Tulasi R. Jinka

Season primes the brain in an arctic hibernator to facilitate entrance into torpor mediated by adenosine A1 receptors

Torpor in hibernating mammals defines the nadir in mammalian metabolic demand and body temperature that accommodates seasonal periods of reduced energy availability. The mechanism of metabolic suppression during torpor onset is unknown, although the CNS is a key regulator of torpor. Seasonal hibernators, such as the arctic ground squirrel (AGS), display torpor only during the winter, hibernation season. The seasonal character of hibernation thus provides a clue to its regulation. In the present study, we delivered adenosine receptor agonists and antagonists into the lateral ventricle of AGSs at different times of the year while monitoring the rate of O2 consumption and core body temperature as indicators of torpor. The A1 antagonist cyclopentyltheophylline reversed spontaneous entrance into torpor. The adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA) induced torpor in six of six AGSs tested during the mid-hibernation season, two of six AGSs tested early in the hibernation season, and none of the six AGSs tested during the summer, off-season. CHA-induced torpor within the hibernation season was specific to A1AR activation; the A3AR agonist 2-Cl-IB MECA failed to induce torpor, and the A2aR antagonist MSX-3 failed to reverse spontaneous onset of torpor. CHA-induced torpor was similar to spontaneous entrance into torpor. These results show that metabolic suppression during torpor onset is regulated within the CNS via A1AR activation and requires a seasonal switch in the sensitivity of purinergic signaling.

Inhibition of NMDA-type glutamate receptors induces arousal from torpor in hibernating arctic ground squirrels (Urocitellus parryii).

J. Neurochem. (2012) 122, 934–940.

Translating drug-induced hibernation to therapeutic hypothermia.

Therapeutic hypothermia (TH) improves prognosis after cardiac arrest; however, thermoregulatory responses such as shivering complicate cooling. Hibernators exhibit a profound and safe reversible hypothermia without any cardiovascular side effects by lowering the shivering threshold at low ambient temperatures (Ta). Activation of adenosine A1 receptors (A1ARs) in the central nervous system (CNS) induces hibernation in hibernating species and a hibernation-like state in rats, principally by attenuating thermogenesis. Thus, we tested the hypothesis that targeted activation of the central A1AR combined with a lower Ta would provide a means of managing core body temperature (Tb) below 37 °C for therapeutic purposes. We targeted the A1AR within the CNS by combining systemic delivery of the A1AR agonist (6)N-cyclohexyladenosine (CHA) with 8-(p-sulfophenyl)theophylline (8-SPT), a nonspecific adenosine receptor antagonist that does not readily cross the blood-brain barrier. Results show that CHA (1 mg/kg) and 8-SPT (25 mg/kg), administered intraperitoneally every 4 h for 20 h at a Ta of 16 °C, induce and maintain the Tb between 29 and 31 °C for 24 h in both naïve rats and rats subjected to asphyxial cardiac arrest for 8 min. Faster and more stable hypothermia was achieved by continuous infusion of CHA delivered subcutaneously via minipumps. Animals subjected to cardiac arrest and cooled by CHA survived better and showed less neuronal cell death than normothermic control animals. Central A1AR activation in combination with a thermal gradient shows promise as a novel and effective pharmacological adjunct for inducing safe and reversible targeted temperature management.

Circannual Rhythm in Body Temperature, Torpor, and Sensitivity to A1 Adenosine Receptor Agonist in Arctic Ground Squirrels

A1 adenosine receptor (A1AR) activation within the central nervous system induces torpor, but in obligate hibernators such as the arctic ground squirrel (AGS; Urocitellus parryii), A1AR stimulation induces torpor only during the hibernation season, suggesting a seasonal increase in sensitivity to A1AR signaling. The purpose of this research was to investigate the relationship between body temperature (Tb) and sensitivity to an adenosine A1 receptor agonist in AGS. We tested the hypothesis that increased sensitivity in A1AR signaling would lead to lower Tb in euthermic animals during the hibernation season when compared with the summer season. We further predicted that if a decrease in euthermic Tb reflects increased sensitivity to A1AR activation, then it should likewise predict spontaneous torpor. We used subcutaneous IPTT-300 transponders to monitor Tb in AGS housed under constant ambient conditions (12:12 L:D, 18 °C) for up to 16 months. These animals displayed an obvious rhythm in euthermic Tb that cycled with a period of approximately 8 months. Synchrony in the Tb rhythm within the group was lost after several months of constant L:D conditions; however, individual rhythms in Tb continued to show clear sine wave–like waxing and waning. AGS displayed spontaneous torpor only during troughs in euthermic Tb. To assess sensitivity to A1AR activation, AGS were administered the A1AR agonist N6-cyclohexyladenosine (CHA, 0.1 mg/kg, ip), and subcutaneous Tb was monitored. AGS administered CHA during a seasonal minimum in euthermic Tb showed a greater drug-induced decrease in Tb (1.6 ± 0.3 °C) than did AGS administered CHA during a peak in euthermic Tb (0.4 ± 0.3 °C). These results provide evidence for a circannual rhythm in Tb that is associated with increased sensitivity to A1AR signaling and correlates with the onset of torpor.

