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PubMed1976

The coupling effects of some thiol and other sulfur-containing compounds on the circadian rhythm of cell division in photosynthetic mutants of Euglena.

Previous work has demonstrated a persisting, free-running, circadian rhythm of cell division in the P4ZUL photosynthetic mutant of the alga Euglena gracilis Klebs (Strain Z) Pringsheim grown organotrophically in continuous light or darkness at 19 degrees C following prior synchronization by a repetitive LD:10,14 light cycle. A similar circadian rhythmicity has been recently discovered in the W6ZHL heat-bleached and the Y9ZNalL naladixic acid-induced mutants of Euglena grown under comparable conditions. Over extended timespans, however, these mutants appear to gradually lose first their ability to display persisting overt rhythms, and then even their capability of being entrained by imposed LD cycles. These properties can be restored by the addition of certain sulfur-containing compounds to the medium including cysteine, methionine, dithiothreital, sodium monosulfide, sodium sulfite, and sodium thiosulfate, as well as thioglycolic [mercaptoacetic] acid. The implications of these findings toward biological clock mechanisms are discussed: It appears that some sort of coupling process is operating as opposed to the initiation of an underlying oscillation.

Amino Acids, Sulfur↗
PubMed1984

Involvement of serotonergic mechanisms in initiation of small intestine cyclic motor events.

Continuous mechanical and electrical activity recordings of the gastroduodenal junction and duodenum were performed in conscious sheep receiving pharmacologic agents delivered intraduodenally before and after nerve section. Sheep on a normal diet regimen exhibited cyclic periods of maximal activity (phase III of the migrating myoelectric complex) on the duodenum or in-series contractions on the duodenal bulb recurring at a frequency of 13/24 hr and more after nerve section. Among the variety of agents triggering in intact animals premature phases of maximal activity, methysergide, when administered locally, was found to increase the number of complexes to a frequency of 24/24 hr, even when extrinsic nerve supply was removed. The results suggest that in the ovine model the mechanism of cycling of the motor events involved serotonergic myenteric neurons located in the duodenal bulb. The data were consistent with the regulation of the enteric biological clock via 5HT neural receptors mediating inhibition.

Animals↗
PubMed1989

Central melatonin receptors: implications for a mode of action.

The influence of melatonin on circadian and photoperiodic functions in numerous species is well documented. It is known that the effect of melatonin on circadian rhythmicity is mediated via the suprachiasmatic nucleus (SCN), the biological clock of the brain. It is not known however where the photoperiodic effects of melatonin are mediated. Evidence from brain lesioning and melatonin implant studies point to a site in or near the medial hypothalamus. In contrast to these studies, melatonin receptors have been reported in widespread areas of the brain, the pituitary and in peripheral tissues. The characteristics of the reported melatonin receptors vary widely between studies and consequently no definitive description of a physiologically relevant melatonin receptor has received universal recognition. This review marshals recent evidence for the localization and characterization of the melatonin receptor and discusses these findings in the context of the known effects of the hormone in different species.

Animals↗
PubMed1994

From trypanosomes to the nervous system, from molecules to behavior: a survey, on the occasion of the 90th anniversary of Castellani's discovery of the parasites in sleeping sickness.

The observation of Trypanosomes in patients affected by sleeping sickness has been reported in 1903 by Aldo Castellani. On the occasion of the 90th anniversary of this discovery, we here present the findings recently obtained in and experimental model of African trypanosomiasis in the rat. The molecular and cellular mechanisms of the interplay between the parasite and the host have been largely clarified: a bidirectional signalling occurs between trypanosomes and CD8+ T cells of the host animal. This new pathogenetic mechanism of infection involves a lymphocyte triggering factor released by the parasite and interferon-gamma. A recently isolated neuronal interferon-gamma could also play a role in the disease. The selective induction of major histocompatibility antigens class I has revealed the involvement of the hypothalamic paraventricular and supraoptic nuclei in trypanosomiasis. Finally, studies based on the expression of the immediate early gene c-fos have pointed out during the infection a selective dysregulation of the suprachiasmatic nucleus of the hypothalamus, that plays the role of biological clock. The latter finding could account for the disruption of endogenous rhythms in sleeping sickness.

Animals↗
PubMed1996

A speculative model of affective illness cyclicity based on patterns of drug tolerance observed in amygdala-kindled seizures.

