Effects of controllable vs. uncontrollable chronic stress on stress-responsive plasma hormones.

We have previously reported effects of chronic stress on circadian rhythms of temperature, eating, and locomotor activity. These studies were conducted using an around-the-clock signalled intermittent footshock paradigm in which some rats have control over shock termination while other rats are yoked to the rats with control. Although this paradigm is stressful, as suggested by decreases in food intake and disrupted circadian rhythms, rats tolerate the paradigm well, continuing to eat, drink, gain weight, and groom. In the present studies, rats were sacrificed following 3 or 14 days of stress, and plasma was collected for hormonal assays. After 3 days of stress, plasma corticosterone and prolactin levels were elevated in both stress groups compared to controls; yoked rats had higher levels of corticosterone than rats in the group with control over shock termination, while prolactin levels in both stressed groups were similar. ACTH levels were similar in stressed and control rats. After 14 days of stress, ACTH and corticosterone levels in both stress groups were similar to control levels. Prolactin levels were elevated in the yoked experimental group compared to levels in control or controllable stress groups. These data support previous studies suggesting that control over stressors attenuates the effects of stress on physiology and demonstrate that two hormones with diverse biological effects are elevated by chronic stress.     

Behavior and body temperature in rats following chronic foot shock or psychological stress exposure

In an attempt to examine stress-induced behavioral disorders, including circadian rhythm disturbances, we measured motor activity, feeding, drinking, and body temperature over a 14-day period following a long-term stress exposure in rats. Male Wistar rats were exposed to foot shock (physical) or non-foot shock stress (psychological) induced by the communication box for 1 h daily over 12 weeks. Two to three months after the termination of the stress sessions, motor activity, food intake, water intake, and body temperature were measured by means of an automatic behavioral measurement system under a 12:12-h light:dark cycle. Motor activity, feeding, and drinking patterns were not influenced by either of the previous stress exposures. Daily rhythm of body temperature was also unchanged in either stress group, however, a significant elevation in body temperature (by 0.20 degrees C, p<0.05) was observed only in non-foot-shocked rats. The present study suggests that only psychological stress induces an elevation of body temperature following the stress exposures; however, long-term stress exposures in the present experiment do not disturb behavioral activities and daily rhythms of behaviors.     

Serum cholesterol levels and stressor controllability in rats

Whether an organism can control a stressful event is often an important variable determining the impact of the event on physiology and behavior. Numerous behavioral and physiological variables are more adversely affected by uncontrollable stress. The present experiment with rat subjects compared the effect of controllable stress (escape conditioning) or uncontrollable stress (yoked control group) vs. home cage controls on total cholesterol, as well as high-density lipoprotein (HDL) and low/very-low density lipoprotein (LDL/VLDL) serum cholesterol. Results indicated that both stressed groups had higher total and LDL/VLDL cholesterol levels than home cage controls. No group differences were observed with HDL cholesterol. The escape and yoked control subjects did not differ from each other in any dependent measure. Results are discussed in terms of the probable mediators of stress-induced cholesterol increases, and the fact that these mediators may be insensitive to stressor controllability.     

Sleep deprivation in the rat: XVI. Effects in a light-dark cycle.

To avoid a possible confound between the effects of sleep loss and disturbed circadian rhythms in previous studies of total sleep deprivation (TSD) by the disk-over-water method, TSD rats and their yoked control (TSC) rats had been maintained in constant light both before and during the experiment. With circadian rhythms of both groups flattened by constant light, group differences in outcome measures could be attributed to sleep loss. However, the constant light control entailed the possibility that the sleep loss effects might obtain only in constant light. To evaluate this possibility, three TSD-TSC rat pairs maintained on a 12 hour light: 12 hour dark (LD) schedule were studied. TSC rats showed only minor changes during the deprivation period. As in previous studies, TSD rats showed increased food intake; decreased weight; increased energy expenditure; debilitated appearance; lesions on the tail and paws; an initial increase followed by a large decrease in body temperature; impending death; and recovery sleep, which featured large, selective, sustained rebounds of paradoxical sleep and a reversal of all observed TSD-induced changes. Thus, TSD produced the same changes during an LD schedule as during constant light. The amplitude of the diurnal body temperature rhythm declined over the course of TSD and then almost completely recovered during the first day of recovery sleep. The decline was interpreted as the result of deprivation-induced thermoregulatory changes.     

