scholarly journals The Dorsal Medial Habenula Minimally Impacts Circadian Regulation of Locomotor Activity and Sleep

2017 ◽  
Vol 32 (5) ◽  
pp. 444-455 ◽  
Author(s):  
Yun-Wei A. Hsu ◽  
Jennifer J. Gile ◽  
Jazmine G. Perez ◽  
Glenn Morton ◽  
Miriam Ben-Hamo ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Clock Genes ◽  
Wheel Running ◽  
Circadian System ◽  
Sleep Stages ◽  
Constant Darkness ◽  
Running Activity ◽  
Medial Habenula ◽  
Wheel Running Activity ◽  
Central Pacemaker

In nocturnal rodents, voluntary wheel-running activity (WRA) represents a self-reinforcing behavior. We have previously demonstrated that WRA is markedly reduced in mice with a region-specific deletion of the transcription factor Pou4f1 (Brn3a), which leads to an ablation of the dorsal medial habenula (dMHb). The decrease in WRA in these dMHb-lesioned (dMHbCKO) mice suggests that the dMHb constitutes a critical center for conveying reinforcement by exercise. However, WRA also represents a prominent output of the circadian system, and the possibility remains that the dMHb is a source of input to the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. To test this hypothesis, we assessed the integrity of the circadian system in dMHbCKO mice. Here we show that the developmental lesion of the dMHb reduces WRA under both a light-dark cycle and constant darkness, increases the circadian period of WRA, but has no effect on the circadian amplitude or period of home cage activity or the daily amplitude of sleep stages, suggesting that the lengthening of period is a result of the decreased WRA in the mutant mice. Polysomnographic sleep recordings show that dMHbCKO mice have an overall unaltered daily amplitude of sleep stages but have fragmented sleep and an overall increase in total rapid eye movement (REM) sleep. Photoresponsiveness is intact in dMHbCKO mice, but compared with control animals, they reentrain faster to a 6-h abrupt phase delay protocol. Circadian changes in WRA of dMHbCKO mice do not appear to emerge within the central pacemaker, as circadian expression of the clock genes Per1 and Per2 within the SCN is normal. We do find some evidence for fragmented sleep and an overall increase in total REM sleep, supporting a model in which the dMHb is part of the neural circuitry encoding motivation and involved in the manifestation of some of the symptoms of depression.

Genetic analysis of daily physical activity using a mouse chromosome substitution strain

2009 ◽  
Vol 39 (1) ◽  
pp. 47-55 ◽  
Author(s):  
He S. Yang ◽  
Martha H. Vitaterna ◽  
Aaron D. Laposky ◽  
Kazuhiro Shimomura ◽  
Fred W. Turek
Keyword(s):  
Physical Activity ◽  
Physical Activity Level ◽  
Wheel Running ◽  
Daily Physical Activity ◽  
Activity Level ◽  
Constant Darkness ◽  
Circadian Period ◽  
Chromosome 13 ◽  
Running Activity ◽  
Wheel Running Activity

There is considerable evidence for a genetic basis underlying individual differences in spontaneous physical activity in humans and animals. Previous publications indicate that the physical activity level and pattern vary among inbred strains of mice and identified a genomic region on chromosome 13 as quantitative trait loci (QTL) for physical activity. To confirm and further characterize the role of chromosome 13 in regulating daily physical activity level and pattern, we conducted a comprehensive phenotypic study in the chromosome 13 substitution strain (CSS-13) in which the individual chromosome 13 from the A/J strain was substituted into an otherwise complete C57BL/6J (B6) genome. The B6 and A/J parental strains exhibited pronounced differences in daily physical activity, sleep-wake structure, circadian period and body weight. Here we report that a single A/J chromosome 13 in the context of a B6 genetic background conferred a profound reduction in both total cage activity and wheel-running activity under a 14:10-h light-dark cycle, as well as in constant darkness, compared with B6 controls. Additionally, CSS-13 mice differed from B6 controls in the diurnal distribution of activity and the day-to-day variability in activity onset. We further performed a linkage analysis and mapped a significant QTL on chromosome 13 regulating the daily wheel running activity level in mice. Taken together, our findings indicate a QTL on chromosome 13 with dramatic and specific effects on daily voluntary physical activity, but not on circadian period, sleep, or other aspects of activity that are different between B6 and A/J strains.

