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Results for “Biological Clocks”

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PubMed1999

The biological clock of very premature primate infants is responsive to light.

Each year more than 250,000 infants in the United States are exposed to artificial lighting in hospital nurseries with little consideration given to environmental lighting cycles. Essential in determining whether environmental lighting cycles need to be considered in hospital nurseries is identifying when the infant's endogenous circadian clock becomes responsive to light. Using a non-human primate model of the developing human, we examined when the circadian clock, located in the hypothalamic suprachiasmatic nuclei (SCN), becomes responsive to light. Preterm infant baboons of different ages were exposed to light (5,000 lux) at night, and then changes in SCN metabolic activity and gene expression were assessed. After exposure to bright light at night, robust increases in SCN metabolic activity and gene expression were seen at ages that were equivalent to human infants at 24 weeks after conception. These data provide direct evidence that the biological clock of very premature primate infants is responsive to light.

Animals↗
PubMed2005

[A role of nociceptin in the entrainment mechanism of the biological clock].

The ORL1 receptor (nociceptin receptor), the fourth member of the opioid receptor family, is widely distributed throughout the central nervous system and mediates diverse physiological functions including pain, emotion, learning and memory. Nociceptin receptors are densely expressed in the suprachiasmatic nucleus, the principal pacemaker of circadian rhythms, and nociceptin inhibits light-induced phase advances (Allen et al, 1999); however, nociceptin's role in nonphotic entrainment has not been described. We used a small-molecule nociceptin receptor agonist capable of crossing the brain blood-brain barrier, and demonstrated that nociceptin acts as a nonphotic zeitgeiber. In this review, we describe a role for nociceptin in the biological clock and discuss the possibility of developing nociceptin receptor agonists for treatment of circadian rhythm disorders.

Animals↗
PubMedDate not supplied

The heart as a biological clock: phase-locking between heart and efferent vagal activity.

Experiments were performed to evaluate whether the negative inotropic effect of efferent vagal stimulation is more strictly related to the number of stimuli falling with each cardiac cycle (St/c) or to the number of stimuli per second (St/s). Therefore, vagal stimulations were performed in anaesthetized dogs either with constant frequency (CONT), or with trains of 3 stimuli triggered by each atrial activation (SYNCHR). An atrial contractility index was measured while increasing heart rate by artificial heart pacing during CONT and SYNCHR vagal stimulations. The negative inotropic parasympathetic effect was reduced in the former protocol (St/s constant, St/c reduced) and did not change in the latter. It was concluded that the effect of vagal stimulation is more strictly related to St/c rather than to St/s. We suggest that the heart cycle operates as a biological clock with respect to cardiac vagal control.

Animals↗
PubMed1996

Transcription of CABII is regulated by the biological clock in Chlamydomonas reinhardtii.

The small gene family encoding the chlorophyll a/b-binding proteins of photosystem II (CABII or lhcb) is known to exhibit circadian rhythms of mRNA abundance in Chlamydomonas reinhardtii. In this study we investigated the role of transcription in the phenomenon. We used as reporters Chlamydomonas genes that encode nitrate reductase (NITI) and arylsulfatase (ARS2) transcriptionally fused to sequences upstream of one of the CABII genes (called CABII-1). We found that both reporters exhibited the same circadian rhythm of mRNA abundance in phase, period, and amplitude as does the endogenous CABII-1 gene. We also evaluated the efficacy of arylsulfatase enzymatic activity as a reporter and found that its half-life is too long to make it a useful reporter of rhythmic transcription during a circadian or diurnal cycle. The amount of mRNA synthesis from the CABII-1 gene was examined by in vivo labeling experiments and a circadian rhythm in transcription rate was demonstrated. In vivo labeling also revealed a circadian rhythm of mRNA synthesis for the CABII gene family as a whole. The results from the transcriptional reporter assays together with the in vivo labeling experiments strongly support the conclusion that the biological clock regulates the transcriptional activity of the CABII-I gene, and moreover that regulation at the transcriptional level is the predominant mode by which the clock regulates this gene.

Animals↗
PubMed1997

Pituitary adenylate cyclase-activating peptide (PACAP) in the retinohypothalamic tract: a potential daytime regulator of the biological clock.

