LPS fever in old rats depends on the ambient temperature.

In earlier work, we found that following lipopolysaccharide (LPS) injection at an ambient temperature (Ta) of 23 degrees C, old rats developed blunted fevers compared with those of young rats. However, the old rats did become febrile if placed in a thermally graded alleyway: they spent more time in the warm end of the gradient and developed a significantly higher body temperature (Tb) than they did following saline injections. In the present experiments, we maintained old and young rats for 3 days at 20 or 31 degrees C (the Ta preferred by the old rats given LPS). After LPS (50 microg/kg ip), the young rats developed equivalent fevers at both Ta's. The old rats developed fevers that were equivalent to those of the young rats at 31 degrees C. At 20 degrees C, their fever was significantly lower. These results suggest that Ta plays a decisive role in the ability of old rats to mount febrile responses.

Fever and behavioral thermoregulation in young and old rats.

At standard laboratory ambient temperatures (T(a)) of 20-24 degrees C, peripheral injections of lipopolysaccharide (LPS) reliably produce fever in young rats. In contrast, old rats may show a blunted fever, no fever, or even hypothermia after LPS. In the present study we hypothesized that old rats might use behavioral thermoregulation to help them develop a fever. Young and old rats were implanted with temperature transmitters. At least 1 wk postoperatively they were placed in a thermally graded alleyway (T(a) 10-40 degrees C). On the third and sixth day they were taken out of the gradient, placed at an T(a) of 23 degrees C, injected intraperitoneally with LPS or saline, and left at 23 degrees C for 3 h. At the end of that time, all young rats had become febrile, whereas the old rats had not. When the rats were replaced in the thermal gradient, the young animals continued to develop a fever that was similar to fever in young rats left at 23 degrees C. The old animals chose significantly warmer positions in the thermal gradient than did the young animals and only then became febrile. Although there was a tendency for the young rats to prefer higher T(a) after LPS than after saline, these differences were not significant. However, the differences in the old rats were significant. These results suggest that the LPS had increased the thermal set point in the old rats, but they could develop febrile responses only at the warm T(a) they selected.

Prostaglandin E2-induced fever in young and old Long-Evans rats.

Aging is associated with a blunted or absent fever response to naturally occurring infections or to the peripheral administration of bacterial products and proinflammatory cytokines. We have recently shown that old Long-Evans rats are not defective in their capacity to develop a fever in response to brain administration of interleukin-1beta (IL-1beta). Here, we investigated the fever response of young (3-5-month) and old (24-26-month) Long-Evans rats to the intracerebroventricular (i.c.v.) microinfusion of prostaglandin E2 (PGE2), a final common mediator for the production of fever in the brain. Core body temperature was monitored by telemetry in freely moving rats. i.c.v. administered PGE2 (100 ng) induced comparable increases in body temperature in young and old Long-Evans rats. In the two groups, PGE2-induced fever was similar both in latency-to-peak fever and maximal fever response. These data, and the previous data on IL-1beta, demonstrate that the brains of old and young rats are similar with respect to fever generation in response to the i.c.v. administration of two classes of immunomodulators.

Basal and IL-1beta-stimulated cytokine and neuropeptide mRNA expression in brain regions of young and old Long-Evans rats.

Young and old Long-Evans rats respond with fevers of equal magnitude and duration to the brain administration of interleukin-1beta (IL-1beta). Here, we characterized brain regional mRNA expression of cytokine and neuropeptide components in response to the brain administration of IL-1beta. We used specific and highly sensitive RNase protection assays to determine mRNA changes for IL-1beta, IL-1 receptor type I (IL-1RI), IL-1R accessory proteins I and II (IL-1R AcP I and II), IL-1 receptor antagonist (IL-1Ra), transforming growth factor-beta1 (TGF-beta1), glycoprotein 130 (gp 130), leptin receptor (OB-R), neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) in the cerebellum, parieto-frontal cortex, hippocampus, hypothalamus, and midbrain of male young (3-5 months) and old (24-26 months) Long-Evans rats. In both young and old rats, IL-1beta induced a significant up-regulation of cerebellar IL-1Ra, IL-1RI, and TGF-beta1 mRNAs; hippocampal TGF-beta1 mRNA; hypothalamic IL-1beta, IL-1Ra, TGF-beta1, and gp 130 mRNAs; and midbrain IL-1beta and TGF-beta1 mRNAs. There were no age-related differences in any cytokine mRNA levels under basal or IL-1beta-stimulated conditions. Levels of hypothalamic POMC mRNA were different between age groups under basal and stimulated conditions. IL-1R AcP I and leptin receptor did not change in any brain region from either young or old rats, suggesting specificity of transcriptional changes. The data show that old Long-Evans rats are not defective in their capacity to develop an appropriate cytokine response to the brain administration of IL-1beta. The implications of these findings for neuroimmunological-neuroinflammatory and neurotoxic/neurodegenerative processes are discussed.

