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PubMed2002

Elevated arylalkylamine-N-acetyltransferase (AA-NAT) gene expression in medial habenular and suprachiasmatic nuclei of hibernating ground squirrels.

Hibernation, an adaptive response for energy conservation in mammals, involves a variety of physiological changes. Melatonin is linked with the regulation of core body temperature and intervenes in generating circadian cycles; its role in seasonal (circannual) rhythms of hibernation is explored here. Melatonin is primarily produced in the pineal gland. Since arylalkylamine-N-acetyltransferase (AA-NAT) is the rate-limiting enzyme for synthesizing melatonin, AA-NAT gene expression was investigated to assess the possible role of melatonin in hibernation. The findings presented here utilized combined in situ hybridization and immunohistochemistry methodologies to evaluate the AA-NAT mRNA expression in brains of both hibernating and non-hibernating ground squirrels. Brains were examined for the expression of AA-NAT mRNA using a oligonucleotide AA-NAT probe; antibody against neurofilament-70 (NF-70) was used as a neuronal marker. All hibernating animals expressed significantly (P<0.01) elevated levels of AA-NAT mRNA in both the epithalamic medial habenular nuclei (MHb) area and the hypothalamic suprachiasmatic nuclei (SCN), which is also known as the master biologic clock. These findings represent the first demonstration of the expression of mRNA encoding for AA-NAT in the extra-pineal (i.e. SCN and MHb) sites of thirteen-lined ground squirrels and indicate that the habenular nucleus may be an important supplementary location for melatonin biosynthesis. The data presented here indicate that AA-NAT gene is one of the few specific genes up-regulated during hibernation and suggest that elevation of its expression in SCN and MHb may play an essential role in the generation and maintenance of hibernation.

Animals↗
PubMed1997

D1 receptors mediate dopamine action in the fetal suprachiasmatic nuclei: studies of mice with targeted deletion of the D1 dopamine receptor gene.

Studies in rodents suggest the presence of a dopaminergic system that influences the function of a biological clock in the hypothalamic suprachiasmatic nuclei (SCN). To provide insights into mechanisms of dopamine action in the SCN, we studied transgenic mice that had either one allele (+¿-) or both alleles (-/-) of the D1 dopamine receptor gene deleted, along with normal (+/+) littermates. As expected, receptor labelling autoradiography studies using [125I]SCH 23982 showed a complete absence of D1 dopamine receptor binding sites in the SCN of -/- animals. When pregnant mice from +¿- x +¿- matings were injected with the D1 receptor agonist SKF 38393, or the dopamine reuptake blocker GBR 12909 at day 19 of gestation, c-fos mRNA expression was observed in the SCN of +/+ fetuses. In contrast, c-fos mRNA induction was not seen in -/- or +¿- litter mates. Injection of cocaine into pregnant dams also resulted in robust SCN c-fos mRNA expression in +/+ mice. Increases in SCN c-fos mRNA expression were also seen in +¿- and -/- mice suggesting that cocaine action in the SCN involves both D1 receptor-dependent and -independent mechanisms. Collectively, our studies of transgenic mice deficient in D1 receptors support the presence of a functional dopaminergic system in the fetal SCN. We also identify D1 receptors as the prominent transducer of dopamine action in the fetal SCN.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

[Treatment of cluster headache].