The retinohypothalamic tract (RHT) relays photic information from the eyes to the suprachiasmatic nucleus (SCN). Activation of this pathway by light plays a role in adjusting circadian timing via a glutamatergic pathway at night. Here we report a new signaling pathway by which the RHT may regulate circadian timing in the daytime as well. We used dual immunocytochemistry for pituitary adenylate cyclase-activating peptide (PACAP) and the in vivo tracer cholera toxin subunit B and observed intense PACAP-immunoreactivity (PACAP-IR) in retinal afferents in the rat SCN as well as in the intergeniculate leaflet (IGL) of the thalamus. This PACAP-IR in the SCN as well as in the IGL was nearly lost after bilateral eye enucleation. PACAP afferents originated from small ganglion cells distributed throughout the retina. The phase of circadian rhythm measured as SCN neuronal activity in vitro was significantly advanced (3.5 +/- 0.4 hr) by application of 1 x 10(-6) M PACAP-38 during the subjective day [circadian time (CT)-6] but not at night (CT14 and CT19). The phase-shifting effect is channeled to the clock via a PACAP-R1 receptor, because mRNA from this receptor was demonstrated in the ventral SCN by in situ hybridization. Furthermore, vasoactive intestinal peptide was nearly 1000-fold less potent in stimulating a phase advance at CT6. The signaling mechanism was through a cAMP-dependent pathway, which could be blocked by a specific cAMP antagonist, Rp-cAMPS. Thus, in addition to its role in nocturnal regulation by glutamatergic neurotransmission, the RHT may adjust the biological clock by a PACAP/cAMP-dependent mechanism during the daytime.

Animals↗
PubMed1994

Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO.

Circadian rhythms of mammals are timed by an endogenous clock with a period of about 24 hours located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Light synchronizes this clock to the external environment by daily adjustments in the phase of the circadian oscillation. The mechanism has been thought to involve the release of excitatory amino acids from retinal afferents to the SCN. Brief treatment of rat SCN in vitro with glutamate (Glu), N-methyl-D-aspartate (NMDA), or nitric oxide (NO) generators produced lightlike phase shifts of circadian rhythms. The SCN exhibited calcium-dependent nitric oxide synthase (NOS) activity. Antagonists of NMDA or NOS pathways blocked Glu effects in vitro, and intracerebroventricular injection of a NOS inhibitor in vivo blocked the light-induced resetting of behavioral rhythms. Together, these data indicate that Glu release, NMDA receptor activation, NOS stimulation, and NO production link light activation of the retina to cellular changes within the SCN mediating the phase resetting of the biological clock.

Amino Acid Oxidoreductases↗
PubMed2006

Suppressors, receptors and effects of cytokines on the aging mouse biological clock.

During aging, levels of inflammatory cytokines increase and circadian rhythms are frequently altered. We here investigated neurobiological correlates of neuroinflammation and its age-related variation in the hypothalamic suprachiasmatic nucleus (SCN), the master circadian pacemaker. Day/night variations of transcripts encoding cytokine receptors and suppressors of cytokine signaling (SOCS) were correlated in groups of mice of different ages with Fos induction elicited by intracerebroventricular injections of tumor necrosis factor-alpha and interferon-gamma. Cytokine-elicited Fos induction was high at early night, when SOCS1 and SOCS3 levels were low. Such Fos induction was significantly reduced in the older SCN at early night, and paralleled by reduced expression of interferon-gamma receptor transcripts as compared to the younger SCN. In addition, Fos induction at early night exhibited marked sub-regional differences in the SCN between the age groups. The study shows that SOCS1 and SOCS3 are expressed in the biological clock with a day/night variation that may regulate SCN responsiveness to cytokine exposure, and indicates that effects of pro-inflammatory cytokines on the SCN are markedly altered during senescence.

Aging↗
PubMed2002

Prenatal hypoxia impairs circadian synchronisation and response of the biological clock to light in adult rats.

The aim of this study was to test the hypothesis that prenatal hypoxia in rats might lead to consistent changes in the entrainment of the circadian clock by light. Pregnant female rats were placed in a chamber provided with hypoxic gas (10 % O2--90 % N2) at gestational day 5 and returned to normoxia before delivery. Once adult, rats born to hypoxic mothers had significant alterations in their circadian rhythm of locomotor activity (recorded in freely accessible running wheels). Under a regular 12/12 light/dark (LD) cycle, they showed a phase advance of their rhythm of activity (mean phase advance of 87 min) and were less active than control rats. After an abrupt 6 h phase delay in the LD cycle, rats from the prenatal hypoxic group (PNH) took significantly more time to resynchronise to the new LD cycle compared to controls (+53 %; 6.0 +/- 1.5 vs. 9.2 +/- 0.5 days respectively). Under constant darkness, PNH and control rats had a similar period of activity (24.27 +/- 0.20 vs. 24.40 +/- 0.13) but the response of PNH rats to a light pulse in the early subjective night was less marked than that of control rats (101 +/- 9 vs. 158 +/- 13 min). When submitted to acute restraint stress, PNH rats had a prolonged secretion of corticosterone compared to controls. These results indicate that prenatal hypoxia is a factor that has long lasting consequences for the functional output of the biological clock and the hormonal response to stress.

