Biomedical subjects

Urs Albrecht

Publications and source records attributed to Urs Albrecht.

35 records · Page 2Linked to original sources

PubMed2003

Loss of circadian rhythmicity in aging mPer1-/-mCry2-/- mutant mice.

The mPer1, mPer2, mCry1, and mCry2 genes play a central role in the molecular mechanism driving the central pacemaker of the mammalian circadian clock, located in the suprachiasmatic nuclei (SCN) of the hypothalamus. In vitro studies suggest a close interaction of all mPER and mCRY proteins. We investigated mPER and mCRY interactions in vivo by generating different combinations of mPer/mCry double-mutant mice. We previously showed that mCry2 acts as a nonallelic suppressor of mPer2 in the core clock mechanism. Here, we focus on the circadian phenotypes of mPer1/mCry double-mutant animals and find a decay of the clock with age in mPer1-/- mCry2-/- mice at the behavioral and the molecular levels. Our findings indicate that complexes consisting of different combinations of mPER and mCRY proteins are not redundant in vivo and have different potentials in transcriptional regulation in the system of autoregulatory feedback loops driving the circadian clock.

Aging↗

PubMed2003

cGMP-dependent protein kinase II modulates mPer1 and mPer2 gene induction and influences phase shifts of the circadian clock.

BACKGROUND: In mammals, the master circadian clock that drives many biochemical, physiological, and behavioral rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Generation and maintenance of circadian rhythmicity rely on complex interlocked transcriptional/translational feedback loops involving a set of clock genes. Among the molecular components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) genes. Because the periodicity of the clock is not exactly 24 hr, it has to be adjusted periodically. The major stimulus for adjustment (resetting) of the clock is nocturnal light. It evokes activation of signaling pathways in the SCN that ultimately lead to expression of mPer1 and mPer2 genes conveying adjustment of the clock. RESULTS: We show that mice deficient in cGMP-dependent protein kinase II (cGKII, also known as PKGII), despite regular retinal function, are defective in resetting the circadian clock, as assessed by changes in the onset of wheel running activity after a light pulse. At the molecular level, light induction of mPer2 in the SCN is strongly reduced in the early period of the night, whereas mPer1 induction is elevated in cGKII-deficient mice. Additionally, we show that light induction of cfos and light-dependent phosphorylation of CREB at serine 133 are not affected in these animals. CONCLUSIONS: cGKII plays a role in the clock-resetting mechanism. In particular, the ability to delay clock phase is affected in cGKII-deficient mice. It seems that the signaling pathway involving cGKII influences in an opposite manner the light-induced induction of mPer1 and mPer2 genes and thereby influences the direction of a phase shift of the circadian clock.

Animals↗

PubMed2003

The mammalian circadian clock.

Organisms populating the earth are under the steady influence of daily and seasonal changes resulting from the planet's rotation and orbit around the sun. This periodic pattern most prominently manifested by the light-dark cycle has led to the establishment of endogenous circadian timing systems that synchronize biological functions to the environment. The mammalian circadian system is composed of many individual, tissue-specific clocks. To generate coherent physiological and behavioral responses, the phases of this multitude of clocks are orchestrated by the master circadian pacemaker residing in the suprachiasmatic nuclei of the brain. Genetic, biochemical and genomic approaches have led to major advances in understanding the molecular and cellular basis of mammalian circadian clock components and mechanisms.

Animals↗

PubMed2003

Daily variation of clock output gene activation in behaviorally arrhythmic mPer/mCry triple mutant mice.

