Disrupted circadian rhythms in VIP- and PHI-deficient mice

2003 ◽  
Vol 285 (5) ◽  
pp. R939-R949 ◽  
Author(s):  
Christopher S. Colwell ◽  
Stephan Michel ◽  
Jason Itri ◽  
Williams Rodriguez ◽  
J. Tam ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Wheel Running ◽  
Activity Rhythm ◽  
Activity Patterns ◽  
Circadian System ◽  
Diurnal Rhythms ◽  
Constant Darkness ◽  
Light Cycle ◽  
Wild Type ◽  
Deficient Mice

The related neuropeptides vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) are expressed at high levels in the neurons of the suprachiasmatic nucleus (SCN), but their function in the regulation of circadian rhythms is unknown. To study the role of these peptides on the circadian system in vivo, a new mouse model was developed in which both VIP and PHI genes were disrupted by homologous recombination. In a light-dark cycle, these mice exhibited diurnal rhythms in activity which were largely indistinguishable from wild-type controls. In constant darkness, the VIP/PHI-deficient mice exhibited pronounced abnormalities in their circadian system. The activity patterns started ∼8 h earlier than predicted by the previous light cycle. In addition, lack of VIP/PHI led to a shortened free-running period and a loss of the coherence and precision of the circadian locomotor activity rhythm. In about one-quarter of VIP/PHI mice examined, the wheel-running rhythm became arrhythmic after several weeks in constant darkness. Another striking example of these deficits is seen in the split-activity patterns expressed by the mutant mice when they were exposed to a skeleton photoperiod. In addition, the VIP/PHI-deficient mice exhibited deficits in the response of their circadian system to light. Electrophysiological analysis indicates that VIP enhances inhibitory synaptic transmission within the SCN of wild-type and VIP/PHI-deficient mice. Together, the observations suggest that VIP/PHI peptides are critically involved in both the generation of circadian oscillations as well as the normal synchronization of these rhythms to light.

Gonadal hormones organize and modulate the circadian system of the rat

1981 ◽  
Vol 241 (1) ◽  
pp. R62-R66 ◽  
Author(s):  
H. E. Albers
Keyword(s):  
Testosterone Propionate ◽  
Wheel Running ◽  
Activity Rhythm ◽  
Gonadal Hormones ◽  
Circadian System ◽  
Female Rats ◽  
Constant Darkness ◽  
Before And After ◽  
Free Running ◽  
Free Running Period

The circadian wheel-running rhythms of gonadectomized adult male, female, and perinatally androgenized female rats, maintained in constant darkness, were examined before and after implantation of Silastic capsules containing cholesterol (C) or estradiol-17 beta (E). The free-running period of the activity rhythm (tau) before capsule implantation tended to be shorter in animals exposed to perinatal androgen. Administration of C did not reliably alter tau in any group. E significantly shortened tau in 100% of females injected with oil on day 3 of life. In females, injected with 3.5 micrograms testosterone propionate on day 3, and males, E shortened or lengthened tau, with the direction and magnitude of this change in tau inversely related to the length of the individual's pretreatment tau. These data indicate that the presence of perinatal androgen does not eliminate the sensitivity of the circadian system of the rat to estrogen, since estrogen alters tau in a manner that depends on its pretreatment length.

Melatonin and activity rhythm responses to light pulses in mice with the Clock mutation

2003 ◽  
Vol 284 (5) ◽  
pp. R1231-R1240 ◽  
Author(s):  
David J. Kennaway ◽  
Athena Voultsios ◽  
Tamara J. Varcoe ◽  
Robert W. Moyer
Keyword(s):  
Wheel Running ◽  
Activity Rhythm ◽  
Mutant Mice ◽  
Constant Darkness ◽  
Wild Type ◽  
Continuous Darkness ◽  
Light Pulses ◽  
Essentially Normal ◽  
Running Activity ◽  
Wheel Running Activity

Melatonin and wheel-running rhythmicity and the effects of acute and chronic light pulses on these rhythms were studied in Clock Δ19 mutant mice selectively bred to synthesize melatonin. Homozygous melatonin-proficient Clock Δ19 mutant mice ( Clock Δ19/Δ19 -MEL) produced melatonin rhythmically, with peak production 2 h later than the wild-type controls (i.e., just before lights on). By contrast, the time of onset of wheel-running activity occurred within a 20-min period around lights off, irrespective of the genotype. Melatonin production in the mutants spontaneously decreased within 1 h of the expected time of lights on. On placement of the mice in continuous darkness, the melatonin rhythm persisted, and the peak occurred 2 h later in each cycle over the first two cycles, consistent with the endogenous period of the mutant. This contrasted with the onset of wheel-running activity, which did not shift for several days in constant darkness. A light pulse around the time of expected lights on followed by constant darkness reduced the expected 2-h delay of the melatonin peak of the mutants to ∼1 h and advanced the time of the melatonin peak in the wild-type mice. When the Clock Δ19/Δ19 -MEL mice were maintained in a skeleton photoperiod of daily 15-min light pulses, a higher proportion entrained to the schedule (57%) than melatonin-deficient mutants (9%). These results provide compelling evidence that mice with the Clock Δ19 mutation express essentially normal rhythmicity, albeit with an underlying endogenous period of 26–27 h, and they can be entrained by brief exposure to light. They also raise important questions about the role of Clock in rhythmicity and the usefulness of monitoring behavioral rhythms compared with hormonal rhythms.

