Local Cerebral Blood Flow during Hibernation, a Model of Natural Tolerance to “Cerebral Ischemia”

Frerichs, Kai U.; Kennedy, Charles; Sokoloff, Louis; Hallenbeck, John M.

doi:10.1038/jcbfm.1994.26

Cited by 222 publications

(197 citation statements)

References 53 publications

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“…Data are presented as percentage increase above oligomycin-induced state 4 respiration (mean ± SEM; n ≥ 3; unpaired t test; **P < 0.01). per minute (40)] in torpid animals pose formidable obstacles to efficient heat exchange between BAT and nervous tissue. Although we do not exclude a significant contribution of BATmediated heating, our findings offer an additional nervous tissue-autonomous mechanism.…”

Section: Discussionmentioning

confidence: 99%

Neuronal UCP1 expression suggests a mechanism for local thermogenesis during hibernation

Laursen

Mastrotto

Pesta

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Hibernating mammals possess a unique ability to reduce their body temperature to ambient levels, which can be as low as −2.9°C, by active down-regulation of metabolism. Despite such a depressed physiologic phenotype, hibernators still maintain activity in their nervous systems, as evidenced by their continued sensitivity to auditory, tactile, and thermal stimulation. The molecular mechanisms that underlie this adaptation remain unknown. We report, using differential transcriptomics alongside immunohistologic and biochemical analyses, that neurons from thirteen-lined ground squirrels (Ictidomys tridecemlineatus) express mitochondrial uncoupling protein 1 (UCP1). The expression changes seasonally, with higher expression during hibernation compared with the summer active state. Functional and pharmacologic analyses show that squirrel UCP1 acts as the typical thermogenic protein in vitro. Accordingly, we found that mitochondria isolated from torpid squirrel brain show a high level of palmitate-induced uncoupling. Furthermore, torpid squirrels during the hibernation season keep their brain temperature significantly elevated above ambient temperature and that of the rest of the body, including brown adipose tissue. Together, our findings suggest that UCP1 contributes to local thermogenesis in the squirrel brain, and thus supports nervous tissue function at low body temperature during hibernation.T hirteen-lined ground squirrels (Ictidomys tridecemlineatus) are obligatory hibernating mammals. They are found across a wide range of latitudes, from southern Canada to the Gulf of Mexico. In northern habitats with long winters and limited food resources, ground squirrels breed only once a year, in late spring, and then hibernate in underground burrows from October to April. Hibernation consists of cycling between bouts of torpor and brief interbout arousal periods, each usually lasting less than 24 h (1, 2).During the long hibernation season, torpid animals undergo dramatic perturbations, including reduction in heart, respiratory, and overall metabolic rates, as well as decreases in core body temperature from 37°C to just above ambient temperature (often as low as 1-5°C) (2). Despite such a depressed physiologic phenotype, torpid animals remain sensitive to their environment (3). For example, during extreme winters, when ambient burrow temperatures reach the freezing point of water, most hibernating mammals increase metabolic activity and warm up as a safety precaution to prevent freezing (4). Similarly, arousal can be triggered by sound, touch, or a sudden increase in ambient temperature (3, 5). Thus, hibernating animals maintain activity in their peripheral and central nervous systems. Indeed, physiologic experiments conducted on nerve fibers isolated from torpid hamsters and squirrels demonstrated the ability to generate action potentials at temperatures prohibitively low for their nonhibernating relatives (i.e., rats, mice) (6-8).Deeply hibernating animals can keep their brain temperatures elevated above ambient by seve...

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Section: Discussionmentioning

confidence: 99%

Neuronal UCP1 expression suggests a mechanism for local thermogenesis during hibernation

Laursen

Mastrotto

Pesta

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Cerebral blood flow waxes and wanes up to 10-fold in parallel with body temperature throughout the 8-to 9-month hibernation season without neurologic damage (Frerichs et al, 1994;Lust et al, 1989;Ma et al, 2005). Tolerance to hypoxic and ischemic events in hibernating species may have evolved as a means to endure transitions into and out of torpor (Drew et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Arctic Ground Squirrel (Spermophilus Parryii) Hippocampal Neurons Tolerate Prolonged Oxygen—Glucose Deprivation and Maintain Baseline ERK1/2 and JNK Activation Despite Drastic ATP Loss