The mammalian central pacemaker, driving circadian rhythms in behavior, physiology, and metabolism, is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. At the molecular level circadian clocks are based on a system of transcriptional/translational feedback loops oscillating with a period of about 24h. In mammals the CLOCK/BMAL1 transcriptional activator complex regulates a set of central clock genes like mPer1, mPer2, mCry1, and mCry2. The corresponding gene products form protein complexes that translocate into the nucleus and inhibit CLOCK/BMAL1-driven transcription of their own genes and other E-box containing genes. To elucidate whether only one of these four genes of the negative feedback loop is sufficient to generate a 24h rhythm we generated mPer/mCry triple mutant mice. As could be expected on the basis of the arrhythmicity of mPer1/mPer2 and mCry1/mCry2 double mutant mice, we show that none of the triple mutants is able to maintain circadian rhythmicity in constant darkness. This indicates that a single mPer or mCry gene is not sufficient to drive circadian rhythms. Interestingly however, under light-dark conditions (LD) the oscillation of some output genes is persisting in these animals indicating that the LD cycle is able to partially drive rhythmic signalling to the body, through an hour-glass mechanism.

Animals↗

PubMed2003

Hypothalamic circadian organization in birds. II. Clock gene expression.

While the site of the major circadian pacemaker in mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus, is very well characterized, little is known about hypothalamic circadian organization in birds. This paper reviews recent findings on clock gene expression in the hypothalamus of several bird species focusing on circadian pPer2 expression in the house sparrow. In contrast to mammals, rhythmic Per2 gene expression in the house sparrow hypothalamus is not restricted to a single cell group but occurs in two distinct hypothalamic nuclei, the SCN and the lateral hypothalamic nucleus (LHN). The complex temporal and spatial distribution of pPer2 expression suggests a longitudinal compartmentalization of the SCN with period gene expression being initiated in the most rostral portion before lights on. In the lateral hypothalamus, phasing of pPer2-rhythmicity appeared delayed. In pinealectomized house sparrows, the overall circadian pPer2 expression pattern is maintained indicating that rhythmic pPer2 transcription in the SCN and LHN of the house sparrow are not driven by the pineal gland. Rather, they reflect the activity of autonomous hypothalamic circadian oscillators. Certain changes in peak expression levels and the expression phase, however, suggest that the pineal melatonin rhythm affects both the phase and the amplitude of rhythmic hypothalamic pPer2 expression.

Animals↗

PubMed2002

A switch from diurnal to nocturnal activity in S. ehrenbergi is accompanied by an uncoupling of light input and the circadian clock.

The subterranean mole rat Spalax ehrenbergi superspecies represents an extreme example of adaptive visual and neuronal reorganization. Despite its total visual blindness, its daily activity rhythm is entrainable to light-dark cycles, indicating that it can confer light information to the clock. Although most individuals are active during the light phase under laboratory conditions (diurnal animals), some individuals switch their activity period to the night (nocturnal animals). Similar to other rodents, the Spalax circadian clock is driven by a set of clock genes, including the period (sPer) genes. In this work, we show that diurnal mole rats express the Per genes sPer1 and sPer2 with a peak during the light period. Light can synchronize sPer gene expression to an altered light-dark cycle and thereby reset the clock. In contrast, nocturnal Spalax express sPer2 in the dark period and sPer1 in a biphasic manner, with a light-dependent maximum during the day and a second light-independent maximum during the night. Although sPer1 expression remains light inducible, this is not sufficient to reset the molecular clockwork. Hence, the strict coupling of light, Per expression, and the circadian clock is lost. This indicates that Spalax can dissociate the light-driven resetting pathway from the central clock oscillator.

Animals↗

PubMed2002

Disruption of mCry2 restores circadian rhythmicity in mPer2 mutant mice.