scholarly journals Effects of chronic expression of the HIV-induced protein, transactivator of transcription, on circadian activity rhythms in mice, with or without morphine

2008 ◽  
Vol 295 (5) ◽  
pp. R1680-R1687 ◽  
Author(s):  
Marilyn J. Duncan ◽  
Annadora J. Bruce-Keller ◽  
Clayton Conner ◽  
Pamela E. Knapp ◽  
Ruquiang Xu ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Transgenic Mice ◽  
Hiv Infection ◽  
Phase Angle ◽  
Wheel Running ◽  
Constant Darkness ◽  
Intracerebral Injection ◽  
Wild Type ◽  
Transactivator Of Transcription

Patients with human immunodeficiency virus (HIV) infection exhibit changes in sleep patterns, motor disorders, and cognitive dysfunction; these symptoms may be secondary to circadian rhythm abnormalities. Studies in mice have shown that intracerebral injection of an HIV protein, transactivator of transcription (Tat), alters the timing of circadian rhythms in a manner similar to light. Therefore, we tested the hypothesis that chronic Tat expression alters circadian rhythms, especially their entrainment to a light-dark (LD) cycle, by using transgenic mice in which Tat expression in the brain was induced via a doxycycline (DOX)-sensitive, glial fibrillary-associated, protein-restricted promoter. Because opiate substance abuse, which shares comorbidity with HIV infection, also disrupts sleep, a final experiment assessed the effects of morphine exposure on circadian rhythms in wild-type and Tat transgenic mice. Mice housed in cages equipped with running wheels were fed chow with or without DOX. Experiment 1 revealed a small but significant ( P < 0.05) difference between groups in the phase angle of entrainment and a 15% decrease in the wheel running in the DOX group ( P < 0.005). During exposure to constant darkness, DOX did not alter the endogenous period length of the circadian rhythm. Experiment 2 investigated the effect of DOX on circadian rhythms in wild-type and Tat(+) mice during exposure to a normal or phase-shifted LD cycle, or morphine treatment without any change in the LD cycle. Tat induction significantly decreased wheel running but did not affect entrainment to the normal or shifted LD cycle. Morphine decreased wheel running without altering the phase angle of entrainment, and the drug's effects were independent of Tat induction. In conclusion, these findings suggest that chronic brain expression of Tat decreases locomotor activity and the amplitude of circadian rhythms, but does not affect photic entrainment or reentrainment of the murine circadian pacemaker.

scholarly journals Salt sensitivity of blood pressure in NKCC1-deficient mice

2008 ◽  
Vol 295 (4) ◽  
pp. F1230-F1238 ◽  
Author(s):  
Soo Mi Kim ◽  
Christoph Eisner ◽  
Robert Faulhaber-Walter ◽  
Diane Mizel ◽  
Susan M. Wall ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Wheel Running ◽  
Plasma Renin ◽  
Pressure Change ◽  
Standard Diet ◽  
Wild Type ◽  
Vascular Effects ◽  
Arterial Blood ◽  
Deficient Mice