INTRODUCTION: The cluster headache (CH) is one of the most severe types of head pain. It is a typical example of a periodic disease and the International Headache Society classification recognizes two forms of this disease: episodic and chronic CH. Its prevalence is about 0.1 to 0.4% in the general population. CURRENT KNOWLEDGE AND KEY POINTS PATHOPHYSIOLOGY: A global hypothesis is still lacking to explain the pain, the vasodilation, the autonomic features (ipsilateral lacrimation, conjunctiva injection, rhinorrhea, partial Horner syndrome, etc.) and the periodicity of the CH. Pain and vasodilation seem secondary to an activation of the trigeminal vascular system and the periodicity of the attacks is thought to be due to a dysfunction of hypothalamic biologic clock mechanisms. Treatment of acute CH attacks. The most effective agents are oxygen inhalation and subcutaneous sumatriptan, a 5HT1B and D receptor agonist which has vasoconstrictor and anti-neurogenic inflammation properties by blocking the release from the trigeminal-sensitive fibers of neuropeptides such as CGRP and substance P. With subcutaneous sumatriptan, headache relief is very rapid, within 5 to 10 min. Prophylactic treatment of CH: The number of attacks per day varies from one to three, but some patients can have four to eight per day and acute treatments fail to provide sufficient relief or give rise to side-effects. Several different regimens have been proven effective. FUTURE PROSPECTS AND PROJECTS: Contraindications and side-effects of the drugs limit the choice of the prophylactic treatment: corticosteroids in a tapering course, verapamil and methysergide are the most useful treatments of the episodic form. Lithium carbonate is more effective for the chronic stage of CH, but side-effects are often troublesome. Numerous other medications have been used for prophylaxis: valproate, capsaicin, beta-blockers. Unfortunately, double-blind studies are often lacking and are difficult to realize due to spontaneous variable remission of episodic CH. When adequate trials of drug therapies show a total resistance to the treatments, surgery may be considered. Radiofrequency trigeminal rhizotomy is the treatment of choice with 70% of beneficial effects. Risks and complications have to be discussed in balance with the benefit of the different surgical procedures.

Anti-Inflammatory Agents↗
PubMed2003

[Sleep rhythm disturbances in Alzheimer's disease].

PURPOSE: Sleep-wake rhythm disturbances observed in Alzheimer's disease are correlated with the severity of cognitive impairment and often result in institutionalization. These disturbances are also a major cause of psychotropic medication misuse. We report age-related physiologic and disease related pathologic changes in sleep-wake rhythms and propose chronobiological treatment approaches in patients with Alzheimer's disease. CURRENT KNOWLEDGE AND KEY POINT: Alzheimer patients show a greater breakdown of the circadian sleep-wake cycle compared to similarly aged non demented controls. Demented patients spend their nights in a state of frequent restlessness and their days in a state of frequent sleepiness. These sleep-wake disturbances became increasingly more marked with progression of the disease. The architecture of sleep in Alzheimer's disease is marked by further decreases of slow wave sleep (SWS) and rapid eye movement (REM) sleep, and increases of time and frequency of awakening compared to age-matched control subjects. The sleep-wake disturbances in elderly people and particularly Alzheimer patients may result from changes at different levels: a reduction of environmental synchronizers or their perception, a lack of mental and physical activity, an age or disease related anatomical changes with loss of functionality of the biological clock(s). FUTURE PROSPECTS AND PROJECTS: In Alzheimer patients, controlling sleep-wake disturbances with sedative drugs often increases both sleep disturbance and cognitive dysfunction. A chronobiological approach with bright-light therapy, melatonin administration, restricted time in bed, and diurnal activity may be an interesting therapeutic alternative in the management of sleep-wake disorders in Alzheimer patients. The aim of these therapeutics is to improve sleep and diurnal activity and consequently to increase the quality of life in Alzheimer patients.

Aged↗
PubMed2003

Temperature dependency and temperature compensation in a model of yeast glycolytic oscillations.

Temperature sensitivities and conditions for temperature compensation have been investigated in a model for yeast glycolytic oscillations. The model can quantitatively simulate the experimental observation that the period length of glycolytic oscillations decreases with increasing temperature. Temperature compensation is studied by using control coefficients describing the effect of rate constants on oscillatory frequencies. Temperature compensation of the oscillatory period is observed when the positive contributions to the sum of products between control coefficients and activation energies balance the corresponding sum of the negative contributions. The calculations suggest that by changing the activation energies for one or several of the processes, i.e. by mutations, it could be possible to obtain temperature compensation in the yeast glycolytic oscillator.

Biological Clocks↗
PubMed2001

Telomeres and replicative senescence: Is it only length that counts?

