). In the first study the animals were exposed to a long-day photoperiod from birth and throughout the period of hibernation. Hibernation was induced by exposure to cold (10 degrees C). Intact males usually hibernated for approximately 6-7 months and then became euthermic. Males which had been castrated prior to cold exposure continued to hibernate for a longer period. None of the 6 surviving castrated males terminated hibernation by 8 months. Four of these animals survived for more than 2.5 years and continued to hibernate throughout this time. In a second study, hamsters were exposed to a short-day photoperiod to induce testicular regression prior to cold exposure. Most of the intact males again hibernated for 6-7 months while castrated hamsters remained in hibernation for 8-9 months. Thus, in both studies, castration prolonged the hibernation "season." In the second study, the testes, which had regressed in response to exposure to short days, underwent recrudescence in hibernating males at 5-7 months after the initial exposure to short days. A similar time course of testicular recrudescence was displayed by males housed under short days but not exposed to cold. These latter animals remained euthermic throughout the experiment. Thus, it appears that the duration of the seasonal testicular cycle, induced by exposure to short days, was affected little, if at all, by environmental temperature or by body temperature. The testicular cycle appears to influence hibernation, probably through changes in androgen secretion.

Animals↗
PubMed2005

Modulation of apoptotic pathways in intestinal mucosa during hibernation.

Mammalian hibernation is associated with several events that can affect programmed cell death (apoptosis) in nonhibernators, including marked changes in blood flow, extended fasting, and oxidative stress. However, the effect of hibernation on apoptosis is poorly understood. Here, we investigated apoptosis and expression of proteins involved in apoptotic pathways in intestinal mucosa of summer and hibernating ground squirrels. We used terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) to identify possible apoptotic enterocytes in small intestine of summer squirrels and hibernating squirrels throughout the winter. Nuclear TUNEL staining increased as hibernation progressed, but the staining pattern was diffuse and not accompanied by chromatin condensation or apoptotic bodies. Electrophoresis of mucosal DNA revealed no ladders typical of apoptosis. Nuclear levels of proapoptotic p53 protein were fourfold less in hibernators compared with summer squirrels. A 12-fold increase in anti-apoptotic Bcl-x(L) compared with a 2-fold increase in proapoptotic Bax suggested a balance in favor of antiapoptotic signaling in hibernators. There was no change in Bcl-2 protein expression but phospho-Bcl-2 increased in mucosa of hibernators. Hibernation had minimal effects on expression of active caspase-8 or -9, whereas caspase-3-specific activity was lower in hibernators during an interbout arousal compared with summer squirrels. Expression of the prosurvival protein Akt increased 20-fold during hibernation, but phospho-Akt was not altered. These data provide evidence for enhanced expression of antiapoptotic proteins during hibernation that may promote enterocyte survival in a pro-oxidative, proapoptotic environment.

Animals↗
PubMed2002

Periodic arousal from hibernation is necessary for initiation of immune responses in ground squirrels.

Golden-mantled ground squirrels (Spermophilus lateralis) undergo seasonal hibernation during which core body temperature (T(b)) values are maintained 1-2 degrees C above ambient temperature. Hibernation is not continuous. Squirrels arouse at approximately 7-day intervals, during which T(b) increases to 37 degrees C for approximately 16 h; thereafter, they return to hibernation and sustain low T(b)s until the next arousal. Over the course of the hibernation season, arousals consume 60-80% of a squirrel's winter energy budget, but their functional significance is unknown and disputed. Host-defense mechanisms appear to be downregulated during the hibernation season and preclude normal immune responses. These experiments assessed immune function during hibernation and subsequent periodic arousals. The acute-phase response to bacterial lipopolysaccharide (LPS) was arrested during hibernation and fully restored on arousal to normothermia. LPS injection (ip) resulted in a 1-1.5 degrees C fever in normothermic animals that was sustained for > 8 h. LPS was without effect in hibernating squirrels, neither inducing fever nor provoking arousal, but a fever did develop several days later, when squirrels next aroused from hibernation; the duration of this arousal was increased sixfold above baseline values. Intracerebroventricular infusions of prostaglandin E(2) provoked arousal from hibernation and induced fever, suggesting that neural signaling pathways that mediate febrile responses are functional during hibernation. Periodic arousals may activate a dormant immune system, which can then combat pathogens that may have been introduced immediately before or during hibernation.