Fetal tissue containing the suprachiasmatic nucleus restores multiple circadian rhythms in old rats.

The suprachiasmatic nucleus (SCN) is the major circadian pacemaker in mammals. When fetal tissue containing the SCN is transplanted into young rats whose circadian rhythms have been abolished by SCN lesions, the rhythms gradually reappear. Circadian rhythms in many rats deteriorate or disappear with age. The rationale of the present study was that old rats with poor circadian rhythms resemble young rats with SCN lesions. If there is a similar mechanism underlying this resemblance, then fetal tissue containing the SCN should restore rhythms in old rats. Therefore, we implanted such tissue into the third ventricle of intact aged rats with poor circadian rhythms. Body temperature, locomotor activity, and/or drinking were measured simultaneously within subjects. Grafts and hosts were stained immunocytochemically for vasoactive intestinal polypeptide (VIP), arginine vasopressin (AVP), and neuropeptide Y (NPY). Of 23 SCN grafts, 14 were viable (cells observable with Nissl or peptide staining). In 7 of the 14 aged hosts, up to three circadian rhythms were improved or restored. VIP cells were always observable, which was not the case for AVP cells or NPY fibers. In the other seven hosts, no circadian rhythm was improved. Compared with the successful grafts, these unsuccessful grafts had similar amounts of AVP and NPY staining but significantly less VIP cell and/or fiber staining. Fetal cerebellar grafts, which do not contain any of the three peptides, did not improve or restore any rhythms. Thus the degeneration of circadian rhythms in aged rats may be due, at least in part, to deterioration of the aged SCN and in particular, to a loss of function of VIP-containing neurons.

Cytokine-induced fever in obese (fa/fa) and lean (Fa/Fa) Zucker rats.

In earlier work, we reported that genetically obese (fa/fa) Zucker rats exhibited significantly greater anorexia than did lean (Fa/Fa) Zucker rats to intracerebroventricular infusion of interleukin (IL)-1beta. Here, we investigated the fever response of obese (fa/fa) and lean (Fa/Fa) Zucker rats to intracerebroventricular microinfusion of IL-1beta as well as to the following other cytokines: IL-2, IL-6, and tumor necrosis factor-alpha (TNF-alpha). Core body temperature was monitored by a radiotelemetry system in freely moving rats. The results show that 1) both IL-1beta and IL-6 induce fevers in obese and lean rats; 2) IL-1beta induces a significantly higher fever response in obese rats than it does in lean rats; 3) IL-6 induces a significantly higher fever response in lean rats than it does in obese rats; 4) IL-2 induces a moderate fever response in lean but not obese rats; 5) TNF-alpha induces a similar fever response in obese and lean rats; and 6) the fevers induced by each effective cytokine have different time courses. Thus obese (fa/fa) and lean (Fa/Fa) Zucker rats show differential responsiveness to the intracerebroventricular microinfusion of various classes of cytokines. This suggests that genetic obesity in the fa/fa Zucker rat is associated with differential cytokine action on thermoregulatory mechanisms.

Interleukin-1beta-induced fever in young and old Long-Evans rats.

