| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Departments of Psychology and Neuroscience, The Ohio State University, Columbus, Ohio 43210; and Departments of 2 Psychology and 3 Integrative Biology, University of California, Berkeley, California 94720
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Golden-mantled ground squirrels (Spermophilus lateralis) undergo seasonal hibernation during which core body temperature (Tb) values are maintained 1-2°C above ambient temperature. Hibernation is not continuous. Squirrels arouse at ~7-day intervals, during which Tb increases to 37°C for ~16 h; thereafter, they return to hibernation and sustain low Tbs 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°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 E2 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.
circannual rhythms; Spermophilus lateralis; neural-immune interactions
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
MAINTENANCE OF IMMUNE FUNCTION requires considerable energy expenditure (42, 62) and may limit or constrain the extent to which animals engage in other energetically demanding activities (39, 40, 58). Large seasonal increases in energy expenditure associated with reproduction or low ambient temperatures (5) may compete with the day-to-day demands of host defense. Sustained regulated hypothermia, in the form of hibernation or daily torpor, has been adopted by some mammals to contend with seasonal changes in temperature and energy availability. Golden-mantled ground squirrels (Spermophilus lateralis) spend 5-6 mo each year in deep hibernation, during which core body temperature (Tb) is maintained at 1-2°C above ambient temperature (Ta). Many physiological systems, including brain and renal metabolism, respiration, cardiac function, digestion, and mitosis, are arrested or substantially reduced during a hibernation bout (12, 29, 31, 51, 54, 70, 74).
Although immune function during hibernation has been little studied, robust cell-mediated and humoral immune responses to pathogens are thought to be compromised. Impaired immune function in hibernators has been inferred from in vitro splenocyte proliferation or reduced antibody production over the course of an entire hibernation season (4, 7, 15, 32, 46, 48, 60). We are unaware of any studies that have assessed a hibernating individual's acute response to infection during a hibernation bout.
During the hibernation season mammals are not continuously torpid, but
instead arouse to normothermic Tbs (
37°C) at regular intervals, ranging from 2 to 30 days in different species. They sustain
elevated Tbs for <1 day, after which they return to
hibernation (21, 53, 71). Up to 80% of a hibernating
mammal's winter energy budget is consumed during these periodic
arousals (9, 35, 66), and the consequent depletion of
energy stores may contribute to overwinter mortality (71).
The functional significance of periodic arousals has proven enigmatic:
hypotheses that arousals are required to clear metabolic waste
(16), replenish blood glucose (20), restore
cellular electrolyte balance (17), regenerate the gonads
(1), prevent muscular atrophy (68), or
eliminate sleep debt (10, 56) have been proposed. Each of
these hypotheses has been challenged or rejected, and the function of
periodic arousals remains unclear (71). We considered that
maintenance of the immune system may have played a role in the
evolution of periodic arousals. If Tbs during deep
hibernation are below a threshold required to sustain minimal
immunocompetence, then hibernators might benefit from a periodic return
to normothermia during which they could recognize and combat pathogens
introduced during the preceding hibernation bout.
To test these conjectures, we assessed whether hibernating
golden-mantled ground squirrels can respond to a simulated infection induced by Escherichia coli lipopolysaccharide (LPS), a
standard immunological challenge. Recognition of LPS triggers the
acute-phase response (APR) to bacterial infection (56),
which involves release of a cascade of pyrogenic cytokines
[principally interleukin (IL)-1
, IL-6 and tumor necrosis
factor-
] that provoke prostaglandin (PG) secretion in the brain and
ultimately induce fever (14, 23, 43, 56). Evidence of a
febrile response to LPS during deep torpor would suggest that
hibernating animals can mount adequate cell-mediated immune responses;
absence of fever would imply that cell-mediated immune function is
impaired in anapyrexic animals. A return of immunocompetence, as
indicated by fever during the subsequent periodic arousal from
hibernation in an infected animal, would be consistent with an
immunorestorative function for periodic arousals. Diminished capacity
of a simulated pathogen to elicit fever during deep hibernation may
reflect deficits in either peripheral recognition of LPS or central
responsiveness to endogenous pyrogens (i.e., cytokines, PGs); to
address the latter issue, we challenged hibernators with
intracerebroventricular infusions of PGE2, the final
humoral mediator of LPS-induced fever in hypothalamic and preoptic
structures (50, 57).
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Animals. Adult male and female golden-mantled ground squirrels (n = 31) born in the laboratory to field-caught pregnant dams, trapped in Donner State Park, Truckee, CA, at an altitude of 1,783 m, were housed from birth in a light-dark cycle that provided 14 h light/day (lights on: 0700 Pacific Standard Time) at a Ta of 21 ± 3°C. Squirrels were provided ad libitum access to water and food (Simonsen rat chow, maintenance diet). Animals were weighed (±0.1 g) before the initiation of all treatments.