Animals↗
PubMed1999

Major changes in the brain histamine system of the ground squirrel Citellus lateralis during hibernation.

Hibernation in mammals such as the rodent hibernator Citellus lateralis is a physiological state in which CNS activity is endogenously maintained at a very low, but functionally responsive, level. The neurotransmitter histamine is involved in the regulation of diurnal rhythms and body temperature in nonhibernators and, therefore, could likely play an important role in maintaining the hibernating state. In this study, we show that histamine neuronal systems undergo major changes during hibernation that are consistent with such a role. Immunohistochemical mapping of histaminergic fibers in the brains of hibernating and nonhibernating golden-mantled ground squirrels (C. lateralis) showed a clear increase in fiber density during the hibernating state. The tissue levels of histamine and its first metabolite tele-methylhistamine were also elevated throughout the brain of hibernating animals, suggesting an increase in histamine turnover during hibernation, which occurs without an increase in histidine decarboxylase mRNA expression. This hibernation-related apparent augmentation of histaminergic neurotransmission was particularly evident in the hypothalamus and hippocampus, areas of importance to the control of the hibernating state, in which tele-methylhistamine levels were increased more than threefold. These changes in the histamine neuronal system differ from those reported for the metabolic pattern in other monoaminergic systems during hibernation, which generally indicate a decrease in turnover. Our results suggest that the influence of histamine neuronal systems may be important in controlling CNS activity during hibernation.

Animals↗
PubMed2004

[Investigation of mechanisms of mammalian hibernation and its possible application in medical treatment].

Mammalian hibernation has been reported to increase resistance to various harmful events such as low body temperature, severe ischemia, bacterial infection, irradiation, and muscle disuse, and to prolong the lifespan of the mammal. Therefore, hibernation mechanisms are thought to play a critical role in maintaining healthy organisms. Although the application of this physiological phenomenon to medical fields has strongly been desired, it has been prevented by a poor understanding of the hibernation mechanism. In order to clarify how mammalian hibernation is controlled in organisms, we have looked for a physiological signal of hibernation and found marked changes in cardiac calcium regulation associated with a circannual hibernation. Focusing on these changes, we initially discovered a molecular marker of hibernation, hibernation-specific proteins (HP), of which production in the liver and the blood content are controlled by an endogenous circannual rhythm responsible for hibernation. Our recent studies on HP regulation have revealed that circannual signals for the timing of hibernation are transmitted through the neuroendocrine system and that HP are actively transported into the cerebrospinal fluid (CSF) prior to the onset of hibernation. This suggested that hibernation is controlled by HP in the brain and its regulation system. Based on these results, the future medical application of these results is discussed.

Animals↗
PubMed1990

14C-2-deoxyglucose uptake in the ground squirrel brain during entrance to and arousal from hibernation.

Neuronal activity underlying various phases of the mammalian hibernation cycle was investigated using the 14C-2-deoxyglucose (2DG) method. Relative 2DG uptake (R2DGU) values were computed for 96 brain regions across 7 phases of the hibernation cycle: euthermia, 3 body temperature (Tb) intervals during entrance into hibernation, stable deep hibernation, and 2 Tb intervals during arousal from hibernation. Multivariate statistical techniques were employed to identify objectively groups of brain regions whose R2DGU values showed a similar pattern across all phases of hibernation. Factor analysis revealed that most of the variability in R2DGU values for the 96 brain regions across the entire cycle could be accounted for by 3 principal factors. These factors could accurately discriminate the various phases of hibernation on the basis of the R2DGU values alone. Three hypothalamic and 3 cortical regions were identified as possibly mediating the entrance into hibernation because they underwent a change in R2DGU early in entrance into hibernation and loaded strongly on one of the principal factors. Another 4 hypothalamic regions were similarly identified as possibly causally involved in the arousal from hibernation. These results, coupled with characteristic changes in ordinal rank of the 96 brain regions in each phase of hibernation, support the concept that mammalian hibernation is an active, integrated orchestration of neurophysiological events rather than a state entered through a passive process.

Animals↗
PubMed2000

[Myocardial hibernation: another view].