Aging is associated with a blunted or absent fever response to naturally occurring infections or to the peripheral administration of bacterial products and proinflammatory cytokines, including interleukin-1beta (IL-1beta). Whether old rats also exhibit an attenuated fever response when challenged with direct brain administration of IL-1beta is unknown. Here we investigated the fever response of young (3-5 mo) and old (24-26 mo) Long-Evans rats to the intracerebroventricular microinfusion of IL-1beta. Core body temperature was monitored by telemetry in freely moving rats. Intracerebroventricularly administered IL-1beta induced comparable increases in body temperature in young and old Long-Evans rats. In the two groups, IL-1beta-induced fever was similar both in latency to peak fever and maximal fever response, whether the cytokine was administered 2 h after lights on or just before lights off. These data show that old Long-Evans rats are not defective in their capacity to develop a fever in response to brain administration of IL-1beta.

Patterns of circadian body temperature rhythms in aged rats.

1. Old rats of the same chronological age are not homogeneous with respect to their circadian temperature rhythm (CTR). Some old rats maintain a robust CTR, comparable with that of young rats, while others have a weakened and unstable CTR. Often, in the latter group, the CTR becomes flat and disappears. In almost all old rats there is a clear decrease in the amplitude of the CTR. 2. The present paper describes several methods that are useful for distinguishing between old rats in different categories. Three patterns can be distinguished: (i) good (there is a clear difference between the daily body temperature (Tb) means in the light and dark, relatively high density (power) at a period of 24 h, low hour-to-hour fluctuation in Tb within a given day (low intradaily variability; IV) and high day-to-day stability in Tb (high interdaily stability; IS)); (ii) unstable (there is a variable difference between daily Tb means in the light and dark, very low density at the 24h period, moderate IV and low IS); and (iii) flat (there is little or no difference or variation in daily Tb means in the light and dark, low or insignificant density at 24 h, highest IV and lowest IS). 3. The importance of these distinctions in old rats is two-fold. First, differences at a behavioural level may reflect fundamental differences in the brain. Second, the degree of deficits in one system, for example in the CTR, may be correlated with deficits in other systems, such as sleep-waking. The methods described in the present paper are useful for obtaining qualitative information on the progressive deterioration of the CTR as animals age.

Suprachiasmatic nuclei lesions do not eliminate homeostatic thermoregulatory responses in rats.

Electrolytic lesions aimed at the suprachiasmatic nuclei (SCN) were made in male Long-Evans rats. Body temperature (Tb), activity, and drinking were monitored continuously in a 12-h light:12-h dark (12:12 LD) cycle at an ambient temperature of 23 degrees C. Large SCN lesions eliminated activity and drinking rhythms and abolished or reduced the circadian rhythm of Tb. The Tb responses of the rats were measured in L after exposure to cold and injection of lipopolysaccharide (LPS), a fever-producing drug, and in both L and D during a 30-min exposure to a novel cage. Rats with SCN lesions (SCNX) maintained their Tb as well as did controls during 2-h exposure to 2 degrees C. They also showed the expected increases in Tb in response to novelty and LPS. Nevertheless, there were differences between SCNX rats and other rats. When measured 9 h after LPS injection, SCNX rats had lower Tb in D than did sham-lesioned or intact rats or rats with lesions that missed the SCN. This is not surprising; the Tb of SCNX rats does not go as high as that of intact rats in D. However, it was surprising that at night SCNX rats increased their Tb in response to novelty (lights on in the test situation), whereas normal rats did not. For some reason, light inhibits the Tb rise to novelty in normal rats but does not do so in rats with SCN lesions.

Individual differences in response to LPS and psychological stress in aged rats.

Old rats may show blunted fever or hypothermia after injection of lipopolysaccharide (LPS), a fever-producing agent, and have a reduced body temperature (Tb) rise in response to psychological stress. These results may partly be a consequence of aging per se, partly a sex difference, and partly an effect of differences in types and doses of pyrogen. Here we tested age and gender differences in Tb responses to 30-min exposure to a novel environment and to injection of several doses of LPS. There were age-related reductions in novelty-induced hyperthermia, and some old rats even became hypothermic. Sensitivity to the pyrogenic activity of LPS and to the toxic effects of endotoxin (manifested by hypothermia) both increased in aged female rats. A major finding was that there were no correlations between age-related changes in Tb in response to novelty and to LPS injection. Tb responses in aged rats were variable; in each situation, there were old rats whose Tb rose as high as did younger ones. We did not observe significant gender differences in response either to novelty or to LPS in young or old rats.

Body temperature and sleep in intact and ovariectomized female rats.