In this article, we discuss molecular mechanisms involved in the evolution of amygdala kindling and the episodic loss of response to pharmacological treatments during tolerance development. These phenomena allow us to consider how similar principles (in different neurochemical systems) could account for illness progression, cyclicity, and drug tolerance in affective disorders. We describe the phenomenon of amygdala-kindled seizures episodically breaking through effective daily pharmacotherapy with carbamazepine and valproate, suggesting that these observations could reflect the balance of pathological vs compensatory illness-induced changes in gene expression. Under certain circumstances, amygdala-kindled animals that were initially drug responsive can develop highly individualized patterns of seizure breakthroughs progressing toward a complete loss of drug efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mechanisms and illness-induced endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness-induced adaptations dissipate (the "time-off seizure" effect), leading to the re-emergence of seizures, a re-induction of a new, but diminished, set of endogenous compensatory mechanisms, and a temporary period of renewed drug efficacy. As this pattern repeats, an intermittent or cyclic response to the anticonvulsant treatment emerges, leading toward complete drug tolerance. We also postulate that the cyclic pattern accelerates over time because of both the failure of robust illness-induced endogenous adaptations to emerge and the progression in pathophysiological mechanisms (mediated by long-lasting changes in gene expression and their downstream consequences) as a result of repeated occurrences of seizures. In this seizure model, this pattern can be inhibited and drug responsivity can be temporarily reinstated by several manipulations, including lowering illness drive (decreasing the stimulation current), increasing drug dosage, switching to a new drug that does not show crosstolerance to the original medication, or temporarily discontinuing treatment, allowing the illness to re-emerge in an unmedicated animal. Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression of individual patterns of episodic cyclicity in the recurrent affective disorders. A variety of clinical studies are outlined that specifically test the hypotheses derived from this formulation. Data from animal studies suggest that illness cyclicity can develop from the relative ratio between primary pathological processes and secondary endogenous adaptations (assisted by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to the neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the biological clock. The formulation predicts that early and aggressive long-term interventions may be optimal in order to prevent illness emergence and progression and its associated accumulating neurobiological vulnerability factors.

Affect↗
PubMed2006

Ethanol self-administration and reinstatement of ethanol-seeking behavior in Per1(Brdm1) mutant mice.

RATIONALE: Alcohol consumption shows circadian rhythmicity, i.e., alcohol preference and intake change with circadian time. Circadian rhythmicity is controlled by a biological clock, which has been shown to govern behavioral, physiological, and hormonal processes in synchronization with internal as well as external cues. Molecular components of the clock include circadian clock genes such as period (Per) 1, 2, and 3. Previously, our lab demonstrated the involvement of mouse Per1 (mPer1) and Per2 (mPer2) in modulating cocaine sensitization and reward. What is more, we investigated voluntary alcohol consumption in Per2 ( Brdm1 ) mice with the results suggesting a relationship between this circadian clock gene and ethanol consumption. Objective To further complement the mPer2 study, our lab proceeded to assess mPer1's possible role on alcohol intake using operant and free choice two bottle paradigms. METHODS: Using operant conditions, Per1 ( Brdm1 ) and wild type mice were trained to self-administer ethanol (10%) under a fixed ratio 1 (FR1) paradigm. This was ensued by a progressive ratio (PR) schedule. Furthermore, extinction sessions were introduced, followed by reinstatement measures of ethanol-seeking behavior. In another set of animals, the mice were exposed to voluntary long-term alcohol consumption, ensued by a 2-month deprivation phase, after which the alcohol deprivation effect (ADE) was measured. RESULTS: Mutant mice did not display a significantly divergent number of reinforced lever presses (FR1 and PR) than wild type animals. Furthermore, no significant differences between groups were obtained regarding reinstatement of ethanol-seeking behavior. Similar results were obtained in the two bottle free choice paradigm. Specifically, no genotype differences concerning consumption and preference were observed over a broad range of different ethanol concentrations. Moreover, after the deprivation phase, both groups exhibited significant ADEs, yet no genotype differences. CONCLUSIONS: Contrary to the mPer2 data, the present findings do not suggest a relationship between the circadian clock gene mPer1 and ethanol reinforcement, seeking, and relapse behavior.

Alcohol Drinking↗
PubMed2006

Impaired daily glucocorticoid rhythm in Per1 ( Brd ) mice.

