Biomedical subjects

R E Mistlberger

Publications and source records attributed to R E Mistlberger.

At least 19 recordsLinked to original sources

PubMed2000

Sleep deprivation stimulates serotonin release in the suprachiasmatic nucleus.

Recent literature suggests that sleep deprivation has a general stimulatory effect on the central serotonergic system. Herein we report that in hamsters, sleep deprivation induced by gentle handling for 3 h under dim red light at midday stimulates serotonin release in the suprachiasmatic nuclei by as much as 171%. Basal levels of 5-HT release are re-established within 1 h after cessation of treatment. Sleep deprivation also evokes phase advances of the circadian activity rhythm averaging 2 h. When sleep deprivation is undertaken in bright light, serotonin release is stimulated, but phase-shifting is greatly inhibited. It is therefore proposed that if the phase-resetting response to sleep deprivation is mediated by increased serotonin release, light inhibits the phase-resetting effect by blocking the postsynaptic or other downstream actions of serotonin.

Animals↗

PubMed2000

5-HT(1A) autoreceptor antagonist-induced 5-HT release in the hamster suprachiasmatic nuclei: effects on circadian clock resetting.

Serotonin (5-HT) has been implicated in phase shifting of mammalian circadian rhythms by non-photic stimuli. This study tests whether pharmacological induction of endogenous 5-HT release can shift circadian phase in the Syrian hamster. Systemic injections of the 5-HT(1A) antagonist WAY100635 during the mid-subjective day significantly increased 5-HT in dialysate from the hamster suprachiasmatic nucleus (SCN) circadian pacemaker by approximately 50% for 40-60 min. However, this was not associated with phase shifts or with potentiation of phase shifts induced by a 3 h bout of running. These results indicate that enhanced 5-HT release in the SCN or possibly other regions is not sufficient to induce phase shifts in the subjective day.

Animals↗

PubMed2000

Food anticipatory activity and photic entrainment in food-restricted BALB/c mice.

The BALB/c mouse was evaluated as a model for the study of entrainment of circadian rhythms by feeding schedules. Mice were housed in a 12:12-h light-dark (LD) environment with food available for 3-5 h/day (5 h before dark onset). Food anticipatory activity (FAA) rhythms were evident in all mice, ranging from robust in some to weak and variable in others. Advancing transients of the end of nocturnal activity were evident in many cases, culminating in a significant shortening of the main bout of nocturnal activity. Transients and contraction of nocturnal activity were not dependent on the expression of FAA. Following restricted feeding, nocturnal activity expanded by a series of delaying transients. On the first day of constant dark (DD) with ad libitum food access following restricted feeding in LD, the phase from which activity free-ran was advanced by comparison with control tests. Transients, compressed nocturnal activity, and advanced phase of free-run suggest that feeding schedules cause phase advancement of light-entrained rhythms in BALB/c mice. When restricted feeding was imposed in DD, several mice expressed robust FAA concurrent with a free-running activity component. In some cases, free-running rhythms entrained to feeding time, and in other cases, the period of the free run lengthened toward 24 h. These data show that restricted feeding in BALB/c mice can engage a circadian mechanism driving FAA rhythms and can also modulate the phase of photic entrainment, possibly by a direct entraining effect on the light-entrained rhythm. The BALB/c mouse strain, in several respects, appears to be a useful model for the study of scheduled feeding and circadian rhythms.

Animals↗

PubMed2000

Behavioral feedback regulation of circadian rhythm phase angle in light-dark entrained mice.

Induced and spontaneous wheel running can alter the phase and period (tau) of circadian rhythms in rodents. The relationship between spontaneous running and the phase angle (psi) of entrainment to 24-h light-dark (LD) cycles was evaluated in C57BL/6j mice. With a wheel freely available, psi was significantly correlated with the absolute (r = 0.32) and relative (r = 0.44) amount of activity during the first 2 h of the activity period. When wheels were locked during the first half of the night in LD and then unlocked in constant dark (DD), mice exhibited a delayed psi and lengthened tau compared with mice that had wheels locked during the second half of the night. In DD, tau correlated negatively with total daily activity. To evaluate if wheel running modulates the phase-resetting actions of LD, phase shifts to light pulses were measured at two time points in DD, when daily activity levels differed by 40%. Phase delays to light were 56% greater when activity levels were lower. However, in a counterbalanced follow-up experiment, phase advances and delays to light pulses were not affected by the availability of wheels, although an effect of time in DD was replicated. Spontaneous activity can regulate psi and tau without altering the response of the pacemaker to light.