Circadian effects of escapable and inescapable shock on the food intake and wheelrunning of rats.

The feeding and running activities of rats were used to characterize the stressful effects of footshock. A 12-hour light/dark cycle was continuously in effect. During the preshock stage, all rats lived in individual cages where they could drink water, press a lever once for each 45 mg food pellet or run in an attached running wheel. During the shock stage, rats were moved to cages where they could drink and eat, but not run. Five s of light followed by 5 s of a light + tone compound preceded five progressively more intense shock levels. Rats in group AE were trained to pull a ceiling chain to avoid/escape from footshocks that were scheduled 24 hours per day. In group YS, the frequency, intensity and pattern of shocks for a rat were yoked to a rat in group AE. Rats in group CN were not shocked. During recovery, rats were allowed to resume running. During the dark, but not the light of the first day of shock, the intake of groups AE and YS was less than the intake of group CN. By the third day of shock, the food intake of group AE recovered and was no longer different from the intake of group CN. Intake of group YS remained less than the intakes of groups AE and CN during the remainder of the shock stage. When shock was terminated, the intake of the YS group recovered, but neither running nor food intake differed among groups. These results suggest that although inescapable shock disrupts food intake more than escapable shock, this disruption is specific to the duration of the shock stage and depends on rat's circadian pattern of intake.     

Effect of a short photoperiod on circadian rhythms of body temperature and motor activity in old rats

Circadian rhythms of body temperature and motor activity were documented in young and old rats (four 8-week-old and five 22-month-old male Wistars, implanted with telemetric probes and housed in a chronobiological facility) under two different photoperiod conditions. The animals were maintained in a light:dark (LD) cycle of 12 h each (LD 12:12) for 4 weeks and then exposed to a LD 6:18 cycle for 7 weeks to assess the effect of age on the desynchronization of the temporal structure of the rhythms. In old rats under LD 12:12, the power of the 24-h component and the circadian amplitude of body temperature and motor activity were markedly lower than in the young and both rhythms were phase-advanced. After the shift to LD 6:18, the circadian rhythmicity was maintained for both variables and the same phase delay (+5+/-1 h) was observed in both age groups, as was a gradual expansion of the patterns of both functions with the longer night. The photoperiod reduction (6 weeks under LD 6:18) did not modify the power of the 24-h component of body temperature and motor activity in old rats. In young rats, however, the power and amplitude of the 24-h component of motor activity rhythm fell to the levels of those in old rats, while the power of the 24-h component of body temperature rhythm and the amplitude did not change. Our data show that the circadian rhythm of motor activity, but not of body temperature, responds age dependently to a photoperiod reduction.     

Effects of stress and ovariectomy on the plasma cholesterol, serum triglyceride, and aortic cholesterol levels of female rats

Female Sprague-Dawley rats were either ovariectomized or sham-operated prior to puberty. As adults, they were maintained on a cholesterol-supplemented diet and subjected to either predictable, controllable shock; unpredictable, uncontrollable shock; or no shock for 30 days (51-min daily sessions). Sham-operated rats had higher plasma cholesterol levels than ovariectomized rats, but neither group showed an effect of stress treatments. For both groups, serum triglyceride and aortic cholesterol levels were lower in stressed than nonstressed rats. Additionally, the ovariectomized rats had higher levels of serum triglycerides than sham-operated controls.     