NKCC1 is a widely expressed isoform of the Na-2Cl-K cotransporter that mediates several direct and indirect vascular effects and regulates expression and release of renin. In this study, we used NKCC1-deficient (NKCC1−/−) and wild-type (WT) mice to assess day/night differences of blood pressure (BP), locomotor activity, and renin release and to study the effects of high (8%) or low (0.03%) dietary NaCl intake on BP, activity, and the renin/aldosterone system. On a standard diet, 24-h mean arterial blood pressure (MAP) and heart rate determined by radiotelemetry, and their day/night differences, were not different in NKCC1−/− and WT mice. Spontaneous and wheel-running activities in the active night phase were lower in NKCC1−/− than WT mice. In NKCC1−/− mice on a high-NaCl diet, MAP increased by 10 mmHg in the night without changes in heart rate. In contrast, there was no salt-dependent blood pressure change in WT mice. MAP reductions by hydralazine (1 mg/kg) or isoproterenol (10 μg/mouse) were significantly greater in NKCC1−/− than WT mice. Plasma renin (PRC; ng ANG I·ml−1·h−1) and aldosterone (aldo; pg/ml) concentrations were higher in NKCC1−/− than WT mice (PRC: 3,745 ± 377 vs. 1,245 ± 364; aldo: 763 ± 136 vs. 327 ± 98). Hyperreninism and hyperaldosteronism were found in NKCC1−/− mice during both day and night. High Na suppressed PRC and aldosterone in both NKCC1−/− and WT mice, whereas a low-Na diet increased PRC and aldosterone in WT but not NKCC1−/− mice. We conclude that 24-h MAP and MAP circadian rhythms do not differ between NKCC1−/− and WT mice on a standard diet, probably reflecting a balance between anti- and prohypertensive factors, but that blood pressure of NKCC1−/− mice is more sensitive to increases and decreases of Na intake.

Circadian rhythms in blinded rats: correlation between pineal and activity cycles

1978 ◽  
Vol 234 (3) ◽  
pp. R110-R114
Author(s):  
C. R. Pohl ◽  
F. P. Gibbs
Keyword(s):  
Pineal Gland ◽  
Activity Rhythm ◽  
Diurnal Rhythms ◽  
Light Cycle ◽  
Activity Phase ◽  
Running Activity ◽  
Free Running ◽  
Activity Cycles ◽  
Rat Pineal Gland ◽  
Sampling Times

The rat pineal gland exhibits diurnal rhythms in levels of N-acetyltransferase activity and its substrate serotonin. We attempted to demonstrate the endogenous nature of these changes by measuring the pineal enzyme and its substrate in rats blinded for 37 and 60 days. In order to determine the proper sampling times for these one-time, terminal measurements, the running activity rhythm of each rat was monitored continuously and the animals were killed at either midrest or midrun. Circadian changes of pineal N-acetyltransferase and serotonin were demonstrated, with enzyme levels high and substrate content low during midrun. Absolute values during each activity phase were similar to those of control rats entrained to a light cycle (LD 12:12). Levels of the pineal constituents were unrelated to local time. These results suggest that rats blinded for up to 60 days maintain their free-running pineal rhythms with undamped amplitudes and in synchronization with the activity rhythm.

scholarly journals Bright light during lactation alters the functioning of the circadian system of adult rats

2000 ◽  
Vol 278 (1) ◽  
pp. R201-R208 ◽  
Author(s):  
M. M. Canal-Corretger ◽  
T. Cambras ◽  
J. Vilaplana ◽  
A. Díez-Noguera
Keyword(s):  
Motor Activity ◽  
Activity Rhythm ◽  
Bright Light ◽  
Circadian System ◽  
Constant Darkness ◽  
Adult Rats ◽  
Light Pulses ◽  
Circadian Time ◽  
Role Of Light

To examine the role of light in the maturation of the circadian pacemaker, twelve groups of rats were raised in different conditions of exposure to constant bright light (LL) during lactation: both duration and timing of LL were varied. We studied the motor activity rhythm of the rats after weaning, first under LL and then under constant darkness (DD). In DD, two light pulses [at circadian time 15 (CT15) and CT22] were applied to test the response of the pacemaker. Greater exposure to LL days during lactation increased the number of rhythmic animals and the amplitude of their motor activity rhythm in the LL stage and decreased the phase delay due to the light pulse at CT15. The timing of LL during lactation affected these variables too. Because the response of the adult to light depended on both the number and timing of LL days during lactation, the exposure to light at early stages may influence the development of the circadian system by modifying it structurally or functionally.

Selective deficits in the circadian light response in mice lacking PACAP

2004 ◽  
Vol 287 (5) ◽  
pp. R1194-R1201 ◽  
Author(s):  
C. S. Colwell ◽  
S. Michel ◽  
J. Itri ◽  
W. Rodriguez ◽  
J. Tam ◽  
...  
Keyword(s):  
Wheel Running ◽  
Light Exposure ◽  
Light Response ◽  
Phase Shifts ◽  
Circadian System ◽  
Loss Of Function ◽  
Running Activity ◽  
Wheel Running Activity ◽  
Deficient Mice

