旭川医大HPへ移動します。
先頭ページに戻ります。
本ページ改訂履歴などいろいろなニュースを表示します。
研究内容概略を紹介します。
このページです。
講義・実習関係情報(学内限定)
講座内限定
関連学会HPなどへのリンク集です。
各種募集に関する情報
 
 



 

OSBORNE, Peter Graham, PhD (Guest Scientist)

      posborne@asahikawa-med.ac.jp

 

 
Hibernation Research:
Exploring the extra dimension in mammalian life
   
1. Background
2. Past research
3. Current research
   

1. Background

I have studied many things over the years, ecology, neurochemistry and analytical chemistry but recently my research has focused on the study of the mammalian hibernation. This is a totally fascinating subject and research of hibernation physiology requires employing a challenging combination of imagination, unorthodoxy and dedication coupled with good grasp of standard physiology and analytical competence.

Western hibernation research is accredited with having its origin in the laboratory of E. Dubois in 1896. However the ancients were well aware of the existence of hibernation, and the close association of humans with their natural environment enable Aristotle, in History of Animals book 8, to correctly interpret the hibernation of bears as a light winter sleep, an understanding that was lost and remains lost to the general public today. However, Aristotle and his observers weren't without error and they incorrectly interpreted the winter disappearance of some animals, such as swallows, as hibernation and not migration. This stimulated the fictitious belief that swallows hibernated in mud at the bottom of rivers. This fallacy persisted in English/American general knowledge, until the 19 century. In precommunist Chinese and current Japanese scripts the ancient meaning or origin of a word can sometimes be discerned from its pictographic form. In Japanese language, tomin (hibernation utilising the kanji for winter and sleep) and suimin (sleep) and nemeru (sleep) all have the same basic kanji. Both tomin and suimin are of chinese origin and older than nemeru but it is not possible to determine if the kanji that is attributed to both animal and human sleep is applied to hibernation to suggest a recognition of the similiarity to sleep or is applied by default since no subtleties of the depth of sleep were recognised in earlier times. In English, the nomenclature within the field of hibernation research is at present disastrously imprecise. This results, in part, from the recent understanding that hibernation is not a continuous inert state but rather a state of continuous regulation that requires new nomenclature to unambiguously describe the specific phases of the hibernation cycle, that under natural conditions occurs in the winter season. The interchangeable use of torpor and hibernation is incorrect, makes obscure distinct physiological states and appears to result from American scientific imperialism. In the absence of better official terminology a normal body temperature of 36-37oC will be called cenothermia ['cenothermia' is the official term replacing 'euthermia', approved by the Thermal Commission of the International Union of Physiological Sciences (IUPS); see Jpn J Physiol 51, 245?280, 2001].

In this text I will use the phrases - entrance to hibernation, the maintenance phase of hibernation and arousal from hibernation to describe 3 of the 4 phases of a bout of hibernation. In hamsters, these 3 phases last about 100 h and are separated by a 10-14 h period of cenothermia called interbout arousal that is the 4th phase of the bout of hibernation. It is clear that each of these phases is not a homogeneous physiological state but a dynamic period. As our understanding of the biochemistries of each phase improves, each will in turn require additional subdivision for descriptive accuracy. In hamsters, the hibernation season can be induced by cold dark environments that once initiated persists for about 3-4 months during which time the hamster displays bouts of hibernation (see Fig 1). At the end of this time the hamster will cease to hibernate, increases food intake, and hence bodyweight, despite the fact that the environment remains dark and cold (Fig.1).
   
   
  Figure 1: Hibernation of syrian hamsters (Mesocricetus auratus)  

Seasonal hibernation or opportunistic torpor are displayed by a small number of warm blood animals from within many of the 21 orders of mammals and at present it is the general consensus that the ability to reduce body temperature and engage in hypometabolism is an ancient physiology retained and rarely expressed rather than a physiology that has evolved independently in numerous animal lineages.

I am not completely convinced by this argument but feel that if hypothermia was an ancient trait, it has been so substantially modified by different hibernators over the course of evolution that any search for a biochemistry common to hibernation per se will be confounded by inconsistencies. Certainly the biochemical dissimilarities between hibernation in hamsters and ground squirrels appear to be more numerous than the similarities. This philosophy determines that each species of hibernator presents unique biochemical adaptations the better understanding of which will provide a rich resource for future biomedical applications and strategies for life. Towards this goal and towards elevating hibernation research from the realm of phenomenology, researchers need to apply creative techniques to describe the physiologies of hibernation and then experimentally test the hypothesis established and apply the finding to the warm world.