Telomeres are well established as a major 'replicometer', counting the population doublings in primary human cell cultures and ultimately triggering replicative senescence. However, neither is the pace of this biological clock inert, nor is there a fixed threshold telomere length acting as the universal trigger of replicative senescence. The available data suggest that opening of the telomeric loop and unscheduled exposure of the single-stranded G-rich telomeric overhang might act like a semaphore to signal senescent cell cycle arrest. Short telomere length, telomeric single-strand breaks, low levels of loop-stabilizing proteins, or other factors may trigger this opening of the loop. Thus, both telomere shortening and the ultimate signalling into senescence are able to integrate different environmental and genetic factors, especially oxidative stress-mediated damage, which might otherwise become a thread to genomic stability.

Cell Division↗
PubMed2000

Daily changes of cytochrome oxidase activity within the suprachiasmatic nucleus of the Syrian hamster.

Cytochrome oxidase (CO) activity was studied over a 24-h period in the Syrian hamster suprachiasmatic nucleus (SCN) (site of the biological clock), anterior hypothalamic area (AHA), and motor cortex. The SCN CO activity was highest at the middle of the day (Zeitgeber time (ZT) 05), decreased at the end of the light period (ZT 10) and continued at a low level during the night (ZT 13, 16, 21.5 and 24). AHA and motor cortex showed a similar profile of CO activity and no changes of CO activity were found in animals maintained under darkness (DD). We propose that photic input plays a role in the SCN neuronal activity that modulates metabolic activity on this area.

Animals↗
PubMed2000

Effects of estrogen on the expression of connexin32 and connexin43 mRNAs in the suprachiasmatic nucleus of female rats.

The suprachiasmatic nucleus of the hypothalamus (SCN) is the site of the endogenous biological clock that regulates circadian rhythms in mammals. It has been shown that the gap junction couples neurons in the rat SCN. To determine the effects of estrogen on gap junction communication in the SCN, we examined the effects of estrogen on the expression of connexin32 and connexin43 mRNAs in the SCN and cerebral cortex (CX) of female rats. Ovarectomized adult rats were injected with 20 microg of 17beta-estradiol and killed 24 h after the treatment. Northern blot revealed that the expression of connexin32 mRNA was significantly increased in the SCN but not in the CX. On the other hand, estrogen increased the connexin43 mRNA level in the CX but not in the SCN. These results suggest that the gap junction with connexin32 is specifically regulated by estrogen in the SCN of female rats.

Animals↗
PubMed1999

Season of birth modulates morningness-eveningness preference in humans.

The aim of present work is to test if circadian typology could be modulated by environmental light-dark cycle acting at the time of birth. A sample of 1584 university students was administered the Morningness-Eveningness Questionnaire. Subjects were subdivided in four season groups, according to the birth date. We found more morning types among the students born in autumn and winter than in spring and summer, while we found an opposite pattern for evening types. The exposition to a decreasing photoperiod at birth seems to favour a phase advance of the biological clock (morning typology), while an increasing photoperiod seems to favour a phase delay (evening typology) of the human circadian system. Nevertheless we found no differences if female subjects separately were considered, as though the circadian typology of human females was not modulated by seasonal photoperiod at birth.

Adaptation, Physiological↗
PubMed2001

Artificially accelerated aging by shortened photoperiod alters early gene expression (Fos) in the suprachiasmatic nucleus and sulfatoxymelatonin excretion in a small primate, Microcebus murinus.

