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P C Zee

Publications and source records attributed to P C Zee.

34 records · Page 2Linked to original sources
PubMed1996

Effects of aging on light-induced phase-shifting of circadian behavioral rhythms, fos expression and CREB phosphorylation in the hamster suprachiasmatic nucleus.

Aging is associated with a variety of alterations in circadian rhythms, including changes in the response to environmental stimuli. The underlying causes for these age-related changes in the circadian system remain unknown. Recent studies have demonstrated that light induces the expression of Fos and phosphorylation of the cyclic-AMP response element-binding protein in the rodent suprachiasmatic nuclei, the location of a master circadian pacemaker in mammals, suggesting that these transcription factors may mediate the effects of light on the circadian clock. The purpose of this study was to determine the effects of aging upon light-induced phase-shifting of circadian locomotor activity rhythms, Fos protein expression and cyclic-AMP response element-binding protein phosphorylation in the suprachiasmatic nuclei. Young (three to four months) and old (18-22 months) male golden hamsters free-running in constant darkness were exposed to 5-min monochromatic light pulses of different irradiance levels, at circadian time 19, after which either steady-state phase shifts of locomotor activity rhythms were measured, or else immunocytochemistry for Fos or for phospho-cyclic-AMP response element-binding protein was performed. Old hamsters were approximately 20 times less sensitive to the phase-shifting effects of light on the activity rhythm, and the photic irradiance threshold for Fos-like immunoreactivity induction in the suprachiasmatic nuclei was elevated when compared to young animals. Aging was also associated with a deficit in cyclic-AMP response element-binding protein phosphorylation by light. These data indicate that there are dramatic changes in light-activated molecular responses in the suprachiasmatic nuclei of old hamsters, and suggest that these molecular changes may underlie age-related changes in the effects of light on the circadian clock system.

Age Factors↗
PubMed1996

A low-protein diet ameliorates disrupted diurnal locomotor activity in rats after portacaval anastomosis.

In previous studies we noted a disruption of the circadian locomotor activity rhythm in rats after portacaval anastomosis (PCA). To examine whether this abnormality is related to factors that aggravate hepatic encephalopathy in humans, we studied the effect of dietary formulation and protein content on body weight, locomotor activity, and entrainment to the light-dark cycle in rats after PCA or sham operation. Postoperative weight loss was prevented by pair-feeding with a purified liquid diet. However, the behavioral abnormalities persisted in PCA rats fed a high-protein diet, with a reduction in total activity and entrainment to the light-dark cycle. These were ameliorated by a low dietary protein content. Since this treatment reduces the load of gut-derived nitrogenous substances that might alter brain metabolism, our data strengthen the hypothesis that the abnormal circadian activity patterns in PCA rats may be part of the spectrum of hepatic encephalopathy.

Animals↗
PubMed1995

Disruption of the diurnal rhythm of plasma melatonin in cirrhosis.

OBJECTIVES: To assess 24-hour plasma melatonin profile as a marker of output rhythm from the circadian clock and to study sleep diaries as reflections of subjective sleep quality in patients with liver cirrhosis. DESIGN: Prospective cohort study. SETTING: Clinical research center in a university hospital. PATIENTS: Seven patients with cirrhosis but not alcoholism and seven age-, sex-, and education-matched controls. MEASUREMENTS: Neuropsychological testing to confirm subclinical hepatic encephalopathy. Plasma melatonin levels measured every 30 minutes for 24 hours by radioimmunoassay. Sleep diaries kept for 1 week before admission. RESULTS: Patients with cirrhosis had markedly elevated melatonin levels during daytime hours; in addition, the time of onset of melatonin increase and the time at which melatonin levels peaked were consistently and significantly delayed in these patients. Sleep diaries indicated more nocturnal awakenings and more frequent daytime naps in patients with cirrhosis. CONCLUSION: Disruption of the diurnal rhythm of melatonin may reflect alterations of circadian function that could contribute to the disturbances of the sleep-wake cycle frequently seen in patients with cirrhosis.

Adult↗
PubMed1995

A serotonin neurotoxin attenuates the phase-shifting effects of triazolam on the circadian clock in hamsters.