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.

Circadian rhythms of sleep and wakefulness in mice: analysis using long-term automated recording of sleep

1985 ◽  
Vol 248 (3) ◽  
pp. R320-R330 ◽  
Author(s):  
G. S. Richardson ◽  
M. C. Moore-Ede ◽  
C. A. Czeisler ◽  
W. C. Dement
Keyword(s):  
Circadian Rhythms ◽  
Rem Sleep ◽  
Wheel Running ◽  
Nrem Sleep ◽  
Sleep State ◽  
Continuous Darkness ◽  
Running Activity ◽  
Wheel Running Activity ◽  
Significant Difference ◽  
Wake State

Circadian rhythms of wheel-running activity and polygraphically defined wakefulness, rapid-eye-movement (REM) sleep and non-REM (NREM) sleep were continuously observed in ten mice (Mus musculus) under both alternating light-dark (LD 12:12) and continuous darkness (DD) conditions. Sleep-wake state was determined automatically using a computer-based method that allowed continuous recordings of from 60 to 280 days in duration. The sleep-wake state percentages (of the circadian cycle) thus obtained were in substantial agreement with other estimates for this or similar strains and showed no significant difference between LD 12:12 (wake 54.3%, NREM sleep 38.1%, REM sleep 7.6%) and DD (wake 53.1%, NREM sleep 39.9%, REM sleep 7.0%) conditions. All 10 mice exhibited clear circadian rhythms in each of the three states and wheel-running activity under both lighting conditions for the entire duration of observation. Probability functions, computed using stationary sections of data from all 10 mice, showed distinct waveforms for all three states and wheel running. These waveforms were remarkably similar under entrained and free-running conditions. This documentation of sustained circadian rhythmicity in sleep-wake state throughout observations of unprecedented length contradicts the currently common assertion that circadian control of sleep state is weaker than that of activity.

Effects of aging on the circadian rhythm of wheel-running activity in C57BL/6 mice

1997 ◽  
Vol 273 (6) ◽  
pp. R1957-R1964 ◽  
Author(s):  
Verónica S. Valentinuzzi ◽  
Kathryn Scarbrough ◽  
Joseph S. Takahashi ◽  
Fred W. Turek
Keyword(s):  
Wheel Running ◽  
Activity Rhythm ◽  
Laboratory Mouse ◽  
Active Phase ◽  
Constant Darkness ◽  
Age Difference ◽  
Running Activity ◽  
Wheel Running Activity ◽  
Activity Onset ◽  
Old Mice

The effects of age on the circadian clock system have been extensively studied, mainly in two rodent species, the laboratory rat and the golden hamster. However, less information is available on how aging alters circadian rhythmicity in a commonly studied rodent animal model, the mouse. Therefore, in the present study we compared the rhythm of wheel-running activity in adult (6–9 mo) and old (19–22 mo) C57BL/6J mice maintained under different lighting conditions for a period of 4 mo. During this period, mice were subjected to phase advances and phase delays of the light-dark (LD) cycle and eventually to constant darkness (DD). In LD (12 h light, 12 h dark), old mice exhibited delayed activity onset relative to light offset and an increase in the variability of activity onset compared with adult mice. After a 4-h phase advance of the LD cycle, old mice took significantly longer to reentrain their activity rhythm when compared with adult animals. Old mice also demonstrated a decline in the number of wheel revolutions per day and a tendency toward a decrease in the length of the active phase. An increase in fragmentation of activity across the 24-h day was obvious in aging animals, with bouts of activity being shorter and longer rest periods intervening between them. No age difference was detected in the maximum intensity of wheel-running activity. In DD, the free-running period was significantly longer in old mice compared with adults. In view of the rapidly expanding importance of the laboratory mouse for molecular and genetic studies of the mammalian nervous system, the present results provide a basis at the phenotypic level to begin to apply genetic methods to the analysis of circadian rhythms and aging in mammals.

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.