In mammals, a number of anatomical and functional changes occur in the circadian timing system with aging. In certain species, aging can be modified by various factors which induce a number of pathological changes. In a small primate, the gray mouse lemur (Microcebus murinus), long-term acceleration of seasonal rhythms by exposing the animals to a shortened photoperiodic regime (up to 2.5 times the natural photoperiodic regime) alters longevity, based on survival curves and morphological changes. This provides a model for challenging the idea that modifications of the circadian pacemaker are related to chronological (years) versus biological (photoperiodic cycles) age. To assess the effect of aging and accelerated aging on the circadian pacemaker of this primate, we measured body weight variations, the daily rhythm in urine 6-sulfatoxymelatonin and the light-induced expression of the immediate early gene (Fos) in the suprachiasmatic nucleus of mouse lemurs that had been exposed to different photoperiodic cycles. Urine samples were collected throughout the day and urine 6-sulfatoxymelatonin levels were measured by radioimmunoassay. Light-induced Fos expression in the suprachiasmatic nucleus was studied by exposing the animals to a 15-min monochromatic pulse of light (500 nm) at saturating or sub-saturating levels of irradiance (10(11) or 10(14) photons/cm(2)/s) during the dark phase. The classical pattern of 6-sulfatoxymelatonin excretion was significantly altered in aged mouse lemurs which failed to show a nocturnal peak. Fos expression following exposure to low levels of irradiance was reduced by 88% in the suprachiasmatic nucleus of aged mouse lemurs. Exposure to higher irradiance levels showed similar results, with a reduction of 66% in Fos expression in the aged animals. Animals subjected to artificially accelerated aging demonstrated the same alterations in melatonin production and Fos response to light as animals that had been maintained in a routine photoperiodic cycle. Our data indicate that there are dramatic changes in melatonin production and in the cellular response to photic input in the suprachiasmatic nucleus of aged mouse lemurs, and that these alterations depend on the number of expressed seasonal cycles rather than on a fixed chronological age. These results provide new insights into the mechanisms underlying artificial accelerated aging at the level of the molecular mechanisms of the biological clock.

Aging↗
PubMed2001

Circadian rhythms in firing rate of individual suprachiasmatic nucleus neurons from adult and middle-aged mice.

The suprachiasmatic nucleus contains a biological clock that drives circadian rhythms in vivo and in vitro. It has been suggested that the suprachiasmatic nucleus is a primary target of the aging process, because age-related changes in behavioral rhythms are mirrored in alterations in circadian pacemaker function. Using long-term, single-cell recording, we assessed the effect of age on firing-rate patterns of individual suprachiasmatic nucleus neurons of young adult (2-4 months) and middle-aged (9-11 months) C3H mice. Individual suprachiasmatic nucleus neurons from adult mice maintained in culture for at least one week exhibited robust circadian rhythms in spontaneous activity that were similar in the free-running period (23.7+/-0.3 h mean+/-S.E.M.) to recordings from neurons dispersed from neonatal tissue, and showed evidence of entrainment to prior light cycles by exhibiting peak activity, in vitro, approximately 4.0+/-0.3 h (mean+/-S.E.M.) after the time of expected light onset. Aging led to a decreased amplitude of impulse activity in dispersed suprachiasmatic nucleus neurons and increased variability in the circadian waveform. From these results we suggest that age-related deterioration in circadian clock function occurs at the level of individual cells, which may account for some of the age-related deficits observed in the expression of behavioral rhythmicity.

Action Potentials↗
PubMed2003

Serotonergic serotonin (1A) mixed agonists/antagonists elicit large-magnitude phase shifts in hamster circadian wheel-running rhythms.

The biological clock that generates circadian rhythms in mammals is located within the suprachiasmatic nuclei at the base of the hypothalamus. The circadian clock is entrained to the daily light/dark cycle by photic information from the retina. The retinal input to the clock is inhibited by exogenously applied serotonin agonists, perhaps mimicking an endogenous inhibitory serotonergic input to the clock arriving from the midbrain raphe. In the present study, a unique class of serotonergic compounds was tested for its ability to modulate retinal input to the circadian clock. The serotonergic ligands 8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-8-azaspiro(4.5)decane-7,9-dione dihydrochloride (BMY 7378), S 15535, and 8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspiro[4.5]decane-7,9-dione hydrochloride (MDL 73005 EF) can all be classified as mixed agonists/antagonists at type 1A serotonin receptors. Circadian wheel-running activity rhythms were monitored in Syrian hamsters maintained in constant darkness. Dim white-light pulses administered to the hamsters at circadian time 19 advanced the phase of their running rhythms by 1-2 h. Injection of BMY 7378, S 15535, and to a lesser degree MDL 73005 EF, prior to the light pulses resulted in phase advances from 5 to 6 h, and by as much as 8 h. Neither BMY 7378 nor S 15535 had any effect on light-induced phase delays in hamster activity rhythms at circadian time 14. Further, BMY 7378 is able to phase advance circadian rhythms by approximately 1 h at night even without light exposure. Finally, the effects of BMY 7378 on circadian rhythms is opposite to that observed with the prototypical serotonin 1A agonist (+/-)-8-hydroxy-2-(DI-n-propyl-amino)tetralin hydrobromide (8-OH-DPAT) (8-OH-DPAT elicits non-photic phase advances in the day and inhibits photic-induced phase advances at night). These results suggest that pharmacologically blocking raphe input to the suprachiasmatic circadian clock results in substantially larger photically induced phase advances in wheel-running rhythms. This is further evidence that raphe input to the circadian clock is probably acting to dampen the clock's response to light under certain conditions. The large-magnitude phase shifts, and temporal-activity profile seen with BMY 7378 and S 15535, suggest that compounds with this unique pharmacological profile may be beneficial in the treatment of circadian phase delays recently reported to be a complication resulting from Alzheimer's disease.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Vasopressin-deficient suprachiasmatic nucleus grafts re-instate circadian rhythmicity in suprachiasmatic nucleus-lesioned arrhythmic rats.