Differential changes in noradrenaline turnover in specific regions of rat brain produced by controllable and uncontrollable shocks

A series of three studies was performed to investigate the effects of the ability to avoid or escape shock (controllability) and the lack of ability to do so (uncontrollability) on noradrenergic neurons in various brain regions of male Wistar rats. The levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), in the hypothalamus, amygdala, thalamus, midbrain, hippocampus, cerebral cortex, pons plus medulla oblongata, and basal ganglia were measured fluorometrically. These studies indicated that after 3 hr and 6 hr in a free operant avoidance-escape stress procedure, the experimental rats able to avoid or escape shock showed greater increases in NA turnover (lower NA levels and higher MHPG-SO4 levels) in specific brain regions (i.e., the hypothalamus, amygdala, and thalamus) than the yoked rats unable to control the same shock. After 21 hr of stress, in contrast to stress of either 3-hr or 6-hr duration, the yoked rats exhibited a more marked enhancement of NA turnover in these brain regions than did experimental rats. Once shock-controlling responses had been acquired and well established by experimental rats, the responses of NA neurons in these rats did not differ markedly from those in the nonshocked control rats. Yoked rats given the same repetitive sessions of uncontrollable shock displayed sustained increases in NA turnover preferentially in the hypothalamus and amygdala, compared with the experimental rats. These results suggest that NA release in specific brain regions in the experimental "coping" rats is increased before the rats have learned the effective coping response. However, once a coping response is firmly established, NA release is reduced.     

Social interaction and sex differences influence rat temperature circadian rhythm under LD cycles and constant light

Circadian rhythms produce an efficient organization of animal behaviour over the 24h day. In some species, social cues have been found to have a role as synchronizers of these rhythms. Here, the influence of social interaction on rat circadian behaviour was investigated, addressing the question of whether cohabitation would produce a delay in the appearance of arrhythmicity under constant light conditions. To this end, the circadian rhythms of male and female rat body temperature were studied for 10days under light-dark conditions, followed by 33days under constant bright light. Half of the animals were maintained in individual cages, whilst the others were maintained in larger cages in groups of three rats of the same sex. Results showed that individual circadian rhythms under 24hour light-dark (LD) cycles were more stable and with higher amplitude in grouped than in isolated animals, and higher in males than in females. During the first days under constant light (LL), the stability of the rhythm was also higher in males than in females, but there were no differences according to the group. Moreover, we did not find significant differences in the time of circadian rhythm loss under LL, since high individual variability was found for this variable. On the other hand, female rats living in isolation showed a delayed acrophase in the circadian rhythm under LD conditions compared with those living in groups. These results suggest that cohabitation increases the internal coherence of circadian behaviour, and could be interpreted as indicating that living in isolation may induce a level of stress that disturbs manifestation of the circadian rhythm, especially in females, which are also more reactive than males to external signals.     

Effects of coping behavior on gastric lesions in rats as a function of the complexity of coping tasks

In fixed ratio (FR) 2 coping task condition, experimental rats which could avoid and/or escape shock by emitting a disk-pulling operant response developed less stomach ulceration than did yoked "helpless" rats which had exactly the same shock but which had no control over shock. In variable ratio (VR) 5 coping task condition, however, the experimental rats developed more lesions than did the matched yoked rats. Neither the VR 2- nor the FR 5-experimental group was significantly different from its yoked group. Ulceration of non-shock control group was negligible compared to experimental and yoked rats in each of the four coping task conditions. The level of a complexity or difficulty of coping response tasks required has a detrimental effect on ulcerogenesis for "coping" experimental rats. The effectiveness of a coping behavior covaries with the nature or ease of the coping tasks in a stressful situation.     

Resetting of the rat circadian clock after a shift in the light/dark cycle depends on the photoperiod.