Many biochemical, physiological, and behavioral processes display daily rhythms generated by an internal timekeeping mechanism referred to as the circadian clock. The core oscillator driving this clock is located in the ventral part of the hypothalamus, the so called suprachiasmatic nuclei (SCN). At the molecular level, this oscillator is thought to be composed of interlocking autoregulatory feedback loops involving a set of clock genes. Among the components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) and Cryptochrome 1 and 2 (mCry1 and mCry2) genes. A mutation in the mPer2 gene leads to a gradual loss of circadian rhythmicity in mice kept in constant darkness (DD). Here we show that inactivation of the mCry2 gene in mPer2 mutant mice restores circadian rhythmicity and normal clock gene expression patterns. Thus, mCry2 can act as a nonallelic suppressor of mPer2, which points to direct or indirect interactions of PER2 and CRY2 proteins. In marked contrast, inactivation of mCry1 in mPer2 mutant mice does not restore circadian rhythmicity but instead results in complete behavioral arrhythmicity in DD, indicating different effects of mCry1 and mCry2 in the clock mechanism

Animals↗

PubMed2002

Circadian genes in a blind subterranean mammal II: conservation and uniqueness of the three Period homologs in the blind subterranean mole rat, Spalax ehrenbergi superspecies.

We demonstrated that a subterranean, visually blind mammal has a functional set of three Per genes that are important components of the circadian clockwork in mammals. The mole rat superspecies Spalax ehrenbergi is a blind subterranean animal that lives its entire life underground in darkness. It has degenerated eyes, but the retina and highly hypertrophic harderian gland are involved in photoperiodic perception. All three Per genes oscillate with a periodicity of 24 h in the suprachiasmatic nuclei, eye, and harderian gland and are expressed in peripheral organs. This oscillation is maintained under constant conditions. The light inducibility of sPer1 and sPer2, which are similar in structure to those of other mammals, indicates the role of these genes in clock resetting. However, sPer3 is unique in mammals and has two truncated isoforms, and its expressional analysis leaves its function unresolved. Per's expression analysis in the harderian gland suggests an important participation of this organ in the stabilization and resetting mechanism of the central pacemaker in the suprachiasmatic nuclei and in unique adaptation to life underground.

Animals↗

PubMed2002

The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator.

Mammalian circadian rhythms are generated by a feedback loop in which BMAL1 and CLOCK, players of the positive limb, activate transcription of the cryptochrome and period genes, components of the negative limb. Bmal1 and Per transcription cycles display nearly opposite phases and are thus governed by different mechanisms. Here, we identify the orphan nuclear receptor REV-ERBalpha as the major regulator of cyclic Bmal1 transcription. Circadian Rev-erbalpha expression is controlled by components of the general feedback loop. Thus, REV-ERBalpha constitutes a molecular link through which components of the negative limb drive antiphasic expression of components of the positive limb. While REV-ERBalpha influences the period length and affects the phase-shifting properties of the clock, it is not required for circadian rhythm generation.

ARNTL Transcription Factors↗

PubMed2002

Cocaine sensitization and reward are under the influence of circadian genes and rhythm.

Investigations using the fruit fly Drosophila melanogaster have shown that the circadian clock gene period (Per) can influence behavioral responses to cocaine. Here we show that the mouse homologues of the Drosophila Per gene, mPer1 and mPer2, modulate cocaine sensitization and reward, two phenomena extensively studied in humans and animals because of their importance for drug abuse. In response to an acute cocaine injection mPer1 and mPer2 mutant mice as well as wild-type mice exhibited an approximately 5-fold increase in activity compared with saline control levels, showing that there is no initial difference in sensitivity to acute cocaine administration in Per mutants. After repeated cocaine injections wild-type mice exhibited a sensitized behavioral response that was absent in mPer1 knockout mice. In contrast, mPer2 mutant mice exhibited a hypersensitized response to cocaine. Conditioned place preference experiments revealed similar behavioral reactions: mPer1 knockout mice showed a complete lack of cocaine reward whereas mPer2 mutants showed a strong cocaine-induced place preference. In another set of experiments, we tested C57/BL6J mice at different Zeitgeber times and found that cocaine-induced behavioral sensitization and place preference are under the control of the circadian clock. In conclusion, we demonstrate that processes involved in cocaine addiction depend on the circadian rhythm and are modulated in an opposing manner by mPer1 and mPer2 genes.