Profile
Born 1957, Australia. High school education: Papua New Guinea & Australia. BSc Hon Zoology: Australian National University. PhD Brain Physiology: HFI, Melbourne University. Currently I hold the ambiguous title of Guest Scientist at Asahikawa Medical College, Japan.

I have lived and researched productively in Australia, Antarctica, America, China, Japan, Sweden and Taiwan in academic and business environments. Life in these cultures has given me a diverse range of skills, honed my ability for independent thought and action and educated me to the value and complexity of diversity. Languages: English - adequate; Japanese - conversational; Mandarin - basic. Hobbies: snow boarding, canoeing, reading. Likes: opera & kabuki, merlot & atsukan, eggplant musaka & choudofu, strong weather & art galleries. Dislikes: inflexible bureaucracy, bigotry.

 
 


2. Past research

In this laboratory we have been working towards improving our understanding of the physiology of hibernation. Practically this entails studying male Syrian hamsters (Mesocricetus auratus) during the maintenance phase, arousal phase or interbout arousal phase of the hibernation bout.

Why choose to study hibernation in hamsters?

Hamsters, unlike the majority of other hibernators, regulate their level of blood glucose at cenothermic levels during the entire bout of hibernation. The regulation of blood glucose is a strict tenet of human biology and this physiological fundamental, that is maintained between humans and hibernating hamsters is, I think, a prerequisite commonality for the eventual application of the biochemistry of hibernation to the human experience.

To date we have established that

A)
Arousal from hibernation to cenothermia is associated with changes in cerebral blood flow (CBF) unparalleled in cenothermic physiology. Chemical regulation of cerebral blood flow by gases dissolved in blood is state dependently regulated, in that, vasodilative and respiratory responses (RR) to hypercapnia observed at cenothermia are reversed during arousal from hibernation (Figure 2; Ref 9).
   

 

Figure 2: Changes of cerebral blood flow (CBF), respiratory rate (RR) and temperature of interscapular brown adipose tissue (BAT) observed during arousal from hibernation in syrian hamsters (Mesocricetus auratus)

     
B)
The maintenance of regional heterothermy during arousal from hibernation (upper body warming faster than hind body) is largely mediated by rapid sympathetic activation of adrenergic vasoconstriction of hind limb vasculature that increases blood volume in the upper body before metabolic activity increases. Once the upper body has attained a temperature of 36oC hind body vascular sympathetic tone is attenuated and anatomical heterothermy is abolished as warm blood is freed to circulate in hind limbs. (Figure 3; Ref 3)
   
Figure 3: Blood redistribution during arousal from hibernation visualised using tecnetium albumin marker.
     
C)
In vivo protein syntheis and mRNA synthesis are essentially inhibited during hibernation and in the early period of arousal from hibernation where body temperature increases by non-shivering thermogenesis. This determines that the majority of the molecular processing required for the maintenance phase of hibernation and arousal from hibernation, up until the onset of shivering thermogensis, occurs in the cemothermic interbout phase before the hamster enters hibernation. (Ref 5)
D)
In brain tissue, arousal from hibernation to cenothermia involves an increased metabolic flux through the xanthine oxidoreductase (XOR) to produce urate, hydrogen peroxide and superoxide free radical. Brain and ECF glutathione appears to have a role other than scavenging free radicals at this time. In contrast, brain ECF ascorbic acid appears to play a role in scavenging free radicals during this transition and in the 2 hours immediately after arousal to cenothermia. It is conceivable that ECF ascorbic acid may also function as an osmotic agent. (Figure 4; Ref 1 & Ref 2)
   

 

Figure 4: Antioxidants in the striatal extracellular fluid during arousal from hibernation

   
     
   

3. Current research

Our current research focuses on

A)
Utilising microdialysis in the examination of the local neurochemical mechanisms by which hibernators maintain non-pathological tissue integrity in the face of the generation of free radicals during increasing metabolism, temperature and cerebral reperfusion that occurs during arousal from hibernation.
B)

Utilising 13C NMR spectroscopy and 14C labeled substrates to investigate the metabolic pathways active in the brain during the maintenance phase of hibernation. The maintenance phase of hibernation, is an actively induced and homeostatically regulated state of hypothermia that, in hamsters, is associated with or dependent upon depressed, to absent EEG, and substantial reorganisation of intracellular and extracellular biochemistry. In the brain specific biochemical pathways are inhibited during the maintenance phase of hibernation while other pathways remain functional. The use of NMR complimented with radioactive isotope studies has enabled us to tease out some of the metabolic secrets of the brain (manuscript in preparation). Our ultimate goal is to mimic the selective biochemical inactivation/activation found during hibernation, in cenothermic animals, to induce reversible metabolic depression. Our objective is a therapy that can quickly and reversibly induce brain hypometabolism so as to preserve the balance between nutrient supply and demand in conditions of compromised blood flow, such as stroke or traumatic brain injury. Applications of whole body hypometabolism in times of limited availability of food have obvious applications in space travel and in times after natural disaster.