Biological clocks have evolved in all kinds of organisms in order to anticipate and adjust to the daily light-dark cycle. Within the last decade, the molecular machinery underlying the circadian system was unraveled. In the present study, the impact of the loss of the Per1 or Per2 genes, key components of the core clock oscillator, on body mass, food and water intake, glucose metabolism, and hypothalamic-pituitary-adrenal axis, was investigated in the Per1 ( Brd ) and Per2 ( Brd ) mouse models. The results reveal that the lack of Per1 but not Per2 has severe consequences for the regulation of these parameters. Specifically, in Per1 ( Brd ) animals, we found an impaired daily glucocorticoid rhythm, with markedly elevated levels during the day compared to control animals. In addition, Per1 ( Brd ) mice showed significant differences in body mass as well as food and water intake. Although the Per1 ( Brd ) are lighter than wildtype mice, food and water intake per gram body mass is elevated. In addition, the Per1 ( Brd ) mice exhibit an increased glucose metabolism after i.p. injection with glucose. In conclusion, our study presents first evidence for a link between an altered metabolism in Per1 and Per2 deficient mice, which in the case of the Per1 ( Brd ) animals might be due to an impaired corticosterone rhythm.

Analysis of Variance↗
PubMed2005

Cyclic vertical deviation after ocular myositis and treatment by recession of the inferior rectus muscle.

BACKGROUND: Cyclic strabismus is a rare disorder in which strabismus and orthotropia regularly alternate over a period of mostly 48 h. It may occur spontaneously, upon squint surgery, or in association with lesions of the central nervous system. In most cases the deviations are convergent. METHODS: Clinical case report. RESULTS: A 34-year-old woman with bilateral recurrent ocular myositis for 2 years had developed cyclic vertical deviation 6 months after clinical remission. A hypotropia of the left eye alternated with an orthotropia, following a 48-h rhythm. Three months after recession of the inferior rectus muscle the alternating squint had disappeared. DISCUSSION: The aetiology of cyclic eye deviations, most of them occurring in a constant rhythm, is not known. The association with lesions of the central nervous system indicates a primary central dysregulation of a "biological clock". Their well-known occurrence, however, after squint surgery and, as in the present case, after orbital myositis, suggests that alteration of peripheral structures may contribute to a central dysregulation. Squint surgery seems to be the treatment of choice, even in rare cases with vertical deviations.

Adult↗
PubMed2000

The tonoplast functioning as the master switch for circadian regulation of crassulacean acid metabolism.

From the initial discovery of free-running endogenous circadian oscillations of Crassulacean acid metabolism (CAM) under constant conditions in the light and in air, it has been disputed whether the underlying oscillator is enzymic or biophysical. The hypothesis of a biophysical hysteresis switch or beat oscillator started from osmotic considerations of malate accumulation and remobilisation, indicating a tonoplast tension/relaxation mechanism. It then advanced to application of non-linear dynamics theory for the analysis of rhythmic and arrhythmic time series of CO2 exchange under the regime of external control parameters, mainly temperature, and the implementation of models for computer simulations of CAM rhythms. This provided strong evidence for the tonoplast functioning as a master switch for circadian regulation of CAM. Conversely, the hypothesis of an enzymic beat oscillator strongly developed on the experimental basis of phosphorylation/dephosphorylation of phosphoenolpyruvate carboxylase (PEPC) regulating the enzyme activity, and hence CO2 fixation and malate synthesis via this enzyme. It was much supported by the discovery that PEPC-kinase gene-transcription was under circadian control. However, biochemical and molecular analysis, as well as model simulation, strongly suggests that this is a secondary and not the primary oscillator. The synchronisation/desynchronisation of leaf patches has revealed spatiotemporal characteristics of circadian rhythmicity that may open new ways for understanding biological clocks.

Circadian Rhythm↗
PubMed2002

Immunoreactive substance P is not part of the retinohypothalamic tract in the rat.