Temperature telemetry. Body temperature was recorded telemetrically from temperature-sensitive radiotransmitters implanted intraperitoneally under deep surgical anesthesia (12.5 mg pentobarbital sodium per initial 100 g body mass ± 0.5 mg per each additional 10 g body mass) (11). After recovery from surgery, squirrels were individually housed at a Ta of 5 ± 3°C in cages placed on receiver boards; Tb data collected every 10 min were transmitted to and stored by a computer for subsequent analyses. The onset of a hibernation bout was defined as the time at which Tb decreased below 33°C and remained below this value for six consecutive hours. A hibernation bout was considered terminated, and a periodic arousal initiated, when Tb increased by >1°C during each of three consecutive 10-min intervals. The normothermic interval between hibernation bouts began when Tb exceeded 33°C and remained above this value for six consecutive hours. The duration of a periodic arousal was calculated as the interval between the onset of normothermia and the onset of the subsequent hibernation bout. Normothermic squirrels were classified as nonhibernators if they failed to exhibit a bout of hibernation after 2 wk at 5°C.
Intraperitoneal injections.
All solutions, syringes, and needles were prechilled to 5 ± 3°C
before the injections were delivered. Normothermic (Tb > 33°C; n = 10) and hibernating (Tb
33°C; n = 21) squirrels were injected intraperitoneally with E. coli LPS (Sigma Chemical, 0111:B4;
500 µg/kg in 0.1 ml sterile saline) or an equal volume of sterile saline between 1400 and 1800. Each normothermic squirrel received a
control (saline) and an LPS injection on separate occasions in a
blocked experimental design. Hibernating squirrels had been torpid for
38.1 ± 7.7 h (LPS) and 36.5 ± 12.2 h (saline) at
the time of injection. Care was taken to minimize disturbance of
hibernating squirrels during the injection procedure so as not to
provoke premature arousal from hibernation. Bedding was cleared away by hand, exposing a hibernating squirrel's lateral lower abdomen. A
sterile 26-gauge hypodermic needle (connected to 9 cm of polyethylene infusion tubing and a 1.0-ml syringe) was inserted slowly through the
peritoneum. Hibernating squirrels were observed for several minutes to
ensure that insertion of the needle did not immediately provoke arousal
from hibernation before injections were delivered. Normothermic
squirrels were briefly restrained by hand and injected intraperitoneally with LPS or saline directly from a 1.0-ml hypodermic syringe.
Intracerebroventricular infusions. Normothermic squirrels (n = 19) implanted with radiotransmitters were fitted with stainless steel guide cannulas under deep surgical anesthesia (pentobarbital sodium). Cannulas (21 gauge) were stereotaxically implanted into the third ventricle (midline coordinates with ear bar at zero: 8.2 mm anterior to bregma and 7.3 mm below dura). After 7-10 days of postoperative recovery at 21°C, all squirrels were housed at 5°C. Infusion cannulas of hibernating squirrels were accessed by moving cage bedding to expose the animal's head. A 26-gauge internal infusion cannula connected to a 10-µl Hamilton syringe was inserted into the guide cannula and chilled (5 ± 3°C) PGE2 (Sigma Chemical; 500 ng in 10 µl; n = 7) or sterile saline (n = 7) was infused over the course of 60 s into the third ventricle. Squirrels had been torpid for 31.2 ± 6.3 h (PGE2) and 31.7 ± 7.4 h (saline) at the time of infusion. All treatments and surgical procedures were approved by the University of California at Berkeley Animal Care and Use Committee.
Statistics. Tb data were collected for at least 1 wk before the initiation of treatments in each individual. The onset and duration of periodic arousals were calculated, as well as mean Tb at various intervals during hibernation, emergence, and arousal. In cases where Tb values were unavailable at a given time point, the arithmetic mean of the immediately preceding and succeeding Tb values was interpolated and used in statistical analyses. Data are presented as means ± SE. Standard parametric statistical analyses (between-subjects and repeated-measures ANOVA, unpaired and paired t-tests) were conducted using Statview 5.0 (SAS Institute, Cary, NC). Where significant F-ratios were obtained, pairwise comparisons were conducted using Fisher's protected least significant difference test, or paired t-tests, as appropriate.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Effects of LPS in normothermic squirrels.
LPS injections significantly increased core Tbs of
normothermic ground squirrels over the first 12 h after treatment
(ANOVA, P < 0.0001; Fig.
1). After handling-induced hyperthermia
abated (hours 0 to +2),
squirrels injected with LPS manifested a 1-1.5°C fever of >8-h
duration, beginning 3-4 h after treatment; saline-treated squirrels, in contrast, exhibited no signs of fever but instead manifested the normal nocturnal decline in Tb typical of
this diurnal species (e.g., Ref. 18) and sustained
Tbs of 36-37°C during this interval (Fig. 1).
Tbs of LPS-treated squirrels were significantly higher than
those of saline-treated squirrels for over 4.5 h of the initial
12-h posttreatment interval (P < 0.05 for each 10-min
interval; Fig. 1). Unlike other stressors (e.g., repeated social
defeat; Ref. 49), which result in long-term (days to
weeks) changes in Tb, the effects of LPS treatments on Tb were limited to the immediate posttreatment interval;
Tbs of LPS-treated squirrels returned to values comparable
to those of saline-treated squirrels within 24 h after treatment
(data not shown).
|
Effects of LPS in hibernating squirrels.
