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Central activation of the A1 adenosine receptor in fed mice recapitulates only some of the attributes of daily torpor

Abstract

Mice enter bouts of daily torpor, drastically reducing metabolic rate, core body temperature (T b), and heart rate (HR), in response to reduced caloric intake. Because central adenosine activation has been shown to induce a torpor-like state in the arctic ground squirrel, and blocking the adenosine-1 (A1) receptor prevents daily torpor, we hypothesized that central activation of the A1 adenosine receptors would induce a bout of natural torpor in mice. To test the hypothesis, mice were subjected to four different hypothermia bouts: natural torpor, forced hypothermia (FH), isoflurane-anesthesia, and an intracerebroventricular injection of the selective A1 receptor agonist N6-cyclohexyladenosine (CHA). All conditions induced profound hypothermia. T b fell more rapidly in the FH, isoflurane-anesthesia, and CHA conditions compared to torpor, while mice treated with CHA recovered at half the rate of torpid mice. FH, isoflurane-anesthesia, and CHA-treated mice exhibited a diminished drop in HR during entry into hypothermia as compared to torpor. Mice in all conditions except CHA shivered while recovering from hypothermia, and only FH mice shivered substantially while entering hypothermia. Circulating lactate during the hypothermic bouts was not significantly different between the CHA and torpor conditions, both of which had lower than baseline lactate levels. Arrhythmias were largely absent in the FH and isoflurane-anesthesia conditions, while skipped beats were observed in natural torpor and periodic extended (>1 s) HR pauses in the CHA condition. Lastly, the hypothermic bouts showed distinct patterns of gene expression, with torpor characterized by elevated hepatic and cardiac Txnip expression and all other hypothermic states characterized by elevated c-Fos and Egr-1 expression. We conclude that CHA-induced hypothermia and natural torpor are largely different physiological states.

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References

  • Ahmad FU, Wang MY, Levi AD (2014) Hypothermia for acute spinal cord injury–a review. World Neurosurg 82(1–2):207–214

    Article  PubMed  Google Scholar 

  • Anderson R, Sheehan MJ, Strong P (1994) Characterization of the adenosine receptors mediating hypothermia in the concious mouse. Br J Pharmacol 113(4):1386–1390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bjorness TE, Greene RW (2009) Adenosine and sleep. Curr Neuropharmacol 7(3):238–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borlongan CV, Hayashi T, Oeltgen PR, Su TP, Wang Y (2009) Hibernation-like state induced by an opioid peptide protects against experimental stroke. BMC Biol 7:31

    Article  PubMed  PubMed Central  Google Scholar 

  • Bouma HR, Verhaag EM, Otis JP, Heldmaier G, Swoap SJ, Strijkstra AM, Henning RH, Carey HV (2011) Induction of torpor: mimicking natural metabolic suppression for biomedical applications. J Cell Physiol 227(4):1285–1290

    Article  Google Scholar 

  • Braulke LJ, Heldmaier G (2010) Torpor and ultradian rhythms require an intact signalling of the sympathetic nervous system. Cryobiology 60(2):198–203

    Article  CAS  PubMed  Google Scholar 

  • Bruns RF, Daly JW, Snyder SH (1983) Adenosine receptor binding: structure–activity analysis generates extremely potent xanthine antagonists. Proc Natl Acad Sci USA 80(7):2077–2080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen G, van den Pol AN (1997) Adenosine modulation of calcium currents and presynaptic inhibition of GABA release in suprachiasmatic and arcuate nucleus neurons. J Neurophysiol 77(6):3035–3047

    CAS  PubMed  Google Scholar 

  • Cheng Y, Tao Y-M, Sun J-F, Wang Y-H, Xu X-J, Chen J, Chi Z-Q, Liu J-G (2010) Adenosine A1 receptor agonist N6-cyclohexyl-adenosine induced phosphorylation of delta opioid receptor and desensitization of its signaling. Acta Pharmacol Sin 31(7):784–790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Constantinides C, Mean R, Janssen BJ (2011) Effects of Isoflurane Anesthesia on the Cardiovascular Function of the C57BL/6 Mouse. ILAR J (National Research Council, Institute of Laboratory Animal Resources) 52:e21–e31