Hibernation: A Natural Model of Tolerance to Cerebral Ischemia/Reperfusion

Hibernation, a means of systemic energy conservation, defies the need for most life-sustaining processes. Hibernation is recognized by a state of prolonged torpor where whole body metabolic rate, core body temperature (T b), heart rate, and blood flow decrease to 1–10 % of values observed during sleep. These bouts of torpor are interrupted at regular intervals by brief episodes of heterogeneous rewarming and reperfusion of vital organs, including the brain. Despite the reduction of cerebral blood flow during torpor or the return of cerebral blood flow during interbout arousals, hibernation produces no evidence of neuropathology. Multiple adaptations, at the whole animal and tissue levels, during torpor reveal a combination therapy–like scenario that likely contributes to ischemic tolerance. Nonetheless, some hibernating species tolerate ischemic-like cerebral blood flow even when not hibernating outside of the hibernation season and when T b is maintained at 37 °C. The arctic ground squirrel (Urocitellus parryii), a species studied extensively as a model of cerebral ischemia tolerance, resists neuronal pathology following cardiac arrest in vivo and following various paradigms designed to mimic cerebral ischemia in brain slices and cultured neurons. Here we review evidence that supports and refutes hypothesized mechanisms of ischemia tolerance in arctic ground squirrels with the caveat that much remains to be learned about mechanisms of ischemia tolerance in arctic ground squirrels and in other mammalian hibernators. Although hibernating mammals resist injury following cerebral ischemia/reperfusion even when not hibernating, torpor nonetheless is a phenotype with obvious neuroprotective advantages including cold tissue temperatures, a decrease in metabolic demand, and suppressed immune responsiveness. Thus we also review recent breakthroughs in the understanding of how the central nervous system regulates the onset of hibernation and discuss prospects for inducing hibernation in humans.

Potential Mechanisms of Metabolic SuppressionDownstream of Central A1AR Activation During Onset of Torpor

Hibernating animals demonstrate a nadir in metabolic demand and body temperature (T b) during torpor that is fundamental to adaptation to seasonal periods of reduced resource availability. A recent study shows how the brain regulates metabolic suppression during onset of torpor suggesting that central A1 adenosine receptor signaling is both necessary and sufficient to trigger decreases in metabolic rate and T b. This leads to an interesting question of how central signals are transduced to the periphery to elicit global suppression of metabolism and this chapter discusses relevant hypotheses.

The Bioenergetic Network of Adenosine in Hibernation, Sleep, and Thermoregulation

Adenosine is a homeostatic bioenergetic network regulator that plays a fundamental role in energy homeostasis through biochemical, bioenergetic, and receptor dependent processes. Hibernation, torpor, and sleep are integral to energy homeostasis. Here we review evidence that adenosine receptor dependent signaling as well as biochemical and bioenergetic influences of adenosine are essential to all three of these processes placing adenosine at the core of mammalian energy homeostasis. Central A1 adenosine receptor (A1R) dependent signaling is necessary for onset of hibernation and fasting-induced torpor in ground squirrels, hamsters, and mice. Activation of A1R within the central nervous system is sufficient to induce hibernation. A seasonally mediated change in sensitivity to central A1R stimulation is necessary for A1R agonist-induced hibernation in ground squirrels and may underlie the distinction between sleep and hibernation. One function of sleep is to restore brain energy homeostasis, while the primary function of hibernation and torpor is to restore or protect somatic energy homeostasis. Where in the brain A1R agonists act to induce torpor and how central A1R dependent signaling reduces metabolic rate to 1–2 % of resting metabolic rate in hibernating animals is a topic for further research. Understanding mechanisms of energy homeostasis may have implications for treatment of stroke, cardiac arrest, and other conditions where delivery of blood fails to meet demand.

Erratum: Circannual rhythm in body temperature,torpor, and sensitivity to A1 adenosine receptor agonist in Arctic ground squirrels (Journal of Biological Rhythms (2013) 28:3 (201-207) DOI: 10.1177/0748730413490667)

Olson JM, Jinka TR, Larson LK, Danielson JJ, Moore JT, Carpluck J, and Drew KL (2013) Circannual rhythm in body temperature, torpor, and sensitivity to A1 adenosine receptor agonist in Arctic ground squirrels. J Biol Rhythms 28(3):201-207. (Original DOI: 10.1177/0748730413490667)