In contrast to normothermic squirrels, hibernating squirrels did not
exhibit fever in the first hours after treatment with LPS. The majority
of squirrels (17 of 22) continued to hibernate after LPS and saline
treatments and did not initiate a periodic arousal until >2 days after
treatment. Saline- and LPS-treated squirrels did not differ in the
latency to onset of periodic arousal (P > 0.05; Fig.
2A). On arousal from
hibernation, LPS-treated squirrels exhibited significantly elevated
Tbs, comparable to those observed in nonhibernating
squirrels injected with LPS (P < 0.05 vs.
saline-treated squirrels; Fig. 2B). Squirrels treated with
saline had Tbs of 37-38°C during the first 8 h
of the subsequent periodic arousal (Fig. 2C), whereas
squirrels injected with LPS sustained Tbs that were
~1°C higher throughout most of this interval (ANOVA,
P < 0.01; Fig. 2C). Tbs of
LPS-treated squirrels were significantly higher than those of the
saline-treated squirrels (Fig. 2C) and significantly higher
than their own Tbs during previous arousals (i.e., before
treatments; Fig. 2B). LPS treatments also significantly
lengthened the duration of the subsequent periodic arousal;
normothermia was sustained for 97 and 16.3 h, respectively, in
squirrels treated with LPS and saline during hibernation
(P < 0.05; Fig. 3).
|
|
Effects of PGE2 in normothermic and hibernating
squirrels.
Central (icv) infusions of PGE2 significantly increased
Tbs of normothermic ground squirrels (ANOVA,
P < 0.0001; Fig. 4); within 10 min of treatment, infusions of PGE2, but not
saline, elicited Tb increases of 1-2°C. This acute,
monophasic hyperthermia was sustained for <2 h after PGE2
treatment (Fig. 4; P < 0.05 vs. saline-treated
squirrels for each 10-min interval). In hibernating squirrels,
PGE2 treatments did not elicit comparably rapid
hyperthermia (not illustrated) but tended to accelerate emergence from
hibernation (Fig. 5A).
Hibernating squirrels treated with PGE2 did not emerge from
hibernation immediately; instead, they initiated periodic arousals
~16 h after treatment, compared with a 49-h latency for squirrels
treated with saline (P = 0.06; Fig. 5A).
PGE2 infusions delivered during hibernation first induced
fever after the squirrels next aroused (Fig. 5, B and
C). Tbs of PGE2-treated squirrels during the immediate posttreatment periodic arousal were significantly higher than those of saline-treated squirrels and significantly higher
than their own Tbs during a pretreatment periodic arousal (P < 0.05, both comparisons; Fig. 5B). As
in nonhibernating animals, PGE2 treatment of hibernators
was associated with a 1.5-2.5°C increase in Tb that
was sustained for ~3 h after arousal (for each 10-min interval,
P < 0.05 vs. saline value and P < 0.05 vs. pretreatment value; Fig. 5C). Squirrels also
remained normothermic on average 3.5 times longer after
PGE2 treatment than after saline treatment; however, this
difference was not statistically significant (P = 0.07;
Fig. 5D).
|
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
These experiments assessed immune function in hibernating and normothermic ground squirrels. In nonhibernating squirrels, LPS, a nonreplicating pathogen that simulates infection, elicited a 1-1.5°C increase in Tb within 4 h; this fever persisted for >8 h. Hibernating squirrels, in contrast, initially exhibited no discernable febrile response to LPS. Tb of hibernating squirrels treated with LPS remained low (5-10°C) during the immediate posttreatment interval, and normal hibernation bouts were sustained and terminated spontaneously ~2 days after LPS treatment. Within 1 h of arousal from hibernation, however, LPS-treated squirrels exhibited a fever of 1-1.5°C, which was sustained for >8 h. The inability of LPS to induce fever while squirrels are in hibernation may indicate that component(s) of the APR to systemic infection (14, 38) are disabled at low Tbs but are reactivated on return to normothermic Tbs.
One or more of the cellular and humoral signaling events involved in
the APR may be interdicted in hibernating squirrels. In normothermic
mammals, LPS treatment induces fever by triggering secretion of
cytokines and other humoral mediators from macrophages and monocytes at
the site of infection (3, 38). The cytokines IL-1,
IL-6, and tumor necrosis factor- mimic, to varying degrees, LPS-induced fever in mice, rats, and rabbits; inhibition of these cytokines attenuates LPS-induced fevers (38). LPS and
cytokines do not cross the blood-brain barrier, but they may act within blood vessels, at the meninges, or at circumventricular sites to
produce diffusible mediators (63), which in turn trigger hyperthermia by their action on temperature-sensitive neurons in the
preoptic area (POA; Ref. 34). Injections of cyclooxygenase inhibitors
to the POA prevent LPS-induced fevers, indicating that PG activity at
this site may be the final endocrine mediator of LPS-induced fever
(57).