Animals↗

PubMed1999

Neonatal monosodium glutamate alters circadian organization of feeding, food anticipatory activity and photic masking in the rat.

In rodents, parenteral administration of monosodium glutamate (MSG) induces marked degeneration of the retina and arcuate nucleus (AN) and disrupts daily rhythms of food intake. We quantified the effects of neonatal MSG (2 mg/g SC, postnatal days 1, 3, 5, 7, 9) on the expression of feeding and activity rhythms in adult rats under schedules of light-dark (LD), constant dark (DD), restricted daily feeding and total food deprivation. AN lesions were confirmed by neuropeptide Y (NPY) immunocytochemistry and Nissl stain. Compared to age-matched control rats, the amplitude (quantified as LD ratios) of daily food intake and food-bin activity rhythms was significantly attenuated in MSG rats in LD 12:12 and on the first day of DD. Control rats, but not MSG rats, showed lower amplitude rhythms in DD compared to LD. The phase angle of feeding and activity rhythms did not differ between groups in either condition. In a short LD cycle (2:2), control rats, but not MSG rats, showed significant inhibition (masking) of activity during the 2 h light periods. When food access was restricted to a 4 h daily meal, MSG rats showed enhanced expression and persistence of food-entrained anticipatory activity rhythms by comparison with control rats. These results indicate that attenuation of daily feeding rhythms in MSG rats is due in part to loss of direct inhibitory effects of light on behavior, and that the AN likely modulates, but does not mediate entrainment of feeding-related rhythms to daily cycles of LD or food access.

Animals↗

PubMed1999

Morphine-induced activity attenuates phase shifts to light in C57BL/6J mice.

Circadian rhythms can be phase shifted and entrained by daily schedules of light and by non-photic stimuli such as locomotor activity. Relatively little is known of how photic and non-photic stimuli interact to regulate circadian phase. Morphine injections were used to examine the effects of locomotor activity on phase shifts to light pulses in mice free-running in constant dark. Morphine injections scheduled early or late in the active period (subjective night) induced hyperactivity, but did not induce phase shifts. Light pulses late in the subjective night induced phase advance shifts that were significantly attenuated (63% smaller, p<0. 01) by pretreatment with morphine. This inhibitory effect of morphine on light-induced phase advances was blocked by preventing mice from running for 6 h after the injections. Light pulses early in the subjective night induced phase delay shifts that were only weakly attenuated (15% smaller, p=0.06) by morphine. These results demonstrate behavioral inhibition of light-induced phase resetting of circadian rhythms in mice, and suggest that the strength of this effect may be phase dependent, although other interpretations are possible.

Animals↗

PubMed1999

Circadian and homeostatic influences on sleep in the squirrel monkey: sleep after sleep deprivation.

A series of sleep deprivation (SD) experiments were performed to examine the relative influence of circadian and homeostatic factors on the timing of sleep in squirrel monkeys free-running in constant illumination. All SDs started at the beginning of subjective night and lasted 0, 1/4, 1/2, 1, 1 1/4, or 1 1/2 circadian cycles. These six lengths represented three pairs: (0.1), (1/4, 1 1/4), (1/2, 1 1/2). Within each pair, SD ended at the same circadian phase but differed by one circadian cycle in duration. Both before and after SD, consolidated sleep (CS) episodes occurred predominantly during subjective night, even after long SDs ending at the beginning of subjective day. CS duration was strongly influenced by circadian phase but had no overall correlation with prior wake duration. Sleep loss incurred during SDs longer than 1/4 cycle was only partially recovered over the next two circadian cycles, though total sleep duration was closer to baseline levels after the second circadian cycle after SD. There was a trend toward a positive correlation between prior wake duration and the amount of NREM and delta activity measures during subjective day. Delta activity was not increased in the first 2 hours of CS after the SD. Relatively high levels of delta activity occurred immediately after the SD ended and again at the time of baseline CS onset. These data indicate that the amount of sleep and delta activity after SD in squirrel monkeys is weakly dependent on prior wake duration. Circadian factors appear to dominate homeostatic processes in determining the timing, duration and content of sleep in these diurnal primates.

Animals↗

PubMed1999

Enhanced food-anticipatory circadian rhythms in the genetically obese Zucker rat.