The present study examined intact and ovariectomized adult rats to assess the effects of removal of sex hormones on body temperature (Tb) and sleep. Subjects were 12 female rats, aged 5-8 mo, half of which were bilaterally ovariectomized (OVX). Sleep or waking and Tb were recorded under a 12:12-h light-dark cycle. There was a strong coupling between level of Tb and the three conditions of waking, slow-wave sleep (SWS), and rapid eye movement sleep (REMS): Tb was significantly positively correlated with waking and significantly negatively correlated with SWS and REMS. These correlations were even higher in OVX rats. In the light, OVX rats had more SWS and stayed awake less than did the intact rats. OVX rats had more REMS than did intact rats in both light and dark. Mean Tb and daily Tb amplitude were the same in both groups. These results suggest that ovariectomy increases and, by extension, gonadal steroids decrease, the coupling between Tb and sleep.

Changes in circadian rhythms of body temperature and sleep in old rats.

We examined the relationship between circadian rhythms of body temperature (CTR) and sleep in adult and old female rats. Body temperature was recorded telemetrically for months and sleep for 24 h in a 12:12-h light-dark cycle at 23 degrees C. Some old rats had robust CTRs (old good), and some had unstable or absent CTRs (old unstable). Old unstable rats had lower daily mean body temperatures, smaller daily amplitudes, and a more advanced CTR phase than adult rats and old good rats. Old good rats matched adult rats in all measures. In old good rats, circadian parameters of sleep were normal, whereas in old unstable rats the amplitudes of slow-wave and rapid eye movement sleep were decreased, although the amounts were equivalent. Rhythmic parameters of sleep correlate well with the stability or instability of the CTR, whereas homeostatic regulation of rapid eye movement and slow-wave sleep do not seem to be impaired during aging and are independent of the stability of the CTR.

Do the suprachiasmatic nuclei oscillate in old rats as they do in young ones?

The basis of the decline in circadian rhythms with aging was addressed by comparing the patterns of three behavioral rhythms in young and old rats with the in vitro rhythm of neuronal activity in the suprachiasmatic nuclei (SCN), the primary circadian pacemaker. In some old rats, rhythms of body temperature, drinking, and activity retained significant 24-h periodicities in entraining light-dark cycles; in others, one or two of the rhythms became aperiodic. When these rats were 23-27.5 mo old they were killed, and single-unit firing rates in SCN brain slices were recorded continuously for 30 h. There was significant damping of mean peak neuronal firing rates in old rats compared with young. SCN neuronal activities were analyzed with reference to previous entrained behavioral rhythm patterns of individual rats as well. Neuronal activity from rats with prior aperiodic behavioral rhythms was erratic, as expected. Neuronal activity from rats that were still maintaining significant 24-h behavioral rhythmicity at the time they were killed was erratic in most cases but normally rhythmic in others. Thus there was no more congruence between the behavioral rhythms and the brain slice rhythms than there was among the behavioral rhythms alone. These results, the first to demonstrate aberrant SCN firing patterns and a decrease in amplitude in old rats, imply that aging could either disrupt coupling between SCN pacemaker cells or their output, or cause deterioration of the pacemaking properties of SCN cells.

Effects of p-chlorophenylalanine on thermoregulation and sleep in rats.

Sleep/waking and body temperature (Tb) were recorded in male rats in a 12:12 light-dark photoperiod at one of 3 ambient temperatures (Ta's): 20, 30, or 32 degrees C. After adaptation to the sleep recording chamber for at least 48 h, the rats were injected with saline at the beginning of lights-on (day S1). Twenty-four hours later (day P1), they were injected with PCPA (300 mg/kg, i.p.) and recordings continued for 4 more days (P2-P5). At these Ta's, hypothalamic 5-HT was depleted by 66-75% 30 h post-PCPA. Changes in both amplitude and acrophase of Tb depended on Ta. Compared to S1, amplitude was reduced on P2-P4 at 20 degrees C and on P3-P4 at 30 degrees C. Acrophase was advanced on P1-P3 at Ta 20 degrees C only. Sleep variables were generally independent of Ta and largely unchanged in the dark. In the light, amounts of slow-wave sleep (SWS) were depressed on P2-P4, number of bouts decreased on P3-P5 and percent nocturnality decreased on P2-P5. Bout length was depressed on P2 and lengthened on P4-P5. Acrophase was delayed on P2-P4 at Ta 30 degrees C. Amounts of rapid-eye-movement sleep (REMS) were depressed on P1-P3. REMS bout length decreased on P1-P3. The decreases in number of REMS bouts seen on P1-P3 depended on Ta. Changes in percent nocturnality and acrophase of REMS were minor. Waking----SWS transitions decreased on P3-P5 while SWS----REMS transitions were reduced on P1-P2. These results suggest that PCPA affects circadian aspects of both Tb and sleep, that 5-HT is important in the initiation of SWS bouts, and finally that the mechanisms by which 5-HT depletion affects Tb, SWS and REMS are different.