Low Tbs characteristic of hibernation may preclude fever by
inhibiting endocrine and immune function at any of a number of stages
of the febrile cascade, e.g., encounters between target cells and LPS,
LPS binding or internalization, LPS induction of cytokine production,
or cytokine induction of PG secretion. Torpor is accompanied by reduced
blood pressure and circulation (30), and the proportion of
leukocytes is substantially reduced during hibernation
(72). Temperature effects on membrane LPS binding are
complex and do not lend themselves to simple interpretation: depending
on the strain of LPS and the host cell type and source, low
temperatures (4-10°C) can inhibit (22, 24, 37, 67) or have no effect (28, 37, 67) on in vitro LPS binding and motility. However, low temperatures reliably inhibit internalization of
LPS (36, 67), as well as potentiators of LPS-induced
cytokine release (e.g., heparin-binding protein; Ref. 28).
Temperature dependence of LPS internalization may account for
observations that low temperatures inhibit LPS-induced cellular
responses (phagocytosis, Ref. 41; endothelial cell
detachment, Ref. 26; clearance of immune complexes, Ref.
55). Cytokine synthesis may also be inhibited by low
temperatures (73). Finally, the ability of proinflammatory cytokines to stimulate target cells may also be temperature-sensitive: IL-1 and IL-1 are not internalized by articular chondrocytes at
4°C and are more potent stimulators of PGE2 synthesis at
37°C than at 4°C (8). A decrease in temperature from
36°C to 34°C completely eliminates the ability of IL-1 to stimulate
thymocyte mitosis (25). Low tissue temperatures generally
inhibit the processing of fever signals at any of several stages in the
febrile cascade and may account for the observed nonresponsiveness to LPS of ground squirrels in deep torpor. Although the latency between PGE2 treatment and Tb elevation was greater in
torpid relative to normothermic squirrels, hibernating squirrels were
nonetheless responsive to central infusions of PGE2, as
evidenced by the acceleration of arousal from torpor after
PGE2 infusions. This suggests that eicosanoid receptors and
postreceptor signaling mechanisms are functional at low
Tbs. Thus the physiological basis of nonresponsiveness to
LPS during a hibernation bout appears to be located upstream from PG
receptors in the LPS-fever pathway, perhaps at the level(s) of LPS
induction of cytokine synthesis or cytokine induction of PG secretion.
The present findings extend earlier work suggesting that organismal immune responses are inhibited, to varying degrees, during hibernation. For example, antibody production in response to sheep red blood cells and hen egg white lysozome was diminished in hibernating 13-lined ground squirrels (32) and Syrian hamsters (6), respectively, as were in vitro agglutination responses of splenocytes derived from hibernating Syrian hamsters (60). Hibernation delays rejection of skin allografts (59), growth of neoplastic homologous tumors (45), and progression of coxsackie B3 viral infection (13), and it retards the development of cellular damage after lethal doses of x-irradiation (4). Each of these challenges, however, required intervals of days to weeks to elicit measurable immune responses, an interval that encompasses several periodic arousals and hibernation bouts. Such challenges, therefore, do not permit inferences regarding immunocompetence during a given hibernation bout.
In contrast, the present experiment used a pathogen that elicits a primary immune response over a time frame of a few hours; moreover, this challenge was presented during a hibernation bout. No integrated febrile response occurred during the hibernation bout; immediately on arousal from hibernation, however, LPS-treated squirrels exhibited fever, indicative of responsiveness to the LPS treatments administered several days earlier. The magnitude of these fevers was comparable to that elicited in nonhibernating squirrels, suggesting that the febrile response to pathogens is equivalent in nonhibernating squirrels and hibernators undergoing a periodic arousal. It seems unlikely, therefore, that the changes that render hibernating squirrels unresponsive to LPS are a consequence of a seasonal program or rhythm of responsiveness to pathogens, as previously suggested (e.g., Ref. 61); rather, the highly labile and reversible hyporesponsiveness to LPS likely reflects masking by low Tbs in vivo. Thus arousal from hibernation appears necessary for the expression of febrile responses to LPS.
Despite their substantial energetic cost (9, 35, 66), periodic arousals are ubiquitous among mammalian hibernators, and numerous hypotheses have been advanced to explain their functional significance (71). In most instances, arousals are viewed as emerging from constraints imposed on animals that sustain low Tbs for extended intervals; the periodic normothermia is viewed as necessary for removal of this, as yet to be identified, constraint. The abnormally long intervals of normothermia during the initial arousal after LPS treatment may be related to incompatibility of immune activation and anapyrexia, and they are consistent with anecdotal accounts that "sick animals never enter hibernation" (Ref. 44, p. 196-197). This observation, coupled with the finding that responsiveness to bacterial pathogens is arrested during hibernation, but fully restored on arousal, suggests that periodic arousals permit reactivation of a dormant immune system that can monitor for bacterial infection acquired during the preceding hibernation bout. Few studies have addressed immune function specifically during periodic arousals, but available data indicate that multiple, brief returns to normothermia exacerbate the effects of viral infections in hibernators. Sublethal doses of coxsackie B3 virus killed hibernating ground squirrels, with the progression of the infection restricted to periodic normothermic intervals (13). Thus the immune system appears incapable of successfully contending with viruses during the hibernation season. In contrast, activation of the APR in aroused hibernators and induction of fever during a periodic arousal suggest that animals are capable of responding to a bacterial infection in a normal manner during normothermic intervals. This contrast illustrates the potential immunological trade-offs associated with the execution of periodic arousals: such arousals may be required to monitor for and respond to bacterial pathogens while at the same time exacting a cost in potentiating the progression of viral infections.