Adjustment of the circadian clock to shifts in the light/dark (LD) cycle was assessed from the rat pineal N-acetyltransferase (NAT) rhythm which is controlled by a pacemaker in the suprachiasmatic nucleus of the hypothalamus. Re-entrainment to an 8-h delay in the LD cycle took more than 3 days in rats maintained under a regime with 18 h of light and 6 h of darkness per day (LD 18:6) whereas it was completed within 3 days in those maintained under LD 12:12. Re-entrainment to an advance in the LD cycle proceeded through a transient diminution or almost disappearance of the NAT rhythm amplitude following a 5-h, 3-h and even a mere 2-h advance shift under LD 18:6, whereas no such diminution occurred under LD 12:12 even after a 5-h advance shift. Altogether, the data indicate that resetting of the circadian clock after shifts in the LD cycle depends on the photoperiod.     

Expression of fibroblast growth factor-2 and brain-derived neurotrophic factor mRNA in the medial prefrontal cortex and hippocampus after uncontrollable or controllable stress

Neurotrophic factors, including basic fibroblast growth factor (FGF-2) and brain-derived neurotrophic factor (BDNF) are known to be affected by exposure to stressful experiences. Here, we examine the effects of behaviorally controllable (escapable tailshock, ES) or uncontrollable (inescapable tailshock, IS) stress on the expression of FGF-2 and BDNF mRNA in subregions of the medial prefrontal cortex (mPFC) and the hippocampal formation (HF) of male Sprague-Dawley rats. ES rats were placed in Plexiglas boxes equipped with a free spinning wheel and IS rats were placed in identical boxes with the wheels fixed. ES and IS rats were yoked such that they received the same tailshocks, but the ES rat could terminate each shock for both rats. No stress controls (NS) remained in their home cages. Rats were killed 0, 2, 24, or 72 h after termination of the stress session. In situ hybridization was performed to measure FGF-2 and BDNF mRNA in the mPFC and HF. In the mPFC, ES produced a significant increase in FGF-2 mRNA expression at 0 and 2 h post-stress. In the HF, ES produced a greater increase in FGF-2 mRNA expression than IS and NS only in CA2. ES also produced an increase in BDNF mRNA expression in the anterior cingulate at 0 h post-stress. No effects of stressor controllability on BDNF were observed in the HF, although both ES and IS decreased BDNF mRNA in the DG. FGF-2 in the mPFC may be involved in emotional regulation ("coping") during stressful experiences.     

Rapid reentrainment of the circadian clock itself, but not the measurable activity rhythms to a new light-dark cycle in the rat.

Experiments were performed to determine if the circadian clock reentrains more quickly to an 8-hour phase shift in light-dark (LD) cycles than does the overt rhythm of activity. To investigate the reentrainment of the clock itself to an 8-hour advance or delay in the LD cycle, the rats were released into constant darkness only two or three days after a shift in LD cycle, and the amount of the phase shift of the clock itself was estimated from where free-running rhythm started by backward extrapolation. If the circadian clock could rapidly reset itself to the new LD cycle, it was predicted that the free-running rhythm of activity would start from near the dark period of the new LD cycle rather than the preceding one. When rats were released into constant darkness three days after the LD cycle was advanced by 8 hours, the activity of the free-running rhythm started near time of dark period of the new LD cycle in all rats (n = 16). When rats (n = 24) were released into constant darkness two days after the LD cycle was advanced by 8 hours, 12 rats started the activity near time of dark period of the new LD cycle, while 9 rats started the activity near time of dark period of the preceding LD cycle. The remaining 3 rats showed the activity of the free-running rhythm near intermediate phase (transient phase). On the other hand, when the rats were not released into constant darkness after LD cycle was advanced by 8 hours, it took 6.4 days for activity rhythm to reentrain to the advanced LD cycle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spontaneous activity, sleep, and body temperature in rats lacking the CCK-A receptor