    Google Scholar 

  • Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24(1):31–55

    Article  CAS  PubMed  Google Scholar 

  • Fredholm BB, Johansson S, Wang Y-Q (2011) Adenosine and the Regulation of Metabolism and Body Temperature. In: Kenneth AJ, Joel L (eds) Advances in Pharmacology Academic Press. 61: 77–94

  • Gavrilova O, Leon LR, Marcus-Samuels B, Mason MM, Castle AL, Refetoff S, Vinson C, Reitman ML (1999) Torpor in mice is induced by both leptin-dependent and-independent mechanisms. Proc Natl Acad Sci 96(25):14623–14628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geiser F, Currie SE, O’Shea KA, Hiebert SM (2014) Torpor and hypothermia: reversed hysteresis of metabolic rate and body temperature. Am J Physiol Regul Integr Comp Physiol 307(11):R1324–R1329

    Article  CAS  PubMed  Google Scholar 

  • Gluck EF, Stephens N, Swoap SJ (2006) Peripheral ghrelin deepens torpor bouts in mice through the arcuate nucleus neuropeptide Y signaling pathway. Am J Physiol Regul Integr Comp Physiol 291(5):R1303–R1309

    Article  CAS  PubMed  Google Scholar 

  • Gordon CJ (2001) The therapeutic potential of regulated hypothermia. Emerg Med J 18(2):81–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Group T H. a. C. A. S (2002) Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 346(8):549–556

    Article  Google Scholar 

  • Hand LE, Saer BRC, Hui ST, Jinnah HA, Steinlechner S, Loudon ASI, Bechtold DA (2013) Induction of the metabolic regulator txnip in fasting-induced and natural torpor. Endocrinology 154(6):2081–2091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heller HC, Ruby NF (2004) Sleep and circadian rhythms in mammalian torpor. Annu Rev Physiol 66(1):275–289

    Article  CAS  PubMed  Google Scholar 

  • Iliff BW, Swoap SJ (2012) Central adenosine receptor signaling is necessary for daily torpor in mice. Am J Physiol Regul Integr Comp Physiol 303(5):R477–R484

    Article  CAS  PubMed  Google Scholar 

  • Jinka T, Carlson Z, Moore J, Drew K (2010) Altered thermoregulation via sensitization of A1 adenosine receptors in dietary-restricted rats. Psychopharmacology (Berl) 209(3):217–224

    Article  CAS  Google Scholar 

  • Jinka TR, Tøien Ø, Drew KL (2011) Season primes the brain in an arctic hibernator to facilitate entrance into torpor mediated by adenosine A1 receptors. J Neurosci 31(30):10752–10758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jinka TR, Combs VM, Drew KL (2015) Translating drug-induced hibernation to therapeutic hypothermia. ACS Chemi Neurosci 6(6):899–904

    Article  CAS  Google Scholar 

  • Lyman CP, O’Brien RC (1963) Autonomic control of circulation during hibernating cycle in ground squirrels. J Physiol Lond 168(3):477–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maher RL, Barbash SM, Lynch DV, Swoap SJ (2015) Group housing and nest building only slightly ameliorate the cold stress of typical housing in female C57BL/6J mice. Am J Physiol Regul Integr Comp Physiol 308(12):R1070–R1079

    Article  CAS  PubMed  Google Scholar 

  • Mertens A, Stiedl O, Steinlechner S, Meyer M (2008) Cardiac dynamics during daily torpor in the Djungarian hamster (Phodopus sungorus). Am J Physiol Regul Integr Comp Physiol 294(2):R639–R650

    Article  CAS  PubMed  Google Scholar 

  • Miller LP, Hsu C (1992) Therapeutic potential for adenosine receptor activation in ischemic brain injury. J Neurotrauma 9(2):S563–S577

    PubMed  Google Scholar 

  • Milsom WK, Zimmer MB, Harris MB (1999) Regulation of cardiac rhythm in hibernating mammals. Comp Biochem Physiol Part A Mol Integr Physiol 124(4):383–391

    Article  CAS  Google Scholar 

  • Minor RK, Chang JW, De Cabo R (2009) Hungry for life: how the arcuate nucleus and neuropeptide Y may play a critical role in mediating the benefits of calorie restriction. Mol Cell Endocrinol 299(1):79–88

    Article  CAS  PubMed  Google Scholar 

  • Morhardt JE (1970) Heart rates, breathing rates and effects of atropine and acetylcholine on white-footed mice (Peromyscus Sp.) during daily torpor. Comp Biochem Physiol 33(2):441–457