Christian

Ross

Zhao

et al. 2008

J Cereb Blood Flow Metab

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Oxygen-glucose deprivation (OGD) initiates a cascade of intracellular responses that culminates in cell death in sensitive species. Neurons from Arctic ground squirrels (AGS), a hibernating species, tolerate OGD in vitro and global ischemia in vivo independent of temperature or torpor. Regulation of energy stores and activation of mitogen-activated protein kinase (MAPK) signaling pathways can regulate neuronal survival. We used acute hippocampal slices to investigate the role of ATP stores and extracellular signal-regulated kinase (ERK)1/2 and Jun NH 2 -terminal kinase (JNK) MAPKs in promoting survival. Acute hippocampal slices from AGS tolerated 30 mins of OGD and showed a small but significant increase in cell death with 2 h OGD at 371C. This tolerance is independent of hibernation state or season. Neurons from AGS survive OGD despite rapid ATP depletion by 3 mins in interbout euthermic AGS and 10 mins in hibernating AGS. Oxygen-glucose deprivation does not induce JNK activation in AGS and baseline ERK1/2 and JNK activation is maintained even after drastic depletion of ATP. Surprisingly, inhibition of ERK1/2 or JNK during OGD had no effect on survival, whereas inhibition of JNK increased cell death during normoxia. Thus, protective mechanisms promoting tolerance to OGD by AGS are downstream from ATP loss and are independent of hibernation state or season.

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“…Transmem brane ion and electrical potentials cannot be sustained because of energy insufficiency and high membrane per meability for ions under these conditions; metabolic and membrane functions, therefore, become uncoupled, lead ing to cellular dysfunction and irreversible neuronal damage (Hochachka, 1986). The adjustments that char acterize mammalian hibernation, however, confer a state of natural tolerance to cerebral hypoperfusion, to reduced availability of oxygen and glucose, and to hypothermia that permits animals to endure these stresses without any apparent neuronal death (Hochachka, 1986;Frerichs et a!., 1994Frerichs et a!., , 1995. An understanding of the molecular mechanisms that regulate hibernation could guide efforts to increase resistance to brain damage during brain isch emia.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Tyrosine Phosphorylation of a Brain Protein by Hibernation

Ohtsuki

Jaffe

Brenner

et al. 1998

J Cereb Blood Flow Metab

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Summary: Mammalian hibernation is a state of natural toler ance to severely decreased brain blood flow, As protein tyro sine phosphorylation is believed to be involved in the devel opment of resistance to potentially cell-damaging insults, we used immunoblotting for the phosphotyrosine moiety to ana lyze extracts from various tissues of hibernating and nonhiber nating ground squirrels. A single, hibernation-specific phos phoprotein was detected in the brain, but not in any other tissue tested. This protein, designated pp98 to reflect its apparent molecular weight, is distributed throughout the brain, and is associated with the cellular membrane fraction. The presence of the protein is tightly linked to the hibernation state; it is notThe pathophysiology of progressive brain damage and neuronal death during stroke are multifactorial, interwo ven, and complex (Hallenbeck and Frerichs, 1993). Ex perimental therapies that are aimed at counteracting one or another of the many mediators of neuronal damage and death often have worked in animal stroke models that are sensitive to small effects; however, they have tended to perform weakly in clinical trials of acute ce rebral infarction (Dorman et aI., 1996;Hallenbeck and Dutka, 1990). It is difficult to design a new therapeutic approach that accounts for the many factors that partici pate in progressive ischemic brain injury which may act as a constellation of minor causes. Natural states of tol-

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Local Cerebral Blood Flow during Hibernation, a Model of Natural Tolerance to “Cerebral Ischemia”

Cited by 222 publications

References 53 publications

Neuronal UCP1 expression suggests a mechanism for local thermogenesis during hibernation

Neuronal UCP1 expression suggests a mechanism for local thermogenesis during hibernation

Arctic Ground Squirrel (Spermophilus Parryii) Hippocampal Neurons Tolerate Prolonged Oxygen—Glucose Deprivation and Maintain Baseline ERK1/2 and JNK Activation Despite Drastic ATP Loss

Stimulation of Tyrosine Phosphorylation of a Brain Protein by Hibernation

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