Animals↗

PubMed2002

Placing ocular mutants into a functional context: a chronobiological approach.

The behavior of mammals is characterized by a 24-h cycle of rest and activity which is a fundamental adaption to the solar cycle of light and darkness. The pacemaker of this circadian clock is localized in the ventral part of the hypothalamus, the so-called suprachiasmatic nuclei (SCN), and is entrained by light signals mediated by the eye. The eye is directly connected via the retinohypothalamic tract (RHT) to the SCN. Light that reaches the retina elicits glutamate release at the synaptic terminals of the RHT and influences the neurons in the SCN in a manner that alters the behavioral state of the animal. A light pulse that reaches the retina at the beginning of the night elicits a delay of the clock phase, whereas a light pulse that reaches the retina at the end of the dark period leads to an advance of the clock phase. This advance or delay can be quantified by measuring the change in onset of wheel-running activity. Such measurements have, and continue to provide, a remarkably powerful assay of how light is detected and transduced to regulate circadian rhythms. The methods used for such measurements in mice are described in the following article.

Animals↗

PubMed2002

Spatial and temporal variation of passer Per2 gene expression in two distinct cell groups of the suprachiasmatic hypothalamus in the house sparrow (Passer domesticus).

In mammals, the major pacemaker controlling circadian rhythmicity is located in the hypothalamic suprachiasmatic nuclei. Although there is evidence for the presence of a hypothalamic circadian oscillator in birds from lesioning studies, neuroanatomical, neurochemical and functional investigations have failed to identify its exact location. Two cell groups in the avian hypothalamus have been shown to bear characteristics of the mammalian suprachiasmatic nucleus: the suprachiasmatic nucleus and the lateral hypothalamic retinorecipient nucleus. We cloned an avian period homologue (pPer2) and investigated the temporal and spatial expression pattern of this gene in the house sparrow hypothalamus using in situ hybridization. Applying quantitative morphometry, we found rhythmic expression of pPer2 during light-dark as well as in constant conditions in the suprachiasmatic nucleus and in the lateral hypothalamus. The temporal and spatial distribution of pPer2 expression in the suprachiasmatic nucleus suggest a longitudinal compartmentalization of the nucleus with period gene expression being initiated in the most rostral portion of the suprachiasmatic nucleus before lights on. In the lateral hypothalamus, phasing of pPer2-rhythmicity appeared different from the suprachiasmatic nucleus. The major difference between light-dark and constant conditions was a decrease in the amplitude of pPer2 rhythmicity in the suprachiasmatic nucleus. Our data demonstrate that, unlike in mammals, Per gene expression in the suprachiasmatic hypothalamus of the house sparrow is not confined to a single cell group, indicating a more complex organization of the circadian oscillator in the hypothalamus of birds.

Animals↗

PubMed2002

Homeostatic sleep regulation is preserved in mPer1 and mPer2 mutant mice.

A limited set of genes, Clock, Bmal1, mPer1, mPer2, mCry1 and mCry2, has been shown to be essential for the generation of circadian rhythms in mammals. It has been recently suggested that circadian genes might be involved in sleep regulation. We investigated the role of mPer1 and mPer2 genes in the homeostatic regulation of sleep by comparing sleep of mice lacking mPER1 (mPer1 mutants) or a functional mPER2 (mPer2 mutants), and wild-type controls (WT) after 6 h of sleep deprivation (SD). Our main result showed that after SD, all mice displayed the typical increase of slow-wave activity (SWA; EEG power density between 0.75 and 4 Hz) in nonREM sleep, reflecting the homeostatic response to SD. This increase was more prominent over the frontal cortex as compared to the occipital cortex. The genotypes did not differ in the effect of SD on the occipital EEG, while the effect on the frontal EEG was initially diminished in both mPer mutants. Differences between the genotypes were seen in the 24-h distribution of sleep, reflecting especially the phase advance of motor activity onset observed in mPer2 mutants. While the daily distribution of sleep was modulated by mPer1 and mPer2 genes, sleep homeostasis reflected by the SWA increase after 6-h SD was preserved in the mPer mutants. The results provide further evidence for the independence of the circadian and the homeostatic components underlying sleep regulation.