Altered sleep and behavioral activity phenotypes in PER3-deficient mice

2011 ◽  
Vol 301 (6) ◽  
pp. R1821-R1830 ◽  
Author(s):  
Sibah Hasan ◽  
Daan R. van der Veen ◽  
Raphaelle Winsky-Sommerer ◽  
Derk-Jan Dijk ◽  
Simon N. Archer
Keyword(s):  
Rem Sleep ◽  
Wheel Running ◽  
Nrem Sleep ◽  
Light Period ◽  
Behavioral Activity ◽  
Dark Phase ◽  
Running Activity ◽  
Sleep Homeostasis ◽  
Wheel Running Activity ◽  
Delta Activity

Sleep homeostasis and circadian rhythmicity interact to determine the timing of behavioral activity. Circadian clock genes contribute to circadian rhythmicity centrally and in the periphery, but some also have roles within sleep regulation. The clock gene Period3 ( Per3) has a redundant function within the circadian system and is associated with sleep homeostasis in humans. This study investigated the role of PER3 in sleep/wake activity and sleep homeostasis in mice by recording wheel-running activity under baseline conditions in wild-type (WT; n = 54) and in PER3-deficient ( Per3−/−; n = 53) mice, as well as EEG-assessed sleep before and after 6 h of sleep deprivation in WT ( n = 7) and Per3−/− ( n = 8) mice. Whereas total activity and vigilance states did not differ between the genotypes, the temporal distribution of wheel-running activity, vigilance states, and EEG delta activity was affected by genotype. In Per3−/− mice, running wheel activity was increased, and REM sleep and NREM sleep were reduced in the middle of the dark phase, and delta activity was enhanced at the end of the dark phase. At the beginning of the baseline light period, there was less wakefulness and more REM and NREM sleep in Per3−/− mice. Per3−/− mice spent less time in wakefulness and more time in NREM sleep in the light period immediately after sleep deprivation, and REM sleep accumulated more slowly during the recovery dark phase. These data confirm a role for PER3 in sleep-wake timing and sleep homeostasis.

The Food-entrainable Oscillator Is a Complex of Non-SCN Activity Bout Oscillators Uncoupled From the SCN Circadian Pacemaker

2021 ◽  
pp. 074873042110479
Author(s):  
Shinya Nishide ◽  
Yohko Suzuki ◽  
Daisuke Ono ◽  
Sato Honma ◽  
Ken-ichi Honma
Keyword(s):  
Clock Genes ◽  
Wheel Running ◽  
Core Body Temperature ◽  
Circadian Pacemaker ◽  
Loss Mechanism ◽  
Peripheral Tissues ◽  
Daily Feeding ◽  
Activity Peak ◽  
Running Activity ◽  
Wheel Running Activity

The food-entrainable oscillator, which underlies the prefeeding activity peak developed by restricted daily feeding (RF) in rodents, does not depend on the circadian pacemaker in the suprachiasmatic nucleus (SCN) or on the known clock genes. In the present study, to clarify the roles of SCN circadian pacemaker and nutrient conditions on the development of prefeeding activity peak, RF of 3-h daily feeding was imposed on four groups of adult male mice for 10 cycles at different circadian times, zeitgeber time (ZT)2, ZT8, ZT14, and ZT20, where ZT0 is the time of lights-on in LD12:12. Seven days after the termination of RF session with ad libitum feeding in between, total food deprivation (FD) for 72 h was imposed. Wheel-running activity and core body temperature were measured throughout the experiment. Immediately after the RF or FD session, the PER2::LUC rhythms were measured in the cultured SCN slices and peripheral tissues. Not only the buildup process and magnitude of the prefeeding activity peak, but also the percentages of nocturnal activity and hypothermia developed under RF were significantly different among the four groups, indicating the involvement of light entrained circadian pacemaker. The buildup of prefeeding activity peak was accomplished by either phase-advance or phase-delay shifts (or both) of activity bouts comprising a nocturnal band. Hypothermia under FD was less prominent in RF-exposed mice than in naïve counterparts, indicating that restricted feeding increases tolerance to caloric restriction as well as to the heat loss mechanism. RF phase-shifted the peripheral clocks but FD did not affect the clocks in any tissue examined. These findings are better understood by assuming multiple bout oscillators, which are located outside the SCN and directly drive activity bouts uncoupled from the circadian pacemaker by RF or hypothermia.

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.

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