C)

A project in collaboration with Asahiyama Zoological Park to measure heart rate and body temperature of wild free ranging Tanuki (Nyctereutes procyonoides albus) to determine if the Ezo Tanuki hibernates during the long cold winter of Hokkaido. On the basis of its autumnal fattening (a doubling of body weight), its lack of anatomical adaptations for over snow travel, and its dening and lack of feeding in the winter months we speculate that the Ezo Tanuki probably hibernates in a manner similar to bears. In our field studies, wild Ezo Tanuki are surgically implanted with temperature dataloggers, and after recovery, are fitted with radio collars and released into the wild. The following year they are recaptured and the body temperature profile for the preceding year is obtained. The Tanuki is released unharmed into the area it was captured (Figure 5).

The Tanuki is an interesting animal but sadly its ecology is poorly documented and its physiology is largely uninvestigated. It is a wild, crepuscularly active canid endemic to the Asian region and more recently it has been introduced to northern Europe. The genus has 5-6 subspecies. The Japanese Tanuki, unlike the Chinese, Korean or Russian Tanuki has undergone a remarkable chromosomal fusion from 2n = 54 + B chromosomes in the latter animals to 2n = 38 + B chromosomes in the Nippon Tanuki. It is interesting that this reduced chromosomal number appears to be ubiquitous across Japan on Honshyu, Kyushu and surprisingly also on Hokkaido. For mammals, the Tsugaru strait (Blakiston Line) effectively prevents genetic communication between the north island of Hokkaido and the southern island of Honshyu. It is not clear how the Japanese Tanuki comes to be on both sides of this strait. It is possible that Ainu people transported the Tanuki to Hokkaido. In Hokkaido, Tanuki numbers appear to be declining in response to increased competition from foxes and the recently introduced American raccoon. An comprehensive account of Tanuki biology can be found at the following web site: http://www.canids.org/species/.
   
 

Figure 5: Preparation of Tanuki for radio transmitter implant

 
 

PUBLICATIONS FOR THE LAST 10 YEARS

1. Osborne, P.G. and Hashimoto, M. Brain ECF antioxidant interactions in hamsters during arousal from cenothermia. Behav. Brain Res.,178, 115-122, 2007. PubMed

2.

Osborne, P.G. and Hashimoto, M. Brain antioxidant levels in hamsters during hibernation, arousal and cenothermia. Behav. Brain Res. 168: 208-214, 2006. PubMed
3. Osborne, P.G. Sato, J., Shuke, M. and Hashimoto, M. Sympathetic alpha-adrenergic regulation of blood flow and volume in hamsters arousing from hibernation. Am J. Physiol. 289, R554-562, 2005. PubMed
4. Osborne, P.G. and Hashimoto, M. Chemical polymerisation of m-phenylenediamine in the presence of glucose oxidase produces stable enzyme retaining polymer for amperometric detection of glucose from dialysate. Analyst. 129, 759-765, 2004.  PubMed
5. Osborne, P.G., Gao, B.H. and Hashimoto, M. Determination in vivo of newly synthesized gene expression in hamsters during phases of the hibernation cycle. Jap J. Physiol. 54, 295-305, 2004. PubMed
6. Osborne, P.G. Research in Japan. A foreign scientist’s perspective of research at a Japanese University. J. Jap. Physiol Soc. 66 (7-8), 250-253, 2004. [with preface by the author] PDF (AcrobatReader 6 or higher required)
7. Wang L., Li, Y., Han, H., Lui, G. and Osborne, P.G. Perfusate oxygen and carbon dioxide concentration influences basal microdialysate levels of striatal glucose and lactate in conscious rats. Neurosci Let . 344, 91-94, 2003. PubMed
8. Wang L., Osborne, P.G. Yu, X., Shangguan, D., Zhao, R., Han, H. and Lui, G. Hyperoxia caused by microdialysis perfusion decreased striatal monoamines: involvement of oxidative stress. Neurochem Int. 42, 465-470, 2003. PubMed
9. Osborne, P.G. and Hashimoto, M. State dependent regulation of cortical blood flow and respiration in hamsters: response to hypercapnia during arousal. J. Physiology. 547, 963-968, 2003. PubMed
10. Zeng, Y.N., Zheng, N., Osborne, P.G., Li, Y.Z., Chang, W.B. and Wen, M.J. Cyclic voltammetry characterization of metal complex imprinted polymer. J. Mol Recognit. 15 (4), 204-8, 2002. PubMed
11. Mao, L., Osborne, P.G., Yamamoto, K. and Kato, T. Continuous on-line measurement of cerebral hydrogen peroxide using enzyme modified ring-disc plastic carbon film electrode. Anal. Chem. 74 (15), 3684-89, 2002. PubMed
12. Hashimoto, M., Gao, B., Utsumi, K., Ohinata, H. and Osborne, P.G. Arousal from hibernation and BAT thermogenisis against cold: central mechanisms and molecular basis. J.Thermal Biology. 27, 503-515, 2002.
13. Osborne, P.G., Li, X.F., Li, Y.Z. and Han, H.W. An oxygen sensing microdialysis probe for in-vivo use. J. Neurosci. Res. 63, 224-232, 2001. PubMed
14. Drew, K.L., Osborne, P.G., Frerichs, K.U., Hu, Y., Koren, R.E., Hallenbeck, J.M., and Rice, M.E. Ascorbate and glutathione regulation in hibernating ground squirrels. Brain Res. 851, 1-8, 1999. PubMed