Phentolamine and thermoregulation in rats.

Phentolamine (PHEN), a nonselective alpha-adrenoceptor antagonist, causes a dose and ambient temperature (Ta)-dependent fall in body temperature (Tb) when injected intraperitoneally. In this paper, we investigated whether this was caused by integrated behavioral and autonomic thermoregulatory responses and whether it was due to a central action of the drug. Male rats were trained to press a bar for warm air in the cold or cold air in the heat. Rats were tested in both conditions near their Tb peaks and troughs after injections of saline or PHEN (5 and 10 mg/kg, IP). Tb fell significantly within the first 30 min post-PHEN, and after that, in the cold, the rats worked to increase Ta. In the heat they did not change Ta. To determine what was responsible for the Tb fall, we measured heat loss and heat production after saline or PHEN (10 mg/kg; IP) at Ta 2, 20, and 30 degrees C. Decreases in Tb at 2 and 20 degrees C were caused by increased heat loss during the first 15-30 min post-PHEN. At 2 degrees C, heat production increased after the drop in Tb. We conclude that the main reason the rats do not start to work immediately to prevent their core temperature from falling is that skin temperature is high, due to peripheral vasodilation, and that skin temperature is the major stimulus for regulating preferred Ta. We believe these effects are mediated by peripheral mechanisms because intracerebro-ventricular injections of PHEN did not cause a fall in Tb.

Elevated body temperature in female rats after exercise.

Female Sprague-Dawley rats living in basin cages (sedentary rats) under a 12:12 light-dark cycle normally have body temperatures (Tb; measured via telemetry) that vary from a mean peak of 38.1 +/- 0.1 degrees C in the dark to a mean trough of 36.0 +/- 0.1 degrees C C in the light. We have found that if rats are housed in activity wheels, their mean peak Tb in the dark, when they run in the wheels, rises to about 39.5 degrees C. Mean trough Tb in the light also rises, to about 36.5 degrees C, although they never or very rarely run in the wheels in the light. Other rats were rotated through two cycles of wheel-open (WO) and wheel-locked (WL) conditions. During the first WO cycle their mean Tb in the dark gradually rose over the first 2 wk, and their mean Tb in the light gradually fell. In the first WL, mean Tb in the dark fell immediately to sedentary levels, and mean Tb in the light fell more gradually. In the second WO condition, both dark and light Tb rose almost immediately. Since rats in locked wheels have Tb similar to sedentary controls, these results support the hypothesis that steady exercise at night results in an upward resetting of a thermoregulatory set-point during the day.

Interactions between body temperature and wheel running over the estrous cycle in rats.

Female rats were housed in Wahmann wheels under a 12:12 light-dark (LD) photoperiod for 36 days and then were switched to LD 10:14 for 36-64 days. Running was 95-100% nocturnal. Overall amounts of running were higher in LD 12:12, but changes over the estrous cycle were similar. On the night of proestrus running increased by 64% in LD 12:12 and 123% in LD 10:14 (p less than 0.0001) compared to the first night of diestrus. Nighttime Tb's were correlated with running levels. In LD 12:12 Tb on proestrus was higher by 0.3 +/- 0.0 degrees C (p less than 0.0001); in LD 10:14 it was higher by 0.2 +/- 0.0 degrees C (p less than 0.001) compared to diestrus-1. During L, Tb was lowest on proestrus and highest on estrus. Half of the rats exhibited a consistent phase advance of at least 30 min in both Tb and activity on proestrus. The advanced Tb acrophase was correlated with both the activity acrophase (r = .91; p less than 0.0001) and the amount of running (r = .60; p less than 0.01). The wheels of 6 rats were then locked at night in LD 10:14. There were no significant Tb changes from diestrus-1 across the cycle. However, Tb acrophase was delayed a mean of 76 +/- 16 min (p less than 0.01) in these rats. Also, the Tb acrophase across all days of the estrous cycle was delayed by 94 +/- 18 min (p less than 0.001) compared to when the wheels were open.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian rhythms of body temperature and drinking and responses to thermal challenge in rats after PCPA.