In the following, three newer concepts are brought together: myocardial hibernation, heterogeneity in myocardial blood flow and oxidative metabolism, and effects of hibernating animal serum on non-hibernators. Myocardial hibernation is viewed as a protective mechanism that helps to maintain myocardial integrity and viability by down-regulating contractile function as an adaptation to reduced blood flow. Myocardial flow is considerably heterogeneous. Consequently, oxygen supply to the myocardium is also heterogeneous. Many lines of evidence show a close correlation between regional flow and regional metabolism. In low-flow/low-metabolism areas, myocardial function must be reduced, since the myocardium would otherwise undergo necrosis. Thus, others and we hypothesize that function must be down-regulated to induce hibernation in low-flow areas. Because no regional histologic differences exist (the mitochondria are uniformly distributed within the myocardium), the pattern of heterogeneity seems to shift over time. Hence, we hypothesize that such very regional hibernation presents an evolutionary, protective mechanism, permitting subsequent myocardial areas to rest within the ceaselessly working heart. We also hypothesize that this mechanism ensures the down-regulation of function following myocardial ischemia in order to induce myocardial hibernation on a broader level. Surprisingly, a substance (opioid in nature) contained in hibernator serum both induced hibernation-like state in non-hibernators and suppressed myocardial oxygen consumption. Thus, we lastly hypothesize that myocardial hibernation is a remnant of the early stages of evolution and is closer to physiologic hibernation than traditionally viewed.

Animals↗
PubMed1995

The optimal depot fat composition for hibernation by golden-mantled ground squirrels (Spermophilus lateralis).

Golden-mantled ground squirrels (Spermophilus lateralis) are herbivores that hibernate during winter. Although little is known about the nutritional/physiological constraints on hibernation, numerous studies have demonstrated that increasing the amount of linoleic acid (a polyunsaturated fatty acid) in the diet enhances hibernation. This is probably because high linoleic acid diets reduce the melting points of the depot fats produced for hibernation which makes them more metabolizable at low body temperatures. This suggests that a major limitation on hibernation may be obtaining enough linoleic acid in the diet for proper hibernation. In all previous studies, however, the amount of linoleic acid in the diets of free-ranging animals was either not considered, or the range of dietary linoleic acid contents in the experiments was less than that of natural diets. It is thus not known whether the amount of linoleic acid available to hibernators under natural conditions actually limits their torpor patterns. A series of laboratory feeding and hibernation experiments were conducted with S. lateralis and artificial diets with different linoleic acid contents that were either below or above the linoleic acid content of the natural diet. The results demonstrated that when dietary linoleic acid contents are either below or above natural levels, hibernation ability is greatly reduced. Hibernation ability was reduced when the squirrels were maintained on a high linoleic acid diet probably by the production of toxic lipid peroxides in brown adipose tissues. The results indicate that there is an optimal level of dietary linoleic acid for proper hibernation, and this is equal to that of the natural diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed2005

Annual lipid cycles in hibernators: integration of physiology and behavior.

Mammalian hibernation is a temporary suspension of euthermia allowing endotherms to undergo reversible hypothermia and generate a marked savings in energy expenditure. In most fat-storing hibernator species, seasonal changes in food intake, triacylglycerol deposition, metabolism, and reproductive development are controlled by a circannual clock. In ground-dwelling sciurid rodents (ground squirrels and marmots), for example, energy intake increases during a summer body mass gain phase, and toward the end of this phase metabolic rate also begins to decrease, resulting in a profound increase in lipid deposition as fat. Increased activity of lipogenic hormones and enzymes correspond with this increase. The hibernation mass loss phase begins after the body mass peak in the fall and ends in spring. During this phase, stored lipids are slowly utilized in a programmed manner by undergoing deep torpor or hibernation during which the hypothalamic setpoint for body temperature is typically reduced to just above 0 degrees C. Throughout the hibernation season, bouts of deep torpor are punctuated by periodic arousals in which brown adipose tissue thermogenesis plays a critical role. Lipid oxidation nearly exclusively fuels deep torpor and most of the rewarming process. The fatty acid composition of stored lipids can affect the depth and duration of deep torpor, and saturated fatty acids may be preferentially used during hibernation, whereas polyunsaturated fatty acids may be preferentially retained. Female and underweight male hibernators terminate hibernation in spring when aboveground food becomes available; in contrast, heavier males with sufficient lipid reserves spontaneously terminate hibernation several weeks before females and independent of food availability. Mating occurs shortly after emergence from hibernation, and the lipid cycle begins again with the completion of reproduction. Lipid deposition and mobilization, temperature regulation, reproduction, and circannual timing are intimately interdependent. The unique manner in which they are controlled during the annual cycle, especially lipid reserves, makes hibernators valuable and promising models for research into the mechanisms underlying these processes in all mammals.