The retinohypothalamic tract (RHT) is a monosynaptic retinofugal pathway mediating information concerning the light/dark cycle from the retina to the brain's biological clock located in the suprachiasmatic nucleus (SCN). Light information, which daily adjusts (entrains) the rhythms of behaviour and physiology generated by the SCN, is mediated by two neurotransmitters, viz. glutamate and pituitary adenylate cyclase activating polypeptide (PACAP), co-stored in the RHT. Substance P (SP) modulates photic- and glutamate-induced phase shifts but data on its possible presence in the RHT are conflicting. By labelling the RHT projection in the SCN with the anterograde tracer cholera toxin subunit B (ChB) and antibodies against PACAP, we have shown that SP immunoreaction is absent from the PACAP/ChB-labelled nerve fibres in the SCN, indicating that the SP-immunoreactive nerve fibres are not part of the RHT but may originate from SP-immunoreactive cell bodies located within the SCN. In the retina, SP immunoreactivity occurs in amacrine cells in the inner nuclear cell layer, in a few displaced amacrine cells in the ganglion cell layer and in a dense plexus of SP-immunoreactive nerve terminals of the inner plexiform layer. Double immunostaining has revealed that SP-immunoreactive cells and fibres in the retina are not identical with the PACAP-immunoreactive ganglion cells that constitute the RHT. These findings together with the demonstration that bilateral eye enucleation does not decrease the number of SP-immunoreactive nerve fibres in the SCN indicate that SP is not a neurotransmitter in the RHT but could be an intrinsic neurotransmitter of the SCN modulating photic input to the clock.

Animals↗
PubMed2002

Signaling in the suprachiasmatic nucleus: selectively responsive and integrative.

The suprachiasmatic nucleus (SCN) contains a biological clock that generates timing signals that drive daily rhythms in behaviors and homeostatic functions. In addition to this pacemaker function, the SCN gates its own sensitivity to incoming signals, which permits appropriate temporal adjustment to achieve synchrony with environmental and organismic states. A series of time-domains, in which the SCN restricts its own sensitivity to a limited set of stimuli that adjust clock phase, can be distinguished. Pituitary adenylyl cyclase-activating peptide (PACAP) and cAMP directly reset clock phase during the daytime domain; both cause phase advances only during the clock's day-time domain, but are without effect at night. In contrast, acetylcholine and cGMP analogs phase advance the clock only when applied during the night. Sensitivity to light and glutamate arises concomitant with sensitivity to acetylcholine and cGMP. Light and glutamate cause phase delays in the early night, by elevating intracellular Ca(2+) via neuronal ryanodine receptors. In late night, light and glutamate utilize a cGMP-mediated mechanism to induce phase advances. Nocturnal responses of SCN primed by light or glutamate can be modulated by effectors of phase-resetting in daytime, namely, PACAP and cAMP. Finally, the dusk and dawn domains are characterized by sensitivity to the pineal hormone, melatonin, acting through protein kinase C. These changing patterns of sensitivities demonstrate that the circadian clock controls multiple intracellular gates, which ensures that they can be opened selectively only at specific points in the circadian cycle. Discerning the molecular bases of these changes is fundamental to understanding integrative and regulatory mechanisms in the circadian system.

Animals↗
PubMed2004

Trigeminal autonomic cephalalgias: from pathophysiology to clinical aspects.

The strictly unilateral headaches, more commonly known as trigeminal autonomic cephalalgias (TACs), are characterised by severe, strictly unilateral pain in the territory of the distribution of the trigeminal nerve, associated with autonomic manifestations. The recent International Headache Society classification lists the strictly unilateral headaches as cluster headache (CH), episodic and chronic paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. CH is the most common and best-defined of the TACs, whose pathophysiologies have not been adequately defined. Convincing proposals for pathophysiologic mechanisms must explain the trigeminal distribution of the pain, the homolateral autonomic manifestations; and, for CH, the usually periodic recurrence of the crises and clusters. With regard to CH, (i) the pain is always located periorbitally-frontally, implicating nociceptive mechanisms involving the trigeminal nerve; (ii) the autonomic manifestations homolateral to the pain seem to be both parasympathetic (lacrimation and rhinorrhoea) and sympathetic (ptosis and miosis); and (iii) the periodicity of the attacks and seasonal recurrence of the cluster periods suggest involvement of a biological clock within hypothalamus.

Autonomic Nervous System Diseases↗
PubMed2005

Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach.