    Article  CAS  PubMed  Google Scholar 

  • Muzzi M, Blasi F, Masi A, Coppi E, Traini C, Felici R, Pittelli M, Cavone L, Pugliese AM, Moroni F, Chiarugi A (2013) Neurological basis of AMP-dependent thermoregulation and its relevance to central and peripheral hyperthermia. J Cereb Blood Flow Metab 33(2):183–190

    Article  CAS  PubMed  Google Scholar 

  • Oelkrug R, Heldmaier G, Meyer C (2011) Torpor patterns, arousal rates, and temporal organization of torpor entry in wildtype and UCP1-ablated mice. J Comp Physiol B Biochemi Syst Environ Physiol 181(1):137–145

    Article  CAS  Google Scholar 

  • Olson JM, Jinka TR, Larson LK, Danielson JJ, Moore JT, Carpluck J, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pelz KM, Routman D, Driscoll JR, Kriegsfeld LJ, Dark J (2008) Monosodium glutamate-induced arcuate nucleus damage affects both natural torpor and 2DG-induced torpor-like hypothermia in Siberian hamsters. Am J Physiol Regul Integr Comp Physiol 294(1):R255–R265

    Article  CAS  PubMed  Google Scholar 

  • Scirica BM (2013) Therapeutic hypothermia after cardiac arrest. Circulation 127(2):244–250

    Article  PubMed  Google Scholar 

  • Swoap SJ, Gutilla MJ (2009) Cardiovascular changes during daily torpor in the laboratory mouse. Am J Physiol Regul Integr Comp Physiol 297(3):R769–R774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swoap SJ, Weinshenker D (2008) Norepinephrine controls both torpor initiation and emergence via distinct mechanisms in the mouse. PLoS One 3(12):e4038

    Article  PubMed  PubMed Central  Google Scholar 

  • Swoap SJ, Gutilla MJ, Liles LC, Smith RO, Weinshenker D (2006) The full expression of fasting-induced torpor requires {beta}3-adrenergic receptor signaling. J Neurosci 26(1):241–245

    Article  CAS  PubMed  Google Scholar 

  • Swoap SJ, Rathvon M, Gutilla M (2007) AMP does not induce torpor. Am J Physiol Regul Integr Comp Physiol 293(1):R468–R473

    Article  CAS  PubMed  Google Scholar 

  • Swoap SJ, Iliff BW, Le S (2012) Adenosine, AMP, and daily torpor. Springer, Heidelberg

    Book  Google Scholar 

  • Tamura Y, Shintani M, Nakamura A, Monden M, Shiomi H (2005) Phase-specific central regulatory systems of hibernation in Syrian hamsters. Brain Res 1045(1–2):88–96

    Article  CAS  PubMed  Google Scholar 

  • Tupone D, Madden CJ, Morrison SF (2013) Central activation of the A1 adenosine receptor (A1AR) induces a hypothermic, torpor-like state in the rat. J Neurosci 33(36):14512–14525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker J, Glotzbach S, Berger R, Heller H (1977) Sleep and hibernation in ground squirrels (Citellus spp): electrophysiological observations. Am J Physiol Regul Integr Comp Physiol 233(5):R213–R221

    CAS  Google Scholar 

  • Yang JN, Tiselius C, Daré E, Johansson B, Valen G, Fredholm BB (2007) Sex differences in mouse heart rate and body temperature and in their regulation by adenosine A1 receptors. Acta Physiol 190(1):63–75

    Article  CAS  Google Scholar 

  • Yenari MA, Han HS (2012) Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 13(4):267–278

    CAS  PubMed  Google Scholar 

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Correspondence to Steven J. Swoap.

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Communicated by F. Breukelen.

This manuscript is part of the special issue Hibernation—Guest Editors: Frank van Breukelen and Jenifer C. Utz.

M. A. Vicent and E. D. Borre indicates co-first authorship.

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Vicent, M.A., Borre, E.D. & Swoap, S.J. Central activation of the A1 adenosine receptor in fed mice recapitulates only some of the attributes of daily torpor. J Comp Physiol B 187, 835–845 (2017). https://doi.org/10.1007/s00360-017-1084-7

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  • DOI: https://doi.org/10.1007/s00360-017-1084-7

Keywords

  • Torpor
  • Hibernation
  • Adenosine
  • Hypothermia
  • Targeted temperature management