15.

Osborne, P.G., Hu, Y., Covey, D.N., Barnes, B.M., Katz, Z. and Drew, K.L. Determination of striatal extracellular gamma aminobutyric acid in hibernating and non-hibernating Arctic ground squirrels using quantitative microdialysis. Brain Res. 839 (1), 1-6, 1999. PubMed
16. Osborne, P.G. Letter to the editor. Biosensors and Bioelectronics. 14, 439-440, 1999.
17. Osborne, P.G., Niwa, O. and Yamamoto, K. Plastic film carbon electrodes: Enzymatic modification and optimization for on-line, simultaneous measurement of lactate and glucose using microdialysis sampling. Anal. Chem. 70 (9), 1706-1710, 1998. PubMed
18. Osborne, P.G. and Yamamoto, K. Disposable, enzymatically modified plastic film carbon electrodes for use in high performance liquid chromatographic electrochemical detection of glucose or hydrogen peroxide from immobilized enzyme reactors. J.Chromatography B. 707, 3-8, 1998. PubMed
19. O’Connor, W.T., Osborne, P.G. and Ungerstedt, U. Tolerance to catalepsy following chronic haloperidol is not associated with changes in GABA release in the globus pallidus.Brain Res. 787 (2) , 299-303, 1998. PubMed
20. Osborne, P.G., Niwa, O., Kato, T. and Yamamoto, K. On-line, continuous measurement of extracellular brain glucose using microdialysis and electrochemical detection. J. Neurosci. Methods 77 (2), 143-150, 1997. PubMed
21. Osborne, P.G. Hippocampal and striatal blood flow during behavior in rats. Acute and chronic laser Doppler flowmetry study. Physiol. Behav. 61 (4), 485-492, 1997. PubMed
22. Osborne, P.G. Interpretation of microdialysis data. J. Neurochem. 68 (4), 1773-1776, 1997. PubMed
23. Osborne, P.G., Niwa, O., Kato, T. and Yamamoto, K. On-line, real time measurement of extracellular brain glucose using microdialysis and electrochemical detection. Current Separations 15 (1), 19-23, 1996.
24. Kato, T., Lui, J.K.H., Yamamoto, K., Osborne, P.G. and Niwa, O. Detection of basal acetylcholine release in the microdialysis of rat frontal cortex by high performance liquid chromatography using a horseradish peroxidase-osmium redox polymer electrode with pre-enzyme reactor. J. Chromatogr. B. 682, 162-168, 1996. PubMed
25. Niwa, O., Torimitsu, K., Morita, M., Osborne, P.G. and Yamamoto, K. Concentration of extracellular L-glutamate released from cultured nerve cells measured with a small volume on-line sensor. Anal. Chem., 89 (11), 1865-1870, 1996.

 
 

since
access counter
5 February 2006

 
  Department of Physiology, Asahiakwa Medical College  
  Asahikawa 078-8510, Hokkaido, Japan  
  Tel: +81-166-68-2322 / FAX: +81-166-68-2329
御照会はこちらへ