Body temperature (Tb) and drinking were measured for five days in male and female rats. On day 6 (S1) the rats were injected with saline. On day 7 (P1) they were injected with PCPA (300 mg/kg IP). Measurements continued for 12 days. Immediately after PCPA Tb dropped. After that, the amplitude of the daily Tb rhythm was significantly decreased from days P2-P5. Females were more affected than males. Nocturnality of drinking was decreased on days P2-P4. Because the peak of the Tb rhythm advanced after PCPA, while the peak of the drinking rhythm was delayed, we conclude that the attenuation of the Tb rhythm was a direct result of PCPA treatment rather than a masking effect due to the attenuation of other rhythms. Other rats were thermally challenged during the first week post-PCPA. There were no differences in ability to regulate Tb in the cold, and the small variations in the heat were overshadowed by gender differences.

Influence of ambient temperature on sleep and body temperature after phentolamine in rats.

Phentolamine, an alpha-adrenoceptor antagonist, both decreases rapid-eye-movement sleep (REMS) and causes a dose- and ambient temperature (Ta)-dependent drop in body temperature (Tb). The purpose of this paper was to examine the correlation between changes in sleep and changes in Tb after phentolamine at various Ta's. Tb and sleep were recorded in male rats for 4 h after i.p. injection of either saline or phentolamine (1 mg/kg at Ta 20 degrees C; 5 mg/kg at 20, 30 and 32 degrees C; 10 mg/kg at 20, 30, 32, and 34 degrees C). Changes in sleep were highly correlated with changes in Tb: when Tb dropped, amounts of sleep, especially REMS, also were decreased. The largest effects were seen at Ta 20 degrees C. After 5 mg/kg, Tb was below normal for 2 h and latency to REMS increased 82 +/- 27 min (P less than 0.025). After 10 mg/kg Tb was decreased for 3 h, and latency to REMS increased 91 +/- 19 min (P less than 0.001). While Tb was lower amounts of REMS were also decreased. Smaller effects were observed on slow wave sleep. At those conditions where phentolamine had no effect on Tb (i.e. Ta 20 degrees C, 1 mg/kg, and Ta 32 degrees C, 5 and 10 mg/kg) no differences were found in any measure of sleep. These results demonstrate that the effects of phentolamine on sleep are not caused by direct action on sleep mechanisms, but rather by its actions on thermoregulatory and possibly other mechanisms that modulate sleep.

Body temperature rhythms, cold tolerance, and fever in young and old rats of both genders.

The circadian rhythm of body temperature (CTR) of male and female rats living at 23 degrees C, as well as their body temperature response to a yeast injection or to a 2-h exposure to 0 degree C, was investigated by telemetry. Young rats had a clear CTR with a mean nocturnal peak of 38.0 +/- 0.1 degree C and diurnal trough of 36.2 +/- 0.1 degree C. Older rats, starting at about 18 months of age, tended to have poor (that is, lower amplitude) rhythms. Mean daily body temperature was 37.1 +/- 0.2 degree C at all ages. After exposure to the cold, the body temperature of young rats, old rats with a strong CTR, and old rats with a poor CTR changed in the ranges of -0.3 to +1.5 degree C, -3.1 to +0.7 degree C, and -5.2 to +0.4 degree C, respectively. This indicates that old animals, especially but not exclusively those with poor CTRs, are less resistant to cold stress. On the other hand, the capacity to develop a fever in response to a yeast injection was equivalent in the three groups of animals, although females had a smaller response than males. It is concluded that the process of aging does not have a generalized debilitating effect on temperature regulation in rats. Rather, aging seems to affect individual components of the thermoregulatory system differentially.