Central pattern generators (CPGs) are genetically determined neuronal aggregates in the mesencephalon, pons and spinal cord subserving innate motor behaviours essential for survival (feeding, locomotion, reproduction etc.). In higher primates CPGs are largely under neocortical control. We describe how certain motor events observed in parasomnias and epileptic seizures could have similar features and resemble motor behaviours, which can be the expression of the same CPG. Both epilepsy and sleep can lead to a temporary loss of control of neomammalian cortex that facilitates through a common platform (arousal) the emergences of stereotyped inborn fixed action patterns. Therefore we suggest that, independently from the nature of the trigger, be it a seizure or a parasomnia, the same CPGs can be involved, "caught up", leading to a common motor semiology (the "Carillon theory").

Adult↗
PubMed2005

Dynamical heterogeneity of suprachiasmatic nucleus neurons based on regularity and determinism.

The suprachiasmatic nucleus (SCN) is known to be the master biological clock in mammals. Despite the periodic mean firing rate, interspike interval (ISI) patterns of SCN neurons are quite complex and irregular. The aim of the present study was to investigate the existence of nonlinear determinism in the complex ISI patterns of SCN neurons. ISI sequences were recorded from 173 neurons in rat hypothalamic slice preparations using a cell-attached patch recording technique. Their correlation dimensions (D2) were estimated, and were then compared with those of the randomly-shuffled surrogate data. We found that only 16 neurons (16/173) exhibited deterministic ISI patterns of spikes. In addition, clustering analysis revealed that SCN neurons could be divided into two subgroups of neurons each having distinct values of coefficient of variation (CV) and skewness (SK). Interestingly, most deterministic SCN neurons (14/16) belonged to the group of irregularly spiking neurons having large CV and SK values. To see if the neuronal coupling mediated by the gamma-aminobutyric acid (GABA), the major neurotransmitter in the SCN, contributed to the deterministic nature, we examined the effect of the GABAA receptor antagonist bicuculline on D2 values of 56 SCN neurons. 8 SCN neurons which were originally stochastic became to exhibit deterministic characteristics after the bicuculline application. This result suggests that the deterministic nature of the SCN neurons arises not from GABAergic synaptic interactions, but likely from properties inherent to neurons themselves.

Action Potentials↗
PubMed2005

Fractal stochastic modeling of spiking activity in suprachiasmatic nucleus neurons.

Individual neurons in the suprachiasmatic nucleus (SCN), the master biological clock in mammals, autonomously produce highly complex patterns of spikes. We have shown that most (approximately 90%) SCN neurons exhibit truly stochastic interspike interval (ISI) patterns. The aim of this study was to understand the stochastic nature of the firing patterns in SCN neurons by analyzing the ISI sequences of 150 SCN neurons in hypothalamic slices. Fractal analysis, using the periodogram, Fano factor, and Allan factor, revealed the presence of a 1/f-type power-law (fractal) behavior in the ISI sequences. This fractal nature was persistent after the application of the GABAA receptor antagonist bicuculline, suggesting that the fractal stochastic activity is an intrinsic property of individual SCN neurons. Based on these physiological findings, we developed a computational model for the stochastic SCN neurons to find that their stochastic spiking activity was best described by a gamma point process whose mean firing rate was modulated by a fractal binomial noise. Taken together, we suggest that SCN neurons generate temporal spiking patterns using the fractal stochastic point process.

Action Potentials↗
PubMed1986

Osler's maneuver, pseudohypertension, and true hypertension in the elderly.

Up to half of the geriatric population has been reported to have arterial hypertension and, therefore, an augmented risk of heart attack, stroke, congestive heart failure, and sudden death. Recent studies indicate that mechanisms serving to elevate arterial pressure in the elderly diametrically differ from those in younger patients with similar elevation of arterial pressure. Elderly hypertensive patients have a low cardiac output, elevated vascular resistance, impaired tissue flow, and increased arterial stiffness. Arterial stiffness, if marked, can give rise to pseudohypertension--an entity often responsible for inappropriate diagnosis and inappropriate therapy in the geriatric population. Pseudohypertension can be suspected from a simple bedside maneuver that was hinted at by Sir William Osler almost a century ago. Arterial hypertension seems to accelerate the physiologic process of aging in the cardiovascular system and threatens, therefore, to set the biologic clock at a faster pace. Hopefully, antihypertensive agents more closely tailored to underlying mechanisms of pressure elevation will reverse hypertensive damage to target organs and thereby reset the aging process of the cardiovascular system at a slower pace.

Adult↗