Our data suggest that bacterial pathogens introduced during a hibernation bout do not provoke arousal from deep torpor or immune responses. Low Tbs do not, however, deter bacterial growth and proliferation. Indeed, injection of hibernating 13-lined ground squirrels with large numbers of Mycobacterium leprae results in rapid generalized infection and death, despite low Tbs (19). After brief (4-8 h) periods of adaptation, many species of bacteria, including E. coli (65), Campylobacter jejuni (27), Salmonella heidelberg (64), S. enteritidis (33), Listeria monocytogenes (2), Bacillus subtilis (69), and Vibrio vulnificus (47), continue to exhibit exponential growth at 5-10°C, temperatures well within the range of mammalian hibernation. Periodic elevations in Tb appear to be necessary for recognition of introduced pathogens, initiation of the APR response, maintenance of fever, and phagocytosis to avoid colonization and the ground squirrel's eventual death. The marked energetic costs of periodic arousals may in part reflect a trade-off between long-term requirements of maintaining energy balance and the need to contend with the more proximate challenge of parasite colonization.
| |
ACKNOWLEDGEMENTS |
|---|
We thank Evelyn Satinoff for advice on the experimental protocol and Carole Conn, Lisa Leon, Elizabeth Peloso, Kim Pelz, Brian Spar, and Chris Tuthill for expert technical assistance.
| |
FOOTNOTES |
|---|
* B. J. Prendergast and D. A. Freeman contributed equally to this work.
This research was supported by National Institutes of Health Grants HD-14595, MH-57535, and MH-11655.
Address for reprint requests and other correspondence: B. J. Prendergast, Dept. of Psychology, The Ohio State Univ., Townshend Hall, Columbus, OH 43210 (E-mail: prendergast{at}psy.ohio-state.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00562.2001
Received 17 September 2001; accepted in final form 7 December 2001.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Barnes, BM,
Kretzmann M,
Licht P,
and
Zucker I.
The influence of hibernation on testis growth and spermatogenesis in the golden-mantled ground squirrel, Spermophilus lateralis.
Biol Reprod
35:
1289-1297,
1986.
2.
Bayles, DO,
Annous BA,
and
Wilkinson BJ.
Cold stress proteins induced in Listeria monocytogenes in response to temperature downshock and growth at low temperatures.
Appl Environ Microbiol
62:
1116-1119,
1996.
3.
Blatteis, CM,
and
ehíc E.
Prostaglandin E2: a putative fever mediator.
In: Fever: Basic Mechanisms and Management, edited by Mackowiak PA.. Philadelphia, PA: Lippincott-Raven, 1997, p. 117-145.
4.
Brace, KC.
Histological changes in the tissues of the hibernating marmot following whole body irradiation.
Science
116:
570-571,
1952.
5.
Bronson, FH.
Mammalian Reproductive Biology. Chicago, IL: Univ. of Chicago Press, 1989.
6.
Burton, RS,
and
Reichman OJ.
Does immune challenge affect torpor duration?
Functional Ecol
13:
232-237,
1999.
7.
Cahill, JE,
Lewert RM,
and
Jaroslow BN.
Effect of hibernation on course of infection and immune response in Citellus tridecemlineatus infected with Nippostrongylus brasiliensis.
J Parasitol
53:
110-115,
1967.
8.
Chin, JE,
and
Horuk R.
Interleukin 1 receptors on rabbit articular chondrocytes: relationship between biological activity and receptor binding kinetics.
FASEB J
4:
1481-1487,
1990.
9.
Daan, S.
Activity during natural hibernation in three species of Vespertillionid bats.
Neth J Zool
23:
1-71,
1973.
10.
Daan, S,
Barnes BM,
and
Strijkstra AM.
Warming up for sleep? Ground squirrels sleep during arousals from hibernation.
Neurosci Lett
128:
265-268,
1991.
11.
Dark, J,
Miller DR,
and
Zucker I.
Gonadectomy in the spring reinstates hibernation in male golden-mantled ground squirrels.
Am J Physiol Regulatory Integrative Comp Physiol
270:
R1240-R1243,
1996.
12.
Deavers, DR,
and
Musacchia XJ.
Water metabolism and renal function during hibernation and hypothermia.
Fed Proc
39:
2969-2973,
1980.
13.