Adipose Tissue↗
PubMed2003

Increased brain histamine H3 receptor expression during hibernation in golden-mantled ground squirrels.

BACKGROUND: Hibernation is a state of extremely reduced physiological functions and a deep depression of CNS activity. We have previously shown that the histamine levels increase in the brain during hibernation, as does the ratio between histamine and its first metabolite, suggesting increased histamine turnover during this state. The inhibitory histamine H3 receptor has both auto- and heteroreceptor function, rendering it the most likely histamine receptor to be involved in regulating the activity of histamine as well as other neurotransmitters during hibernation. In view of accumulating evidence that there is a global depression of transcription and translation during hibernation, of all but a few proteins that are important for this physiological condition, we reasoned that an increase in histamine H3 receptor expression would clearly indicate an important hibernation-related function for the receptor. RESULTS: In this study we show, using in situ hybridization, that histamine H3 receptor mRNA increases in the cortex, caudate nucleus and putamen during hibernation, an increase that is accompanied by elevated receptor binding in the cerebral cortex, globus pallidus and substantia nigra. These results indicate that there is a hibernation-related increase in H3 receptor expression in cortical neurons and in striatopallidal and striatonigral GABAergic neurons. GTP-gamma-S binding autoradiography shows that the H3 receptors in the globus pallidus and substantia nigra can be stimulated by histamine throughout the hibernation cycle, suggesting that they are functionally active during hibernation. CONCLUSIONS: These results show that the histamine H3 receptor gene is one of the few with a transcript that increases during hibernation, indicating an important role for the receptor in regulating this state. Moreover, the receptor is functionally active in the basal ganglia, suggesting a function for it in regulating e.g. dopaminergic transmission during hibernation.

Animals↗
PubMed2002

Analysis of monoamines, adenosine and GABA in tissues of the land snail Helix lucorum and lizard Agama stellio stellio during hibernation.

The aim of the present study was to determine the levels of monoamines, GABA and adenosine in the brain, heart and haemolymph of the land snail Helix lucorum and in the brain, heart and blood of lizard Agama stellio stellio during long-term hibernation. We measured levels of the monoamines serotonin (5-HT) and its main metabolite 5-hydroxyindole-3-acetic acid (5-HIAA), dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA), norepinephrine (NE) and epinephrine (E). The most abundant amines detected in the brain and heart of active H. lucorum were 5-HT and DA. Of the metabolites examined only 5-HIAA was found in the brain. NE was found at very low levels but only in the brain, while E was not detected in the brain and heart. The levels of 5-HT and 5-HIAA increased in the brain and heart of H. lucorum within the first months of hibernation, showing a significant decrease thereafter. The levels of DA did not change during hibernation. The results indicated that 5-HT might be involved in preparing snails for entry into hibernation. GABA was only found in the brain of H. lucorum, and the levels were low; these levels remained during hibernation. Adenosine was present in brain and heart of H. lucorum, and during hibernation, the level of adenosine decreased significantly in the brain but remained steady in the heart. The monoamines 5-HT, DA and NE were present in the brain of active lizards A. stellio stellio, whereas E was found only at very low levels. Moreover, the metabolites 5-HIAA, DOPAC and HVA were detected in the brain of active lizards. The monoamines 5-HT, DA, NE and E were also detected in the heart and blood of active lizards. During hibernation the levels of these four monoamines were decreased significantly in the brain and heart of A. stellio stellio. In contrast, the levels of E increased in the heart and blood of hibernating lizards. Adenosine was detected in both heart and brain of active lizards, but hibernation caused a marked decrease in its levels at both tissues. GABA was found at higher levels than monoamines and adenosine in the brain of active lizards, and hibernation caused a significant increase in its levels, indicating an important role of GABA in inhibition of neuronal activity in hibernating lizards.