Several lines of evidence suggest the potential involvement of serotonergic pathways in mediating the effects of activity-inducing stimuli on the circadian clock in rodents. The aim of the present 3 experiments was to examine the effects of the serotonergic neurotoxin, p-chloroamphetamine (PCA, 10 mg/kg) on: (1) the monoamine levels of the hypothalamus, frontal cortex and hippocampus in the hamster; (2) the phase shifts in the circadian rhythm of locomotor activity of hamsters in response to treatment with the short-acting benzodiazepine, triazolam (7.5 mg/kg); and (3) the magnitude of the acute increase in locomotor activity associated with triazolam administration in this species. The administration of PCA to hamsters caused changes of specific monoaminergic systems in the hypothalamus, that were limited to a selective decrease in serotonin levels 7 days post-treatment. The phase shifts of the circadian clock in response to triazolam treatment at CT 6 were considerably attenuated following the administration of the 5-HT neurotoxin. The total amount and the profiles of triazolam-induced wheel-running and general cage activity between CT 6 and CT 12 were not significantly affected by the PCA treatment. The finding that a 5-HT neurotoxin can attenuate the phase-shifting effects of triazolam in hamsters, without interfering with its activity-inducing properties, suggests that serotonergic afferents might be involved in the mechanism for non-photic phase-shifting of the circadian system.

Animals↗
PubMed1995

Pharmacological and genetic approaches for the study of circadian rhythms in mammals.

Two different approaches have been utilized to study the controlling mechanisms that underlie the generation and entrainment of circadian rhythms in mammals. The use of specific drugs to alter the period and/or the phase of circadian rhythms has provided new insights into both the pathways by which environmental information reaches the mammalian circadian pacemaker in the suprachiasmatic nuclei (SCN) and the cellular and neurochemical events within the SCN itself which are involved in circadian rhythmicity. A second approach, which seeks to exploit genetic differences in the properties of the circadian system, holds the promise of eventually defining the cellular and molecular events that are part of the clock itself, the events that underlie the entrainment of the circadian clock by environmental factors, and the expression of overt rhythms driven by the clock. It is anticipated that the pharmacological and genetic approaches to the study of circadian rhythms will complement each other as the underlying physiological mechanisms of the circadian clock system become defined.

Afferent Pathways↗
PubMed1995

Aging alters the phase-resetting properties of a serotonin agonist on hamster circadian rhythmicity.

Serotonergic mechanisms are believed to play a considerable role in mediating the effects of photic and nonphotic stimuli on circadian rhythmicity. Because aging is associated with significant changes in the responsiveness of the rodent circadian system to major synchronizing agents in the environment, this study examined the phase-shifting effects of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin [8-OH-DPAT; 2.0, 5.0, and 8.0 mg/kg ip at circadian time 8 (CT 8)], on the 24-h activity rhythm of young (3-4 mo old) and old (18-19 mo old) golden hamsters. Aging was associated with a dramatic attenuation of the phase-shifting effects of 8-OH-DPAT in this species. The results suggest the existence of age-related deficits in the serotonergic control of mammalian circadian rhythmicity, which could interfere with the temporal adaptation of the senescent organism to its environment.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Grafting fetal suprachiasmatic nuclei in the hypothalamus of old hamsters restores responsiveness of the circadian clock to a phase shifting stimulus.

In the present study, 18-25-month-old hamsters free-running in constant dim light were injected, both before and after receiving fetal grafts containing either cerebellar tissue or the suprachiasmatic nuclei (SCN), with a dose of triazolam given at a time known to reliably phase shift the rhythm of locomotor activity in young hamsters. SCN-grafted animals, but not control animals implanted with fetal cerebellar tissue, showed a significantly greater response to the phase shifting effects of triazolam, demonstrating that at least some age-related changes in the circadian system can be reversed by neuronal transplantation. These results raise the possibility that neuropharmacological interventions that can simulate the effects of fetal SCN grafts might be useful in the treatment of age-related disorders in circadian function.

Aging↗
PubMed1994

Monoamine depletion blocks triazolam-induced phase advances of the circadian clock in hamsters.