Dempster, G,
Grodums EI,
and
Spencer WA.
Experimental Coxsackie B-3 virus infection in Citellus lateralis.
J Cell Physiol
67:
443-454,
1966.
14.
Elmquist, JK,
Scammell TE,
and
Saper CB.
Mechanisms of CNS response to systemic immune challenge: the febrile response.
Trends Neurosci
20:
565-570,
1997.
15.
Emmons, RW.
Colorado tick fever: prolonged viremia in hibernating Citellus lateralis.
Am J Trop Med Hyg
15:
428-433,
1966.
16.
Fisher, KC.
On the mechanism of periodic arousal in the hibernating ground squirrel.
Ann Acad Sci Fenn Ser A IV Biol
71:
141-156,
1964.
17.
Fisher KC and Manery JF. Water and electrolyte metabolism in
heterotherms. In Mammalian Hibernation III, edited by Fisher
KC, Dawe AR, Lyman CP, Schonbaum E, and South FE. New York: Elsevier,
1964, p. 235-279.
18.
Freeman, DA,
and
Zucker I.
Temperature-independence of circannual variations in circadian rhythms of golden-mantled ground squirrels.
J Biol Rhythms
15:
336-343,
2000.
19.
Galletti, G,
Cavicchi G,
and
Ussia G.
Replication of Mycobacterium leprae in hibernating ground squirrels (Citellus tridecemlineatus).
Acta Leprol
88:
23-31,
1982.
20.
Galster, WA,
and
Morrison P.
Cyclic changes in carbohydrate concentrations during hibernation in the arctic ground squirrel.
Am J Physiol
218:
1228-1232,
1970.
21.
Geiser, F,
Hiebert S,
and
Kenagy GJ.
Torpor bout duration during the hibernation season of 2 sciurid rodents
interrelations with temperature and metabolism.
Physiol Zool
63:
489-503,
1990.
22.
Girard, R,
Pedron T,
and
Chaby R.
Functional lipopolysaccharide receptors of low affinity are constitutively expressed on mouse bone marrow cells.
Immunology
91:
391-398,
1997.
23.
Green, MH,
and
Vermeulen CW.
Fever and the control of gram-negative bacteria.
Res Microbiol
145:
269-272,
1994.
24.
Halling, JL,
Hamill DR,
Lei MG,
and
Morrison DC.
Identification and characterization of lipopolysaccharide-binding proteins on human peripheral blood cell populations.
Infect Immun
60:
845-852,
1992.
25.
Hanson, DF,
Murphy PA,
Silicano R,
and
Shin HS.
The effect of temperature on the activation of thymocytes by interleukins I and II.
J Immunol
130:
216-221,
1983.
26.
Harlan, JM,
Harker LA,
Reidy MA,
Gajdusek CM,
Schwartz SM,
and
Striker GE.
Lipopolysaccharide-mediated bovine endothelial cell injury in vitro.
Lab Invest
48:
269-274,
1983.
27.
Hazeleger, WC,
Wouters JA,
Rombouts FM,
and
Abee T.
Physiological activity of Campylobacter jejuni far below the minimal growth temperature.
Appl Environ Microbiol
64:
3917-3922,
1998.
28.
Heinzelmann, M,
Mercer-Jones MA,
Flodgaard H,
and
Miller FN.
Heparin-binding protein (CAP37) is internalized in monocytes and increases LPS-induced monocyte activation.
J Immunol
160:
5530-5536,
1998.
29.
Heller, HC.
Hibernation: neural aspects.
Annu Rev Physiol
41:
305-321,
1979.
30.
Hochachka, PW.
Defense strategies against hypoxia and hypothermia.
Science
231:
234-241,
1986.
31.
Hudson, JW,
and
Wang LC.
Hibernation: endocrinologic aspects.
Annu Rev Physiol
41:
287-303,
1979.
32.
Jaroslow, BN,
and
Serrell BA.
Differential sensitivity to hibernation of early and late events in development of the immune response.
J Exp Zool
181:
111-116,
1972.
33.
Jeffreys, AG,
Hak KM,
Steffan RJ,
Foster JW,
and
Bej AK.
Growth, survival and characterization of cspA in Salmonella enteritidis following cold shock.
Curr Microbiol
36:
29-35,
1998.
34.
Katsuura, G,
Arimura A,
Koves K,
and
Gottschall PE.
Involvement of organum vasculosum of lamina terminalis and preoptic area in interleukin 1-induced ACTH release.
Am J Physiol Endocrinol Metab
258:
E163-E171,
1990.
35.
Kayser, C.
L'hibernation des mammiferes.
L'Annee Biol
29:
109-150,
1953.
36.
Kilpatrick-Smith, L,
Maniara G,
Vanderkooi JM,
and
Erecinska M.
Cellular effects of endotoxin in vitro: mobility of endotoxin in the plasma membrane of hepatocytes and neuroblastoma cells.
Biochim Biophys Acta
847:
177-184,
1985.
37.