Adenosine↗
PubMed2003

Evaluation of cardiac function in active and hibernating grizzly bears.

OBJECTIVE: To evaluate cardiac function parameters in a group of active and hibernating grizzly bears. DESIGN: Prospective study. ANIMALS: 6 subadult grizzly bears. PROCEDURE: Indirect blood pressure, a 12-lead ECG, and a routine echocardiogram were obtained in each bear during the summer active phase and during hibernation. RESULTS: All measurements of myocardial contractility were significantly lower in all bears during hibernation, compared with the active period. Mean rate of circumferential left ventricular shortening, percentage fractional shortening, and percentage left ventricular ejection fraction were significantly lower in bears during hibernation, compared with the active period. Certain indices of diastolic function appeared to indicate enhanced ventricular compliance during the hibernation period. Mean mitral inflow ratio and isovolumic relaxation time were greater during hibernation. Heart rate was significantly lower for hibernating bears, and mean cardiac index was lower but not significantly different from cardiac index during the active phase. Contrary to results obtained in hibernating rodent species, cardiac index was not significantly correlated with heart rate. CONCLUSIONS AND CLINICAL RELEVANCE: Cardiac function parameters in hibernating bears are opposite to the chronic bradycardic effects detected in nonhibernating species, likely because of intrinsic cardiac muscle adaptations during hibernation. Understanding mechanisms and responses of the myocardium during hibernation could yield insight into mechanisms of cardiac function regulation in various disease states in nonhibernating species.

Analysis of Variance↗
PubMed1996

Hibernating myocardium: a review.

Within a few seconds after a sudden reduction of coronary blood flow regional contractile dysfunction ensues. The mechanisms responsible for the rapid reduction in contractile function during acute myocardial ischemia remain unclear, but may involve a rise in inorganic phosphate. When severe ischemia, such as resulting from a sudden and complete coronary artery occlusion, is prolonged for more than 20-40 min, myocardial infarction develops, and there is irreversible loss of contractile function. When myocardial ischemia is less severe but nevertheless prolonged, the myocardium is dysfunctional but can remain viable. In such ischemic and dysfunctional myocardium, contractile function is reduced in proportion to the reduction in regional myocardial blood flow; i.e. a state of "perfusion-contraction matching" exists. The metabolic status of such myocardium improves over the first few hours, as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns towards control values. Ischemic myocardium, characterized by perfusion-contraction matching, metabolic recovery and lack of necrosis, has been termed "short-term hibernating myocardium". Short-term hibernating myocardium can respond to an inotropic stimulation with increased contractile function, however, at the expense of a renewed worsening of the metabolic status. This situation of an increased regional contractile function at the expense of metabolic recovery during inotropic stimulation can be used to identify short-term hibernating myocardium. When inotropic stimulation is prolonged, the development of short-term hibernation is impaired and myocardial infarction develops. The mechanisms responsible for the development of short-term myocardial hibernation remain unclear at present; a significant involvement of adenosine and of activation of ATP-dependent potassium channels has been excluded. Whereas short-term hibernation is well characterized in animal experiments, the existence of hibernation over weeks or months (long-term hibernation) can only be inferred from clinical studies. Hibernation, as defined by Rahimtoola, is a state of chronic contractile dysfunction which is fully reversible upon reperfusion. Clinical syndromes consistent with the existence of myocardial hibernation include unstable and stable angina, acute myocardial infarction and left ventricular dysfunction and/or congestive heart failure. In long-term hibernating myocardium morphological alterations occur; the myofibrils are reduced in number and disorganized and myocardial glycogen content as well as the extracellular collagen network are increased. Thus, despite the fact that the myocardium remains viable during persistent ischemia and contractile dysfunction is reversible upon reperfusion, there are severe morphological alterations. Understandably, full functional recovery following reperfusion might therefore require weeks or even months.

Animals↗
PubMed2001

Another view of myocardial hibernation.