Injections with the short-acting benzodiazepine, triazolam (Tz), 6 h before activity onset (CT6) produce large phase advances of the circadian pacemaker in hamsters. An increase in locomotor activity and/or the state of arousal is considered essential for the effects of Tz, suggesting the potential involvement of central monoaminergic systems in this process. The present study examines the effect of reserpine-induced monoamine depletion on the phase-shifting effects of Tz in hamsters. Wheel running activity of 16 male golden hamsters (14 weeks old) was continuously monitored in constant darkness. After a stable free-running circadian rhythm was established half of the animals received reserpine (2.5 mg/kg, s.c.) and the other half vehicle treatment. Ten days later all animals were given Tz injections (10 mg/kg i.p.) at CT6 and the circadian activity rhythm was monitored for 2 more weeks. An additional 10 animals were used to determine the effect of reserpine on the central monamine levels using high pressure liquid chromatography. A circadian rhythm of locomotor activity with reduced amplitude and longer free-running period persisted after reserpine treatment, despite the significant monoamine depletion. Triazolam injections at CT6 induced large phase-advances (93.1 +/- 14.9) in the control group that were markedly attenuated in 7 out of the 8 reserpine-treated animals (3.12 +/- 17.7 min, P < 0.01). Our results suggest that monoaminergic systems are essential for the phase-shifting effect of Tz upon the circadian system in hamsters.

Aging↗
PubMed1993

Fos protein expression in the circadian clock is not associated with phase shifts induced by a nonphotic stimulus, triazolam.

Recent studies have shown that light-induced phase shifts of the circadian rhythm of locomotor activity are associated with c-fos expression in the suprachiasmatic nucleus (SCN) and intergeniculate leaflet (IGL) of the lateral geniculate nucleus of rodents. In order to determine whether c-fos expression is necessary for the phase shifting effects of a non-photic stimulus, we assessed Fos-like immunoreactivity (Fos-lir) in the SCN and IGL at various times after an injection of the short-acting benzodiazepine, triazolam, at circadian time (CT) 6; i.e. at a time when triazolam induces an acute increase in locomotor activity and maximal phase advances in the circadian rhythm of locomotor activity. Specific Fos-lir staining was not observed in the SCN or IGL regions of any animals treated with triazolam or vehicle at any time point examined. These results indicate that exposure to an activity-inducing stimulus at circadian times when this stimulus induces phase shifts does not induce Fos protein synthesis in the SCN or IGL regions.

Amino Acid Sequence↗
PubMed1993

A cholinergic antagonist, mecamylamine, blocks light-induced fos immunoreactivity in specific regions of the hamster suprachiasmatic nucleus.

Recent studies have shown that light-induced phase shifts of the circadian rhythm of locomotor activity are associated with c-fos expression in the suprachiasmatic nucleus (SCN) of rodents. In order to explore further the importance of c-fos expression for the phase-shifting effects of light, we examined the effects of mecamylamine on light-induced Fos-like immunoreactivity (Fos-lir) in the SCN. Mecamylamine was chosen because it is a cholinergic antagonist that blocks the phase-shifting effects of light on the circadian activity rhythm in the golden hamster. Golden hamsters were entrained for at least 14 days to a 14 h light: 10 h dark photoperiod. Animals were then placed in constant darkness (DD) and during exposure to DD were subjected to one or more of the following treatments: (1) vehicle alone; (2) mecamylamine alone (450 micrograms, i.c.v.) at circadian time (CT) 19; (3) vehicle plus a light pulse at CT 19; (4) mecamylamine 10 min prior to the light pulse at CT 19. Mecamylamine blocked the phase-shifting effects of light on the circadian rhythm of locomotor activity when compared to vehicle-treated animals (P < 0.001). A light pulse at CT 19 induced Fos-lir in the SCN within 1 h, whereas treatment with vehicle or mecamylamine had no noticeable effect on Fos-lir in the SCN. Mecamylamine pretreatment dramatically reduced light-induced Fos-lir in the SCN by 75%. The most striking observation was the clear inhibition of Fos-lir by mecamylamine in the dorsomedial region of the SCN while there was little inhibition of Fos-lir in the most ventral portions of the SCN.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Monoamine depletion alters the entrainment and the response to light of the circadian activity rhythm in hamsters.

Reduced amplitude, shorter free-running periods and desynchronization among a number of circadian rhythms are associated with advanced age in rodents. The response of the hamster circadian system to photic stimuli is also altered during senescence. Decreased monoamine levels, receptor sites and neuronal populations are commonly observed in the aging brain. The objective of the present study was to determine if monoamine depletion with reserpine in young hamsters induces changes in the circadian rhythm of locomotor activity similar to those that occur spontaneously with aging. Wheel-running activity of 12 young hamsters under a 14 h-light/10 h-dark cycle was continuously monitored. The total activity level, the times of activity onset, peak and offset and the duration of activity were determined during a 1-week period after vehicle treatment and for three 1-week periods after reserpine treatment (4 mg/kg). A second group of eight reserpine-treated and six vehicle-treated animals was kept in constant darkness (DD). The period of the circadian activity rhythm in DD and the phase-shifts after short light pulses at circadian time 19 (CT19) were determined in the control and reserpine-treated groups. Brain monoamines in the hypothalamus, striatum and pons/medulla after reserpine and vehicle treatment were determined by high-pressure liquid chromatography. The data were analyzed with x2 periodogram and one-way ANOVA followed by Duncan's post hoc test. Reserpine treatment significantly reduced total wheel-running activity and the monoamine levels in the hypothalamus, striatum and pons/medulla.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Aging alters feedback effects of the activity-rest cycle on the circadian clock.