It was investigated whether grafts of the suprachiasmatic nucleus could re-instate circadian rhythmicity in the absence of its endogenous vasopressin production and whether the restored rhythm would have the long period length of the donor. Grafts of 17-days-old vasopressin-deficient homozygous Brattleboro rat fetuses, homotopically placed in arrhythmic suprachiasmatic nucleus-lesioned Wistar rats, re-instated circadian drinking rhythm within 20-50 days similar as seen for grafts of heterozygous control fetuses. Period length of the recovered rhythm revealed a similar difference (average 24.3 vs. 23.8 h) as reported for the rhythm between the adult Brattleboro genotypes. In all transplants, also those of the two-third non-recovery rats, a surviving suprachiasmatic nucleus was visible as a vasoactive intestinal polypeptide-positive neuronal cell cluster, whereas heterozygous transplants also revealed the complementary vasopressinergic cell part. Explanation of the absence of recovery failed since no undisputable correlation emerged between recovery of rhythm and vasoactive intestinal polypeptide, vasopressin and/or somatostatin immunocytochemical characteristics of the suprachiasmatic nucleus of the transplant. Special focus on the somatostatinergic neurons revealed their presence only occasionally near or in between the vasoactive intestinal polypeptidergic and (in the case of heterozygous grafts) vasopressinergic cell cluster. However their aberrant cytoarchitectural position appeared not to have affected the possibility to restore drinking rhythm of the suprachiasmatic nucleus-lesioned arrhythmic rat. It was concluded that grafted Brattleboro fetal suprachiasmatic nucleus develop their intrinsic rhythm conform their genotype and that vasopressin is not a crucial component in the maintenance nor in the transfer of circadian activity of the biological clock for drinking activity. Vasopressin of the suprachiasmatic nucleus may instead serve modulation within the circadian system.

Animals↗
PubMed2000

GABAergic modulation of gap junction communication in slice cultures of the rat suprachiasmatic nucleus.

We employed morphological and electrophysiological methods in order to elucidate mechanisms which are responsible for communication between cellular oscillators in the cultured rat suprachiasmatic nucleus, the site of the endogenous biological clock that regulates circadian rhythms in mammals. When a gap junction-permeable dye, Lucifer Yellow, was injected into single neurons in the suprachiasmatic nucleus culture, the dye was transferred to neighboring cells in a gap junction blocker-sensitive manner. Optical imaging of neural activity evoked by electrical stimulation in the culture revealed that the spread of depolarization was inhibited by gap junction blockers but not by a blocker of voltage-dependent Na(+) channels. Depolarization propagation was inhibited by muscimol, a GABA(A) receptor agonist, in a dose-dependent manner and the inhibition was reversed by bicuculline, a GABA(A) receptor antagonist. Furthermore, muscimol inhibited dye-transfer between neurons in the suprachiasmatic nucleus culture in a dose-dependent fashion.These independent lines of evidence suggest that the gap junction communication is involved in interneuronal communication in the suprachiasmatic nucleus slice culture and that the coupling state between neurons is not static but dynamically regulated via GABA(A) receptor systems.