Previous studies indicate that light information reaches the suprachiasmatic nucleus through a subpopulation of retinal ganglion cells that contain both glutamate and pituitary adenylyl cyclase-activating peptide (PACAP). Although the role of glutamate in this pathway has been well studied, the involvement of PACAP and its receptors is only beginning to be understood. To investigate the functions of PACAP in vivo, we developed a mouse model in which the gene coding for PACAP was disrupted by targeted homologous recombination. RIA was used to confirm a lack of detectable PACAP protein in these mice. PACAP-deficient mice exhibited significant impairment in the magnitude of the response to brief light exposures with both light-induced phase delays and advances of the circadian system impacted. This mutation equally impacted phase shifts induced by bright and dim light exposure. Despite these effects on phase shifting, the loss of PACAP had only limited effects on the generation of circadian oscillations, as measured by rhythms in wheel-running activity. Unlike melanopsin-deficient mice, the mice lacking PACAP exhibited no loss of function in the direct light-induced inhibition of locomotor activity, i.e., masking. Finally, the PACAP-deficient mice exhibited normal phase shifts in response to exposure to discrete dark treatments. The results reported here show that the loss of PACAP produced selective deficits in the light response of the circadian system.

Melatonin administration entrains female rat activity rhythms in constant darkness but not in constant light

1988 ◽  
Vol 255 (2) ◽  
pp. R237-R242
Author(s):  
E. M. Thomas ◽  
S. M. Armstrong
Keyword(s):  
Estrous Cycle ◽  
Activity Rhythm ◽  
Onset Time ◽  
Circadian System ◽  
Female Rats ◽  
Male Rats ◽  
Constant Darkness ◽  
Female Rat ◽  
Continuous Darkness ◽  
Activity Rhythms

In female rats the luteinizing hormone (LH) is timed by the circadian system and is followed by a display of intense, estrogen-induced running behavior. This proestrous running on the night of ovulation can be used as a marker of the estrous cycle. Entrainment of the mammalian circadian system by exogenous melatonin (MT) has been demonstrated only in the activity rhythms of male rats. The present experiments were designed to study the effect of daily MT injections on activity rhythms and proestrous running of female rats in 1) continuous dim white light (LL) and 2) continuous darkness (DD). In LL, MT injections (50 micrograms/kg or 1 mg/kg) had no discernible effect on activity rhythms. In DD, four of the six MT-treated rats (100 micrograms/kg) entrained to the injection, and a fifth animal showed phase advances in its activity rhythm when onset of activity passed through injection time. The sixth animal was not injected with MT at activity onset time. None of the six control animals showed either effect. MT had no effect on the length of the estrous cycle. Thus MT injections can entrain circadian rhythms of activity and proestrous running in female rats in DD but not in LL.

scholarly journals The Clock Keeps Ticking: Circadian Rhythms of Free-Ranging Polar Bears

2020 ◽  
Vol 35 (2) ◽  
pp. 180-194 ◽  
Author(s):  
Jasmine V. Ware ◽  
Karyn D. Rode ◽  
Charles T. Robbins ◽  
Tanya Leise ◽  
Colby R. Weil ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Sea Ice ◽  
Behavioral Plasticity ◽  
Prey Availability ◽  
Activity Patterns ◽  
The Arctic ◽  
Constant Darkness ◽  
Polar Bears ◽  
Cold Temperatures ◽  
Daily Movement

Life in the Arctic presents organisms with multiple challenges, including extreme photic conditions, cold temperatures, and annual loss and daily movement of sea ice. Polar bears ( Ursus maritimus) evolved under these unique conditions, where they rely on ice to hunt their main prey, seals. However, very little is known about the dynamics of their daily and seasonal activity patterns. For many organisms, activity is synchronized (entrained) to the earth’s day/night cycle, in part via an endogenous (circadian) timekeeping mechanism. The present study used collar-mounted accelerometer and global positioning system data from 122 female polar bears in the Chukchi and Southern Beaufort Seas collected over an 8-year period to characterize activity patterns over the calendar year and to determine if circadian rhythms are expressed under the constant conditions found in the Arctic. We reveal that the majority of polar bears (80%) exhibited rhythmic activity for the duration of their recordings. Collectively within the rhythmic bear cohort, circadian rhythms were detected during periods of constant daylight (June-August; 24.40 ± 1.39 h, mean ± SD) and constant darkness (23.89 ± 1.72 h). Exclusive of denning periods (November-April), the time of peak activity remained relatively stable (acrophases: ~1200-1400 h) for most of the year, suggesting either entrainment or masking. However, activity patterns shifted during the spring feeding and seal pupping season, as evidenced by an acrophase inversion to ~2400 h in April, followed by highly variable timing of activity across bears in May. Intriguingly, despite the dynamic environmental photoperiodic conditions, unpredictable daily timing of prey availability, and high between-animal variability, the average duration of activity (alpha) remained stable (11.2 ± 2.9 h) for most of the year. Together, these results reveal a high degree of behavioral plasticity in polar bears while also retaining circadian rhythmicity. Whether this degree of plasticity will benefit polar bears faced with a loss of sea ice remains to be determined.

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