This manuscript brings together three newer concepts: myocardial hibernation, heterogeneity in myocardial blood flow and oxidative metabolism, and effects of hibernating animal serum on non-hibernators. Myocardial hibernation is viewed as a protective mechanism that helps to maintain myocardial integrity and viability by down-regulating contractile function as an adaptation to reduced blood flow. Myocardial flow is considerably heterogeneous. Consequently, oxygen supply to the myocardium is also heterogeneous. Many lines of evidence show a close correlation between regional flow and regional metabolism. In low-flow/low-metabolism areas, myocardial function must be reduced, since the myocardium would otherwise undergo necrosis. Because no regional histological differences exist, the pattern of heterogeneity seems to shift over time. Hence, we hypothesize that such very regional hibernation presents an evolutionary, protective mechanism, permitting subsequent myocardial areas to rest within the ceaselessly working heart. We also hypothesize that a similar mechanism ensures the down-regulation of function following myocardial ischemia in order to induce myocardial hibernation on a broader level. Surprisingly, a substance (opioid in nature) contained in hibernator serum both induced hibernation-like state in non-hibernators and suppressed myocardial oxygen consumption. Thus, we lastly hypothesize that myocardial hibernation is a remnant of the early stages of evolution and is closer to physiological hibernation than traditionally viewed.

Animals↗
PubMed1995

[Pathophysiology of the "hibernating" myocardium].

Myocardial ischemia has traditionally been viewed as an imbalance between energy supply and demand. Within the first few seconds following an acute reduction of myocardial blood flow, energy demand of the hypoperfused myocardium clearly exceeds the reduced energy supply. However, this imbalance between energy supply and demand is an inherently unstable condition since ischemia induces mechanisms which are not yet understood, but reduce contractile function and thus energy demand. In the subsequent steady-state condition, the amount of contractile dysfunction is in proportion to the reduction of myocardial blood flow. A situation of persistent ischemic contractile dysfunction in viable myocardium which normalizes upon reperfusion has been termed myocardial hibernation. The metabolic status of such hibernating myocardium improves over the first few hours as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns towards control values. The hibernating myocardium can respond to an inotropic stimulation by dobutamine with increased contractile function, however, at the expense of a renewed worsening of the metabolic status. This situation of an increased regional contractile function at the expense of metabolic recovery during inotropic stimulation can be used to identify hibernating myocardium. The development of such delicate balance between regional myocardial blood flow and function during early ischemia is disturbed by unfavorable alterations in supply and demand. When after 5 min of ischemia, at a blood flow reduction compatible with the development of myocardial hibernation over 90 min, energy supply is further reduced by a further reduction of myocardial blood flow, necroses develop. Likewise, increasing energy demand by continuous inotropic stimulation with dobutamine induces necroses. Thus, both the further reduction in energy supply by an increasing severity of ischemia and an enhanced energy expenditure by continuous inotropic stimulation impair the development of myocardial hibernation and precipitate myocardial infarction. Hibernation over the first few hours of ischemia (short-term hibernation) is well characterized in animal experiments. Increased release of endogenous adenosine and activation of ATP-dependent potassium channels as the underlying mechanisms have been ruled out. The existence of hibernation over weeks or months (long-term hibernation) can only be inferred from clinical studies. In long-term hibernating myocardium morphological alterations occur. In myocardial biopsies from patients with prolonged contractile dysfunction which was reversible after bypass surgery, myofibrils are reduced in number and disorganized. Myocardial glycogen content as well as the extracellular collagen network are increased. Thus, despite the fact that the myocardium remains viable during persistent ischemia and contractile dysfunction is reversible upon reperfusion, there are severe morphological alterations. Understandably, full functional recovery following reperfusion can therefore require weeks or even months.

Animals↗
PubMed1964

CYTOCHEMICAL DIFFERENCES IN KIDNEYS FROM WINTER HIBERNATING AND AROUSED BATS (MYOTIS LUCIFUGUS), WITH PARTICULAR REFERENCE TO THE GOLGI ZONE.