This study examines the effects of the leptin receptor mutation in obese Zucker rats on entrainment of food-anticipatory rhythms to daily feeding schedules. Leptin is secreted by adipocytes in proportion to fat content, exhibits a daily rhythm in plasma that is synchronized to feeding time, and inhibits activity of arcuate neuropeptide Y neurons that stimulate feeding behavior and regulate metabolism. Activity within this neuropeptide Y system is enhanced by food deprivation and attenuated by overfeeding and diet-induced obesity. Diet-induced obesity, in turn, attenuates food-anticipatory rhythms. If the effects of obesity on food-entrained rhythms are mediated by leptin inhibition of neuropeptide Y neurons, then these rhythms may be enhanced in leptin-insensitive Zucker obese rats. Alternatively, if daily rhythms of leptin mediate the generation or entrainment of these rhythms, Zucker rats may fail to anticipate daily feedings. Zucker obese and lean rats received food for 3 h/day during the midlight period. Both groups exhibited significant food-anticipatory activity that persisted during three cycles of food deprivation, but this rhythm was significantly more robust in obese rats, when expressed as anticipation and persistence ratios, and as peak values. Anticipatory rhythms did not persist in either group when food was provided ad lib. These results indicate that central actions of leptin may mediate the inhibitory effects of obesity on the expression of food-anticipatory rhythms in rats, but do not mediate the inhibitory effects of ad lib food access, and do not serve as necessary internal entrainment cues or clock components for the food-entrainable circadian system.

Animals↗

PubMed1999

Circadian blood pressure and heart rate rhythms in mice.

The circadian pattern of mean arterial pressure (MAP) and heart rate (HR) was measured in C57BL mice with carotid arterial catheters. Cardiovascular parameters were recorded continuously with a computerized monitoring system at a sampling rate of 100 Hz. The tethered animals were healthy, showing stabilized drinking and eating patterns within 2 days of surgery and little loss of body weight. Analysis of the 24-h pattern of MAP and HR was conducted using data from 3-6 consecutive days of recording. A daily rhythm of MAP was evident in all mice, with group mean dark and light values of 101.4 +/- 7.3 and 93.1 +/- 2.9 mmHg, respectively. The group mean waveform was bimodal, with peak values evident early and late in the dark period, and a trough during the middle of the light period. The phase of maximum and minimum values showed low within-group variance. Mean heart rate was greater at night than during the day (561.9 +/- 22.7 vs. 530.3 +/- 22.3 beats/min). Peak values generally occurred at dark onset, and minimum values during the middle of both the dark and the light periods. We conclude that it is possible to perform measurements of circadian cardiovascular parameters in the mouse, providing new avenues for the investigation of genetic models.

Animals↗

PubMed1998

Serotonin antagonists do not attenuate activity-induced phase shifts of circadian rhythms in the Syrian hamster.

A variety of observations from several rodent species suggest that a serotonin (5-HT) input to the suprachiasmatic nucleus (SCN) circadian pacemaker may play a role in resetting or entrainment of circadian rhythms by non-photic stimuli such as scheduled wheel running. If 5-HT activity within the SCN is necessary for activity-induced phase shifting, then it should be possible to block or attenuate these phase shifts by reducing 5-HT release or by blocking post-synaptic 5-HT receptors. Animals received one of four serotonergic drugs and were then locked in a novel wheel for 3 h during the mid-rest phase, when novelty-induced activity produces maximal phase advance shifts. Drugs tested at several doses were metergoline (5-HT1/2 antagonist; i.p.), (+)-WAY100135 (5-HT1A postsynaptic antagonist, which may also reduce 5-HT release by an agonist effect at 5-HT1A raphe autoreceptors; i.p.), NAN-190 (5-HT1A postsynaptic antagonist, which also reduces 5-HT release via an agonist effect at 5-HT1A raphe autoreceptors; i.p.) and ritanserin (5-HT2/7 antagonist; i.p. and i.c.v.). Mean and maximal phase shifts to running in novel wheels were not significantly affected by any drug at any dose. These results do not support a hypothesis that 5-HT release or activity at 5HT1, 2 and 7 receptors in the SCN is necessary for the production of activity-induced phase shifts in hamsters.

Animals↗

PubMed1998

Behavioral inhibition of light-induced circadian phase resetting is phase and serotonin dependent.