Kirkland, TN,
Virca GD,
Kuus-Reichel T,
Multer FK,
Kim SY,
Ulevitch RJ,
and
Tobias PS.
Identification of lipopolysaccharide-binding proteins in 70Z/3 cells by photoaffinity cross-linking.
J Biol Chem
265:
9520-9525,
1990.
38.
Kluger, MJ.
Fever: role of pyrogens and cryogens.
Physiol Rev
71:
93-127,
1991.
39.
König, C,
and
Schmid-Hempel P.
Foraging activity and immunocompetence in workers of the bumble bee, Bombus terrestris L.
Proc R Soc Lond B Biol Sci
260:
225-231,
1995.
40.
Kraaijeveld, AR,
and
van Alphen JJM
Geographical variation in encapsulation ability of Drosophila melanogaster larvae and evidence for parasatoid-specific components.
Evol Ecol
9:
10-17,
1995.
41.
Leijh, PCJ,
van der Barselaar M,
van Tweet TL,
Dubbeldeman-Rempt I,
and
van Furth R.
Kinetics of phagocytosis of Staphylococcus aureus and Escherichia coli by human granulocytes.
Immunology
37:
453-465,
1979.
42.
Lochmiller, RL,
and
Deerenberg C.
Trade-offs in evolutionary immunology: just what is the cost of immunity?
Oikos
88:
87-98,
2000.
43.
Luheshi, GN.
Cytokines and fever. Mechanisms and sites of action.
Ann NY Acad Sci
856:
83-89,
1998.
44.
Lyman, CP.
Hibernation: responses to external challenges.
In: Hibernation and Torpor in Mammals and Birds, edited by Lyman CP,
Willis JS,
Malan A,
and Wang LCH. New York: Academic, 1982, p. 196-205.
45.
Lyman, CP,
and
Fawcett DW.
The effect of hibernation on the growth of sarcoma in the hamster.
Cancer Res
14:
25-28,
1954.
46.
Manasek, FJ,
Adelstein SJ,
and
Lyman CP.
The effects of hibernation on the in vitro synthesis of DNA by hamster lymphoid tissue.
J Cell Physiol
65:
319-324,
1965.
47.
McGovern, VP,
and
Oliver JD.
Induction of cold-responsive proteins in Vibrio vulnificus.
J Bacteriol
177:
4131-4133,
1995.
48.
McKenna, JM,
and
Musacchia XJ.
Antibody formation in hibernating ground squirrels (Citellus tridecemlineatus).
Proc Soc Exp Biol Med
129:
720-724,
1968.
49.
Meerlo, P,
van den Hoofdakker RH,
Koolhaas JM,
and
Daan S.
Stress-induced changes in circadian rhythms of body temperature and activity in rats are not caused by pacemaker changes.
J Biol Rhythms
12:
80-92,
1997.
50.
Milton, AS.
Thermoregulatory actions of eicosanoids in the central nervous system with particular regard to the pathogenesis of fever.
Ann NY Acad Sci
559:
392-410,
1989.
51.
Nelson, RA.
Protein and fat metabolism in hibernating bears.
Fed Proc
39:
2955-2958,
1980.
52.
Nordling, D,
Andersson M,
Zohari S,
and
Gustafsson L.
Reproductive effort reduces specific immune response and parasite resistance.
Proc R Soc Lond B Biol Sci
265:
1291-1296,
1998.
53.
Pengelley, ET,
and
Fisher KC.
Rhythmical arousal from hibernation in the golden-mantled ground squirrel, Citellus lateralis tescorum.
Can J Zool
39:
105-120,
1961.
54.
Riedesel, ML,
and
Steffen JM.
Protein-metabolism and urea recycling in rodent hibernators.
Fed Proc
39:
2959-2963,
1980.
55.
Rubel, C,
Miliani de Marval P,
Vermeulen M,
Isturiz MA,
and
Palermo MS.
Lipopolysaccharide enhances FcgammaR-dependent functions in vivo through CD11b/CD18 up-regulation.
Immunology
97:
429-437,
1999.
56.
Saper, CB.
Neurobiological basis of fever.
Ann NY Acad Sci
856:
90-94,
1998.
57.
Scammell, TE,
Griffin JD,
Elmquist JK,
and
Saper CB.
Microinjection of a cyclooxygenase inhibitor into the anteroventral preoptic region attenuates LPS fever.
Am J Physiol Regulatory Integrative Comp Physiol
274:
R783-R789,
1998.
58.
Sheldon, BC,
and
Velhurst S.
Ecological immunology: costly parasite defences and trade-offs in evolutionary ecology.
Trends Ecol Evol
11:
317-321,
1997.
59.
Shivatcheva, TM.
Survival of skin allografts in European ground squirrels, Spermophilus citellus L., during hibernation.
Folia Biol (Warsaw)
36:
213-221,
1988.
60.
Sidky, YA,
and
Auerbach R.
Effect of hibernation on the hamster spleen immune reaction in vitro.
Proc Soc Exp Biol Med
129:
122-127,
1968.
61.