Because of a genetic mutation, the Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat, a model for human non-insulin-dependent diabetes mellitus (NIDDM), shows no expression of the CCK-A receptor gene. We investigated the spontaneous physical activity, sleep, and body temperature in young OLETF rats that had not yet developed diabetes mellitus, and compared these data with age-matched control LETO (non-diabetic strain, Long-Evans-Tokushima-Otsuka) rats. The amount of large movements during the dark phase for the OLETF rats was significantly less than that of control rats. Thus, the amounts of total daily large movement and the ratio of dark-to-light phase movement in the OLETF rats were less than those of control rats, although the amount of small movement was similar for both groups. The diurnal rhythm of body temperature was similar for both groups. In addition, the amount of and circadian rhythm for each vigilance state and slow-wave activity were similar for the two groups. This study demonstrates that the CCK-A receptor might play a role in affecting the level of motor activity, adding hyperphagia, and the circadian rhythm of large movement in these rats prior to the manifestation of NIDDM. In contrast, a CCK-A receptor deficiency does not appear to affect sleep or body temperature in these rats.     

Social interaction with a rhythmic rat enhances the circadian pattern of the motor activity and temperature of LL-induced arrhythmic rats

Although light is the main factor that influences circadian rhythms, social interaction may also have a role on their regulation. Here, the influence of social interaction on rat circadian behavior was investigated, addressing the question of whether cohabitation would induce the appearance of a circadian rhythm in arrhythmic rats due to constant light. To this end, circadian rhythms of motor activity and body temperature of male and female LL-induced arrhythmic rats were studied before, during and after a 20-day period in which rats stayed in the same cage with a rat of the same sex but with stronger rhythm. Results showed that the manifestation of the circadian motor activity rhythm of LL-induced arrhythmic rats increased after cohabitation. In the case of the expression of the body temperature rhythm, there was a progressive daily increase in the power content of a daily 24 hour pattern throughout the cohabitation days, which remained when animals were again isolated. Thus, the presence of a rhythmic rat increases the strength of the circadian behavior of rats showing a weak circadian rhythm.     

Importance of feeding time in pair-fed, ovariectomized rats

The present investigation was designed to determine the effects of feeding time on body weight gain in ovariectomized (OVX) rats pair-fed with sham operated control rats. In pair feeding, a test and a control rat were each fed the same amount of food. In the first experiment, OVX rats and controls were pair-fed at 1900, just before the dark phase of the light-dark cycle. Body weight gain was observed for 36 days. There was no significant difference in weight gain between the two groups. In the second experiment, when rats were pair-fed chow, starting from 1200, there was a significant increase in the body weight of the OVX group compared to the sham operated control group. Observation continued for 56 days. In the third experiment, the OVX group in the pair-fed condition and the sham control group were pair-fed at 1900 for 56 days and feeding was then switched to 0500 (just before the beginning of the light cycle) for 28 days. The body weight gain in the OVX pair-fed group was quite similar to that of the sham control group when feeding started at 1900, but a significant increase in body weight gain of the OVX group was observed after switching the starting time of feeding to 0500. In conclusion, the results suggest that the time of daily feeding may be important for body weight gain during the dynamic phase after ovariectomy.     

Influence of diurnal phase on startle response in adult rats exposed to dexamethasone in utero

Depression and pathological anxiety disorders are among the most prevalent neurological diseases in the world and can be precipitated and exacerbated by stress. Prenatal stress alters both behavioral and endocrine responses to stressful stimuli in later life. We have previously observed increased basal acoustic startle response (ASR) in Wistar rats exposed to stress or dexamethasone (DEX) in utero when tested during the light phase of the circadian rhythm, and decreased prepulse inhibition (PPI) in similar animals tested during the dark phase of the cycle. We speculated that this observation of increased basal startle might be influenced by diurnal phase. In the present study, adult female Sprague Dawley rats, stressed prenatally with DEX (200 μg/kg, gestational days 14-21) and postnatally by blood sampling under restraint, were tested for the ASR during both circadian phases (light and dark). Basal startle was increased in animals tested both during the light and the dark phases of the cycle. We hereby replicated our earlier findings in a new strain and laboratory, thus strengthening the validity of our model regarding prenatal stress effects on ASR in female offspring. Our results indicate that observation of increased basal ASR is not solely dependent on diurnal phase. We found no difference in hippocampal glucocorticoid and mineralcorticoid receptor expression between groups.     