Animals↗
PubMed2003

Primary cell culture of suprachiasmatic nucleus.

In mammals, the suprachiasmatic nucleus (SCN) contains a biological clock that drives circadian rhythms in vivo and in vitro. Primary dissociated neuronal culture is a useful research tool, which allows cell-by-cell morphological and physiological study of the SCN. A long-term primary dissociated SCN neuron culture is the prerequisite to understanding how neural activity and morphology interact in the SCN. The essential details of recent effective SCN culture methods are reviewed, including preparation of cells, medium and substrate, maintenance of cultures, and characterization of cultured SCN neurons. This technique is growing in importance, especially with the advent of multi-electrode array (MEA) recording.

Animals↗
PubMed1999

Emerging and entraining patterns of the sleep-wake rhythm in preterm and term infants.

It has been repeatedly reported that the sleep-wake rhythm in infants entrains around 3-4 months of age after a transient free-run rhythm. To clarify the emerging and entraining patterns of the sleep-wake rhythm, the sleep and wakefulness of 84 infants (44 preterm and 40 term infants) were longitudinally recorded at home for more than 16 weeks by the day-by-day plot method. Our results showed that the entrained sleep-wake rhythm emerged after transient manifestation of either ultradian or irregular sleep-wake patterns for 3-4 weeks in 75% of the infants. Only 7% of the infants showed a free-running sleep-wake rhythm before the entrainment. These facts suggest that most infants would be entrained to an ordinary daily schedule of mothers without expression of overt free-running rhythm of the biological clock. The mean age of the entrainment was 44.8 postconceptional weeks. There were no significant differences in either frequency of each pattern or the mean age of the entrainment, between preterm and term infants. In conclusion, the entrained sleep-wake rhythm emerges around 1 corrected month, after ultradian patterns in the majority of infants.

Circadian Rhythm↗
PubMed2000

Circadian and sleep disturbances in the elderly.

The incidence of disturbed sleep is strongly increased in healthy and demented elderly. Age-related alterations in the circadian timing system appear to contribute strongly to these problems. With increasing age, a lack of input to the suprachiasmatic nucleus (SCN), the biological clock of the brain, may accelerate de-activation of neurons involved in the generation of 24-h rhythm or output of this rhythm. This process appears to be reversible, since supplementation of stimuli that impinge on the SCN can re-activate these neurons and ameliorate disturbances in the sleep-wake rhythm.

Aged↗
PubMed2001

Can nutrition influence circadian rhythm and heart rate variability?

Recent studies indicate that there is an interaction between biorhythms, the biological clock and triggers, which may be important in the pathogenesis of altered heart rate variability (HRV) and blood pressure variability (BPV). Circadian rhythms are under the influence of, and physiological variables are mediated by the activation of the adrenals, sympathetic/parasympathetic, hypothalamic and pituitary activity. Emotional stress, physical exertion, sleep deprivation and large fatty meals are major triggers of myocardial ischemia, angina, infarction, sudden cardiac death (SCD) and stroke. These events have been reported to exhibit a circadian variation with increased frequency in the second quarter of the day, which has also been observed in our studies on Indians. Recent studies indicate that altered HRV and BPV are also important in the pathogenesis and progression of heart failure, atheroma and thrombosis. Mediation via beta-blockers, oestrogens, n-3 fatty acids, vitamin E and coenzyme Q10 and fasting appears to have a beneficial influence whereas progestins, nifedipine, stress and exercise may have an adverse effect on HRV and BPV. We have reported that plasma levels of vitamin E and C are lower in the second quarter of the day than at other times, indicating their role in the pathogenesis of variability and cardiac events. Prospective studies also indicate that HRV and BPV are important and independent risk factors for cardiovascular events. However, no study has yet been conducted in patients with abnormal HRV and BPV in a randomized, placebo-controlled intervention trial to find out whether improvement in variability can cause a significant reduction in cardiovascular events. There is a need to study the role of n-3 fatty acids, coenzyme Q10, the effect of regular physical training, medication and ACE inhibitors in patients with abnormal HRV and BPV to demonstrate that improving variability can modulate cardiovascular events.

Animals↗