Sidky, YA,
Hayward JS,
and
Ruth RF.
Seasonal variations of the immune response of ground squirrels kept at 22-24 degrees C.
Can J Physiol Pharmacol
50:
203-206,
1972.
62.
Sinclair, JA,
and
Lochmiller RL.
The winter immunoenhancement hypothesis: associations among immunity, density, and survival in prairie vole (Microtus ochrogaster) populations.
Can J Zool
78:
254-264,
2000.
63.
Stitt, JT.
Prostaglandin E as the neural mediator of the febrile response.
Yale J Biol Med
59:
137-149,
1986.
64.
Tang, CC,
and
Jackson H.
Minimal medium recovery of chilled Salmonella heidelberg.
J Appl Bacteriol
46:
143-146,
1979.
65.
Van Bogelen, RA,
and
Neidhardt FC.
Ribosomes as sensors of heat and cold shock in Escherichia coli.
Proc Natl Acad Sci USA
87:
5589-5593,
1990.
66.
Wang, LCH
Time patterns and metabolic rates of natural torpor in the Richardson's ground squirrel.
Can J Zool
57:
149-155,
1978.
67.
Weersink, AJL,
van Kessel KPM,
Torensma R,
van Strijp JAG,
and
Verhoef J.
Binding of rough lipopolysaccharides (LPS) to human leukocytes. Inhibition by anti-LPS monoclonal antibody.
J Immunol
145:
318-324,
1990.
68.
Wickler, SJ,
Horwitz BA,
and
Kott KS.
Muscle function in hibernating hamstersa natural analog to bed rest.
J Therm Biol
12:
163-166,
1987.
69.
Willimsky, G,
Bang H,
Fischer G,
and
Marahiel MA.
Characterization of cspB, a Bacillus subtilis inducible cold shock gene affecting cell viability at low temperatures.
J Bacteriol
174:
6326-6325,
1992.
70.
Willis, JS.
Hibernation: cellular aspects.
Annu Rev Physiol
41:
275-286,
1979.
71.
Willis, JS.
The mystery of the periodic arousal.
In: Hibernation and Torpor in Mammals and Birds, edited by Lyman CP,
Willis JS,
Malan A,
and Wang LCH. New York: Academic, 1982, p. 92-103.
72.
Yasuma, Y,
McCarron RM,
Spatz M,
and
Hallenback JM.
Effects of plasma from hibernating ground squirrels on monocyte-endothelial cell adhesive interactions.
Am J Physiol Regulatory Integrative Comp Physiol
273:
R1861-R1869,
1997.
73.
Yu, CL,
Sun KH,
Shei SC,
Tsai CY,
Tsai ST,
Wang JC,
Liao TS,
Lin WM,
Chen HL,
Yu HS,
Interleukin-8 modulates interleukin-1-beta, interleukin-6 and tumor-necrosis-factor-alpha release from normal human mononuclear-cells.
Immunopharmacology
27:
207-214,
1994.
74.
Zatzman, ML.
Renal and cardiovascular effects of hibernation and hypothermia.
Cryobiology
21:
593-614,
1984.
This article has been cited by other articles:
|
|
 |
|
  T. Ruf and W. Arnold Effects of polyunsaturated fatty acids on hibernation and torpor: a review and hypothesis Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R1044 - R1052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Anisimov, S. V. Dentovskaya, G. M. Titareva, I. V. Bakhteeva, R. Z. Shaikhutdinova, S. V. Balakhonov, B. Lindner, N. A. Kocharova, S. N. Senchenkova, O. Holst, et al. Intraspecies and Temperature-Dependent Variations in Susceptibility of Yersinia pestis to the Bactericidal Action of Serum and to Polymyxin B Infect. Immun., November 1, 2005; 73(11): 7324 - 7331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. F. Ruby, M. T. Barakat, and H. C. Heller Phenotypic Differences in Reentrainment Behavior and Sensitivity to Nighttime Light Pulses in Siberian Hamsters J Biol Rhythms, December 1, 2004; 19(6): 530 - 541. [Abstract] [PDF]
|
|
|
|
 |
|
 K. L. Drew, M. B. Harris, J. C. LaManna, M. A. Smith, X. W. Zhu, and Y. L. Ma Hypoxia tolerance in mammalian heterotherms J. Exp. Biol., August 15, 2004; 207(18): 3155 - 3162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Kauffman, M. J. Paul, and I. Zucker Increased heat loss affects hibernation in golden-mantled ground squirrels Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2004; 287(1): R167 - R173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. V. CAREY, M. T. ANDREWS, and S. L. MARTIN Mammalian Hibernation: Cellular and Molecular Responses to Depressed Metabolism and Low Temperature Physiol Rev, October 1, 2003; 83(4): 1153 - 1181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Scholz Prostaglandins Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2003; 285(3): R512 - R514. [Full Text] [PDF]
|
|
|
|
|
|
H. Scholz Fever Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R913 - R915. [Full Text] [PDF]
|
|
|
|
|
|
G. F. DiBona Thermoregulation Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R277 - R279. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