AVP V1受体阻断剂对昼光和暗光中正常大鼠体温的影响

目的: 研究内源性精氨酸加压素(AVP)是否参与正常的体温调节过程。方法: 用无线体温遥测仪测量大鼠的体温变化,观察腹腔注射AVPV₁受体阻断剂对昼光和暗光中(明∶暗=12∶12)大鼠体温的影响。结果: 腹腔注射AVPV₁受体阻断剂可明显提高大鼠的正常体温,在昼光中(6:00AM-6:00PM)体温升高持续的时间长达6h,雄性大鼠的体温明显高于雌性的体温。在暗光中(6:00PM-6:00AM),AVPV₁受体阻断剂只使进入暗光初期的大鼠体温升高,持续的时间为2h,雄性和雌性之间无明显差别。结论: AVPV₁受体阻断剂可使正常大鼠体温升高,实验结果提示内源性AVP对正常体温有紧张性调节作用。     

Selected ambient temperatures of rats acclimated to heat given on various schedules

We investigated the behavioral thermoregulation of heat-acclimated rats by measuring their selected ambient temperatures (Ts). Rats kept in a light:dark cycle of 12:12 h were subjected to one of four different heat exposure regimes for 10 consecutive days; a constant ambient temperature (Ta) of 32 degrees C (CH), a Ta of 32 degrees C for 5 h daily in the latter half of the dark phase (IHF), a Ta of 32 degrees C for 5 h daily at a random time of day (IHR), or a constant Ta of 24 degrees C (control). After the heat exposure schedule, the rats were placed in a thermal gradient and their intra-abdominal temperature (Tab), Ts and spontaneous activity were measured for 3 days. There were clear day-night variations of Tab and Ts in all groups. The levels of Tab and Ts of the CH rats were significantly higher than those of the IHF, IHR and control rats. The Tab and activity levels of the IHF rats were significantly lower than those of the IHR and control rats only in the latter half of the dark phase. The Ts values of the IHF rats did not differ from those of the IHR and control rats. These results suggest that, after rats were constantly subjected to heat, heat-seeking behavior was induced so that the core temperature was maintained at a high level. However, when rats were acclimated to heat given for several hours at a fixed time daily, core temperature was lowered during the same time period of previous heat exposure in association with a depression of thermogenic behavior.     

Chronic stress exposure influences local cerebral blood flow in the rat hippocampus.

To examine the influence of chronic stress on the brain, we measured local cerebral blood flow in the hippocampus of rats which had been exposed to chronic stress by the hydrogen clearance method in the freely moving status. Rats were exposed, once a day for 12 weeks, to stress of a 15-min immersion in cold water at 4 degrees C (the stress group) or slightly handled for about 1 min (the control group). Local cerebral blood flow values in the hippocampus, which were measured after a 12-week recovery period, were lower in rats in the stress group than those of rats in the control group only in the dark cycle, but not in the light cycle. Accordingly, local cerebral blood flow in the hippocampus of rats in the stress group did not have a daily fluctuation, i.e. lower in the light cycle and higher in the dark cycle, as was shown in rats in the control group. There were no significant changes in motor activity in rats in the stress group as compared to those in the control group. Severe structural damages were observed in the CA2 and CA3 cell fields of the hippocampus of rats in the stress group. We found that an increase in local cerebral blood flow in the hippocampus in the dark cycle was blunted following chronic stress exposure, suggesting that chronic stress exposure caused hippocampal neurons to be less responsive to environmental stimuli derived from motor activity during the dark cycle.