Two different stimuli (i.e., benzodiazepines and dark pulses) inducing phase shifts in the circadian clock of young hamsters through changes in the level of activity do not induce phase shifts in old hamsters, despite the fact that these stimuli induce a similar acute change in locomotor activity in young and old animals. In contrast, old hamsters remain sensitive to the phase-shifting effects of stimuli clearly not associated with any change in locomotor activity (i.e., protein synthesis inhibitors or light). Thus the circadian system of old animals becomes selectively unresponsive to synchronizing signals mediated by the activity-rest state of the animals. Previous age-related changes in circadian rhythmicity that have been observed in mammals, including humans, may be related to a weakened coupling between the activity-rest cycle and the circadian clock.

Activity Cycles↗
PubMed1992

Effects of aging on entrainment and rate of resynchronization of circadian locomotor activity.

The phase angle of entrainment of the circadian rhythm of the locomotor activity rhythm to a light-dark (LD) cycle was examined in young (2-5 mo old) and middle-aged (13-16 mo old) hamsters. An age-related phase advance in the onset of locomotor activity relative to lights off was seen during stable entrainment to a 14:10-h LD cycle. In addition, the effects of age on the rate of reentrainment of the circadian rhythm of locomotor activity were examined by subjecting young and middle-aged hamsters to either an 8-h advance or delay shift of the LD cycle. Middle-aged hamsters resynchronized more rapidly after a phase advance of the LD cycle than did young hamsters, whereas young hamsters were able to phase delay more rapidly than middle-aged hamsters. The age-related phase advance of activity onset under entrained conditions, and the alteration of responses in middle-aged hamsters reentraining to a phase-shifted LD cycle, may be due to the shortening of the free-running period of the circadian rhythm of locomotor activity with advancing age that has previously been observed in this species.

Aging↗
PubMed1991

Portacaval anastomosis disrupts circadian locomotor activity and pineal melatonin rhythms in rats.

To determine whether hepatic encephalopathy may be associated with a disruption of circadian function, the circadian rhythms of locomotor activity and pineal melatonin content were examined in an animal model of complete portal-systemic shunting, rats with a portacaval anastomosis (PCA). The locomotor activity rhythm of all sham-operated animals entrained normally to a light/dark cycle and exhibited a normal free-running period during exposure to constant light. In contrast, PCA led to a dampening of the locomotor activity rhythm in all animals and the abolishment of a circadian periodicity in the activity rhythm of approximately 50% of rats during exposure to either a light/dark cycle or constant light. While normal diurnal variations of pineal melatonin content were seen in sham-operated rats, the amplitude of this variation appeared to be decreased in PCA animals. The similar effects of PCA on both a behavioral and an endocrine circadian rhythm, known to be regulated by a common neural pacemaker, coupled with studies indicating that a variety of other circadian rhythms may be disrupted in both animals and humans with hepatic dysfunction, suggests that this circadian disturbance originates within the pacemaker or on one of its afferent/efferent pathways.

Animals↗
PubMed1991

Phase response curves to light in young and old hamsters.

The phase-shifting effects of 1-h light pulses on the circadian rhythm of locomotor activity were measured in young (less than 12 mo old) and old (greater than 16 mo old) hamsters. Phase response curves (PRCs) for both age groups showed an inactive region [approximately circadian time (CT) 0 through CT12], a delay region (CT12 through CT16), and an advance region (CT16 through CT24) as has been reported for young animals. Significant age group differences in the amplitude of phase shifts were measured, with older animals showing larger shifts limited to the region of the "break point" at CT16. The free-running period of the activity rhythm was measured before the first light pulse; age-related decreases of period length consistent with previous reports were measured. The findings indicate that the response of the circadian clock to the major environmental synchronizing agent, light, is different in old hamsters compared with young adults.

Aging↗