Kidneys from winter bats (Myotis lucifugus) were removed and fixed in cold formalin-calcium while the animals were in the following states: (a) natural hibernation; (b) arousal from hibernation for 24 hours; (c) laboratory maintained hibernation; and (d) no hibernation since the previous winter. With fixed frozen sections, the lead salt method of Wachstein and Meisel with adenosine triphosphate as substrate (pH 7.2) showed enzymic activity localized in large vacuoles and smaller vesicles or droplets in the Golgi region of distal and proximal tubular epithelial cells of kidneys from hibernating bats. No ATPase activity was detected in the basal lamellae of tubular epithelium from hibernating bats. ATPase activity in the Golgi region was not seen in cells from kidney tubules of bats aroused from hibernation 24 hours previously or of animals that had not hibernated, whereas activity for ATPase was present in the basal infoldings of tubular epithelium from these animals. Inosine di- and triphosphatase and calcium activated ATPase activities were also detected in the Golgi region of hibernating bats but were not present in the basal infoldings of tubular epithelium from active animals. There was little or no activity toward the mono- and diphosphates of adenine, thiamine pyrophosphate, and the di- or triphosphates of guanidine, cytidine, or deoxyadenosine. The loss of enzymic activity from the Golgi region of the tubular epithelium from hibernating bats and its increase in the region of the basal infoldings of tubular epithelium in aroused bats suggests that the Golgi region plays a role in the synthesis of enzymic protein usually identified with the external cell membrane.

Adenosine Triphosphatases↗
PubMed2001

Down-regulation in the insulin-like growth factor (IGF) axis during hibernation in the golden-mantled ground squirrel, Spermophilus lateralis: IGF-I and the IGF-binding proteins (IGFBPs).

The golden-mantled ground squirrel, Spermophilus lateralis, undergoes a profound winter hibernation that represents, among other changes, a prolonged period of starvation. In addition to dramatic metabolic and other physiological adaptations during hibernation which serve to reduce fuel energy expenditure, we have hypothesized that there may also be significant changes in the endocrine axis that regulates energetically-expensive somatic growth. As compared with euthermic, non-hibernating controls, hibernating S. lateralis were found to have 75%-reduced serum concentrations of insulin-like growth factor-I (IGF-I; from approximately 625 to approximately 150 ng/ml in both females and males, P < 0.05). While IGFBP-3 was the predominant IGFBP in serum of the euthermic controls, its levels were reduced to a similar degree in serum from the hibernating animals. IGFBP-4 was present at relatively low levels in the euthermic controls, and was reduced to undetectable levels in hibernating animals. Surprisingly, there was no IGFBP detectable in the 30 kDa range in either euthermic or hibernating S. lateralis, suggesting that IGFBP-1 does not play a role in hibernation-related changes in the IGF axis. In accordance with these endocrine changes, when serum from hibernating S. lateralis was added to cartilage explant cultures (at a 5% v/v concentration), it exhibited no ability to alter (35)S-proteoglycan synthetic rate, whereas serum from the euthermic squirrels significantly stimulated synthetic activity by 2-fold. These results suggest that part of hibernation adaptation in S. lateralis includes down-regulation in the growth-regulatory IGF axis. J. Exp. Zool. 289:66-73, 2001.

Animals↗
PubMed2005

MAPKs are differentially modulated in arctic ground squirrels during hibernation.

Hibernating animals are very tolerant of trauma to the central nervous system such that dramatic fluctuations in cerebral blood flow occur during hibernation and arousal without apparent damage. Indeed, it was demonstrated that Arctic ground squirrels (AGS) experience acute and severe systemic hypoxia along with the dramatic fluctuation in cerebral blood flow when the animals are aroused from hibernation. While initial hypotheses concerned protective mechanisms in the hibernating state, recent evidence of sustained elevation of HIF1alpha in euthermic AGS from our laboratory suggests that a preparatory program of protective gene expression is chronically expressed in euthermic AGS. In this study we evaluated potential neuroprotective adaptations by examining the alteration of intracellular MAPK pathways that may be modulated by hypoperfusion/reperfusion in AGS during hibernation and arousal. We found that ERK and JNK are activated in both euthermic and aroused AGS compared to the hibernating group which positively correlated with HIF1alpha levels. The activation of ERK and JNK associated with HIF1alpha may play an important role in mediating neuroprotective adaptations that is essential for successful hibernation. Interestingly, p38 is activated in euthermic AGS but not in aroused AGS, which shows strong correlation with iNOS induction. Therefore, the attenuation of p38 activation and iNOS induction in hibernating and aroused animals may contribute to the attenuation of inflammation that plays important neuroprotective roles during hibernation. Taken together, the differential modulation of the MAPK pathways may be critical for neuroprotection of AGS necessary for fluctuations in oxygen and nutrient delivery during hibernation.

Adaptation, Physiological↗