Animals↗

PubMed2002

The circadian clock as a molecular calendar.

There are two dominant environmental oscillators shaping the living conditions of our world: the day-night cycle and the succession of the seasons. Organisms have adapted to these by evolving internal clocks to anticipate these variations. An orchestra of finely tuned peripheral clocks slaved to the master pacemaker of the suprachiasmatic nuclei (SCN) synchronizes the body to the daily 24h cycle. However, this circadian clockwork closely interacts with the seasonal time-teller. Recent experiments indeed show that photoperiod--the dominant Zeitgeber of the circannual clock--might be deciphered by the organism using the tools of the circadian clock itself. From the SCN, the photoperiodic signal is transferred to the pineal where it is decoded as a varying secretion of melatonin. Different models have been proposed to explain the mechanism by which the circadian clock measures day-length. Recent work using mutant mice suggests a set of two molecular oscillators tracking dusk and dawn, respectively, thereby translating day-length to the body. However, not every aspect of photoperiodism is covered by this theory and majoradjustments will need tobe made toestablish a widely acceptable uniform model of circadian/circannual timekeeping.

Animals↗

PubMed2002

Invited review: regulation of mammalian circadian clock genes.

The circadian clock is a self-sustaining oscillator that has a period of approximately 24 h and controls many physiological and behavioral systems. This clock can synchronize itself to changing environmental conditions to optimize an organisms performance. The underlying circadian rhythms are generated by periodic activation of transcription by a set of clock genes. Besides their own regulation, clock genes can influence biochemical processes by modulating specific genes of biochemical pathways. Developments in the last few years using genetics and molecular biological tools have led to a new understanding of the molecular basis of the circadian clock in mammals. In this mini-review, I will summarize these advances that have led us to begin understanding the mammalian circadian clock at the molecular level.

Animals↗

PubMed2002

Robust circadian rhythmicity of Per1 and Per2 mutant mice in constant light, and dynamics of Per1 and Per2 gene expression under long and short photoperiods.

The Per1 and Per2 genes are components of the mammalian circadian clock. Mutations in these genes alter phase resetting in response to a nocturnal light pulse, and Per2 mutant mice are known to become arrhythmic in constant darkness. We show that under constant light conditions, Per2 mutant mice exhibit robust activity rhythms as well as body temperature rhythms with a period length that is less than 24 h. In Per1 mutants, the period length of both activity and body temperature rhythms is longer than 24 h in constant light. Per1 mutants prolong their period length (tao) when illuminance is increased, whereas Per2 mutants shorten their endogenous period. Additionally, the authors show that the circadian pattern of Per1 and Per2 gene expression in mice is modified under different photoperiods and that there is a mutual influence of these genes on their timing of expression. We propose that, in mice, the phase relationship between Per1 and Per2 gene expression might be critical for transducing day length information to the organism. Per1 could be part of a morning oscillator tracking dawn, and Per2 could be part of an evening oscillator tracking dusk.

Animals↗

PubMedDate not supplied

The human PER1 gene is inducible by interleukin-6.

The mammalian period (Per) genes which are components of the circadian clock are mainly regulated via an autoregulatory feedback loop. Here we show that a human PER1 (hPER1) reporter gene activity is stimulated by interleukin-6 (IL-6), a member of the large cytokine gene family and an inducer of the acute phase reaction, in human hepatoma (HuH-7) cells. Our results confirm and extend the view that the hPER1 promoter acts as a sensor for multiple signaling molecules thereby integrating different physiological parameters.

Cell Cycle Proteins↗