Circadian rhythms in Syrian hamsters can be phase shifted by light exposure during the subjective night and by a bout of wheel running induced during the subjective day. Interactions between photic and behavioral stimuli were examined by comparing phase shifts to 15 min, 50 lux light pulses with and without a bout of running induced by confinement to a novel wheel 30 min prior to and extending through light exposure. Light pulses 6 h after dark onset on the first night of constant dark induced phase advance shifts averaging 80 min. Wheel running attenuated these shifts by 45% on average (p<0.01). Light pulses 1 h or 2.25 h after dark onset induced phase delay shifts averaging 50 min and 20 min, respectively, that were not affected by stimulated running. A significant running response to the novel wheel was evident at all 3 time points, but was greater to wheel confinement at both times early in the night. Stimulated running alone early or late in the night did not produce significant phase shifts. Behavioral attenuation of phase advances to light late in the night was prevented by pretreatment with the general 5HT1 antagonist metergoline (2 mg/kg i.p.). Metergoline did not significantly attenuate running in novel wheels. These results indicate that modulation of light-induced phase shifts by behavior is phase dependent and may involve direct or indirect actions of serotonin within the circadian system.

Animals↗

PubMed1998

Circadian rhythms in the Zucker obese rat: assessment and intervention.

Body temperature (Tb) and activity were recorded by telemetry in obese and lean Zucker rats in light-dark (LD), constant dark (DD) and constant light (LL). In LD, obese rats, by comparison with lean rats, exhibited a 2-4-h phase advance and attenuated amplitude of Tb and activity rhythms. These differences persisted on the first day of DD, and thus were not due to differential sensitivity to masking effects of light. In LL, obese and lean rats exhibited similar free-running periods, thus the phase advance in LD was also not due to a short intrinsic period. In LD, obese rats exhibited more diurnal food intake and a reduced LD intake ratio. To assess the role of diurnal feeding in weight gain, one group of obese rats was fed ad libitum, and another fed only at night. Food intake did not differ significantly between groups, but ad libitum fed rats gained 23% more weight (60 g) over 60 days, suggesting that excessive diurnal feeding may contribute adversely to body weight regulation in this animal model of obesity.

Activity Cycles↗

PubMed1998

Serotonin and feedback effects of behavioral activity on circadian rhythms in mice.

Wheel running activity can shorten the period (tau) of circadian rhythms in rats and mice. The role of serotonin (5HT), in this effect of behavior on circadian pacemaker function, was assessed by measuring tau during wheel-open and wheel-locked conditions in mice sustaining neurotoxic 5HT lesions directed at the suprachiasmatic nucleus (SCN). Intact mice exhibited a significant lengthening of tau (approximately 10 min) within 3 weeks when running wheels were locked. Mice with immunocytochemically confirmed 5HT depletion showed significantly longer tau than intact mice during wheel access, and did not show a significant change in tau up to 6 weeks after wheels were locked. In these mice, variability of tau across wheel access conditions was similar in magnitude to tau variability in intact mice at two time points without wheel access (+/- 3 min). 5HT-depleted mice also exhibited significantly longer activity periods (alpha), and a significantly delayed peak of activity within alpha. Previous studies show that a delayed peak of activity within alpha is associated with longer tau. Group differences in tau, and apparent failure of wheel-locking to lengthen tau in mice with 5HT lesions, may thus be due to loss of a serotonergic behavioral input pathway to the SCN, or to a lesion-induced change in the waveform of the activity rhythm.

5,7-Dihydroxytryptamine↗

PubMed1997

Sleep deprivation can attenuate light-induced phase shifts of circadian rhythms in hamsters.

To determine whether sleep deprivation (SD) affects the response of circadian rhythms to light, hamsters were forced to walk on a slowly rotating treadmill for 6 or 24 h, ending early in the night, with or without a light pulse during the last 30 min. SD alone did not produce a significant phase shift. Light pulses (300 and 50 lx) alone induced significant delay shifts (55 and 35 min, respectively). Twenty-four hours SD significantly attenuated the delay to brighter light and 6 h SD significantly attenuated the delay to moderate light. Sleep loss or attendant low-intensity continuous activity appear to modulate the response of the hamster circadian system to light.

Animals↗

PubMed1997

Both neuropeptide Y and serotonin are necessary for entrainment of circadian rhythms in mice by daily treadmill running schedules.