Age Factors↗
PubMed1992

Biological clocks: mechanisms and developments.

Almost all organisms ranging from unicellular protists to mammals were found to show biological rhythms. Many workers have performed various kinds of experiment to understand the mechanism as well as to find the origin of the clock responsible for these rhythms. However, there is no doubt about the existence of a biologically controlled clock in almost all organisms; yet its origin and mechanism still remain a mystery. Many theories have been put forward to explain the mechanism of these biological clocks and it seems that the cell membrane may play a key role. The existence of a very high electric field of the order of 10(5) V cm-1 across the cell membrane may have some role in the mechanism of the biological clock. Of all the factors which have the effects on biological rhythms, light and temperature are found to be the most common. Also, the study of these biological clocks can help to solve the sleeping problems of international travellers and shift workers as well as to improve diagnosis, cure and prevention from diseases.

Animals↗
PubMed2003

Rhythmic changes in metabolism of dopamine in the chick retina: the importance of light versus biological clock.

Rhythmic changes in dopamine (DA) content and metabolism were studied in retinas of chicks that were adapted to three different lighting conditions: 12-h light : 12-h dark (LD), constant darkness (DD) and continuous light (LL). Retinas of chicks kept under LD conditions exhibited light-dark-dependent variations in the steady-state level of DA and the two metabolites of DA, i.e. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA). Concentrations of DA, DOPAC and HVA were high in light hours and low in dark hours of the LD illumination cycle. In retinas of chicks kept under DD, the content of DA, DOPAC and HVA oscillated in a rhythmic manner for 2 days, with higher values during the subjective light phase than during the subjective dark phase. The amplitudes of the observed oscillations markedly and progressively declined compared with the amplitudes recorded under the LD cycle. In retinas of chicks kept under LL conditions, levels of DA, DOPAC and HVA were similar to those found during the light phase of the LD cycle. Changes in the retinal contents of DA and HVA did not exhibit pronounced daily oscillations, while on the first day of LL the retinal concentrations of DOPAC were significantly higher during the subjective light phase than during the subjective dark phase. Acute exposure of chicks to light during the dark phase of the LD cycle markedly increased DA and DOPAC content in the retina. In contrast, light deprivation during the day decreased the retinal concentrations of DA and DOPAC. It is suggested that of the two regulatory factors controlling the level and metabolism of DA in the retina of chick, i.e. light and biological clock, environmental lighting conditions seem to be of major importance, with light conveying a stimulatory signal for the retinal dopaminergic cells.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

From xeroderma pigmentosum to the biological clock contributions of Dirk Bootsma to human genetics.

This paper commemorates the multiple contributions of Dirk Bootsma to human genetics. During a scientific 'Bootsma' cruise on his sailing-boat 'de Losbol', we visit a variety of scenery locations along the lakes and canals in Friesland, passing the highlights of Dirk Bootsma's scientific oeuvre. Departing from 'de Fluessen', his homeport, with his PhD work on the effect of X-rays and UV on cell cycle progression, we head for the pioneering endeavours of his team on mapping genes on human chromosomes by cell hybridization. Next we explore the use of cell hybrids by the Bootsma team culminating in the molecular cloning of one of the first chromosomal breakpoints involved in oncogenesis: the bcr-abl fusion gene responsible for chronic myelocytic leukemia. This seminal achievement enabled later development of new methods for early detection and very promising therapeutic intervention. A series of highlights at the horizon constitute the contributions of his team to the field of DNA repair, beginning with the discovery of genetic heterogeneity in the repair syndrome xeroderma pigmentosum (XP) followed later by the cloning of a large number of human repair genes. This led to the discovery that DNA repair is strongly conserved in evolution rendering knowledge from yeast relevant for mammals and vice versa. In addition, it resolved the molecular basis of several repair syndromes and permitted functional analysis of the encoded proteins. Another milestone is the discovery of the surprising connection between DNA repair and transcription initiation via the dual functional TFIIH complex in collaboration with Jean-Marc Egly et al. in Strasbourg. This provided an explanation for many puzzling clinical features and triggered a novel concept in human genetics: the existence of repair/transcription syndromes. The generation of many mouse mutants carrying defects in repair pathways yielded valuable models for assessing the clinical relevance of DNA repair including carcinogenesis and the identification of a link between DNA damage and premature aging. His team also opened a fascinating area of cell biology with the analysis of repair and transcription in living cells. A final surprising evolutionary twist was the discovery that photolyases designed for the light-dependent repair of UV-induced DNA lesions appeared to be adopted for driving the mammalian biological clock. The latter indicates that it is time to return to 'de Fluessen', where we will consider briefly the merits of Dirk Bootsma for Dutch science in general.

Amino Acid Sequence↗