This study investigated the role of the suprachiasmatic nucleus (SCN) circadian pacemaker and its neuropeptide Y (NPY) and serotonin (5-HT) afferents in entrainment (synchronization) of mouse circadian rhythms by treadmill running. Blind C57BL/6j mice were run in treadmills for 3 hr/d for 3-10 weeks after receiving radio-frequency lesions of the SCN or the intergeniculate leaflet (IGL, the source of SCN NPY) or infusions of the 5-HT neurotoxin 5,7-DHT into the SCN area. Of 25 intact mice, 22 entrained and three showed period (tau, the mean duration of the circadian cycle) modulations to scheduled running. Arrhythmic SCN-ablated mice did not synchronize to scheduled running in a way suggestive of circadian pacemaker mediation. Of 15 mice with IGL lesions, only two with partial lesions entrained. Mice with complete IGL lesions (five), confirmed by immunocytochemistry, showed no entrainment or tau changes. Of 19 mice with 5-HT lesions, only two with partial lesions entrained. All but two mice with complete (10) or nearly complete (4) 5-HT denervation, confirmed by immunocytochemistry, showed tau modulations during the treadmill schedule. Failure to entrain was not explained by group differences in tau before the treadmill schedules. The results indicate that the SCN and both NPY and 5-HT are necessary for entrainment to 24 hr schedules of forced running but that complete loss of 5-HT does not prevent modulations of pacemaker motion by behavioral stimuli. Treadmill entrainment in mice may involve synergistic interactions between 5-HT and NPY afferents at some site within the circadian system.

Animals↗

PubMed1997

Anticipation and entrainment to feeding time in intact and SCN-ablated C57BL/6j mice.

To characterize properties and mechanisms of non-photic entrainment of circadian rhythms, the effects of scheduled feeding were assessed in intact and suprachiasmatic nuclei (SCN) ablated C57BL/6j mice. During ad libitum food access, mice with no or partial SCN damage exhibited free-running activity and drinking rhythms, whereas mice with complete ablations were arrhythmic. When food was restricted to 4 h/day for 5-9 weeks, intact and partial SCN-ablated mice exhibited anticipatory activity to mealtime, concurrent with free-running rhythms. In some cases, free-running rhythms became entrained to feeding time; this was more prevalent in intact than partial ablated mice and was related to free-running period. Free-running phase or period were modified in other cases, revealing a phase-response profile consistent with other non-photic zeitgebers. Five of 12 mice with complete or near complete SCN ablations showed anticipatory activity. Mice that failed to anticipate were less active generally and sustained larger lesions. Sites of damage unique to non-anticipators were not evident. The results indicate that the SCN is not necessary for anticipatory rhythms in mice, but that cell populations distributed across several hypothalamic areas may be important for at least some behavioral markers of this circadian function.

Animals↗

PubMed1997

Phase shifts to refeeding in the Syrian hamster mediated by running activity.

Circadian rhythms in hamsters can be entrained by restricted daily feeding schedules. Phase control may be exerted by feeding per se, or by wheel running in anticipation of food access. Phase modulation by feeding was examined here by depriving hamsters of food for 9-24 h and refeeding at 1 of 7 different zeitgeber times on the first day of constant dim light. Significant group mean phase-advance shifts were observed only following 24 h and 17 h deprivations ending in the mid-subjective day, 7 h before the usual time of lights off (mean shifts 28 min and 66 min, respectively). The largest phase shifts were associated with wheel running during the first 6 h of refeeding. When running wheels were locked during this time in an additional group, no phase shifts were observed. A trend for small phase delays was evident for 14 h deprivations ending at the beginning of the subjective night, but no significant group mean or individual shifts were observed at other refeeding times. Refeeding after food deprivation, thus, appears to have minimal effects on circadian phase in hamsters; wheel running associated with refeeding may account for occasional shifts observed.

Animals↗

PubMed1997

Scheduled activity reorganizes circadian phase of Syrian hamsters under full and skeleton photoperiods.

Circadian rhythms can be shifted or entrained by light and by arousing nonphotic stimuli. Interactions between photic and nonphotic stimuli were examined by subjecting hamsters to a daily 3 h bout of induced running under full (FPP) or skeleton (two daily light pulses; SPP) photoperiods. Activity scheduled in mid-day of a FPP induced large phase delays (260 +/- 63 min) in hamsters that ran more than 4000 rev/3 h. Split rhythms were not evident in constant dark (DD) tests. Activity scheduled in mid-subjective day of a SPP induced 180 degrees inversions of circadian phase, apparently achieved by oscillator splitting in some cases. Activity scheduled late-day and early-night induced a mix of phase delays, advances and no responses. Activity scheduled at two phase ranges late in the night had no effect, but scheduled 1 h later (beginning the last hour of darkness) induced large phase delays (238 +/- 30 min). There was no evidence of oscillator splitting during DD tests, but free-running period was significantly longer in groups that showed large phase delays. Induced running schedules have powerful effects on the phase of photic entrainment and can alter intrinsic pacemaker properties, including internal oscillator coupling and period.

Animals↗