Temporal changes in the level of expression of γ-aminobutyric acid (GABA)A receptor subunits α2, α5, β1 and β3 were characterized by Western blot analysis in the hamster suprachiasmatic nuclei, retina and median eminence. A nocturnal... more
Temporal changes in the level of expression of γ-aminobutyric acid (GABA)A receptor subunits α2, α5, β1 and β3 were characterized by Western blot analysis in the hamster suprachiasmatic nuclei, retina and median eminence. A nocturnal maximum in the level of GABAA receptor β1 subunit at midday and midnight (12:00 and 00.00 h) was found in the suprachiasmatic nucleus (SCN), the retina and the median eminence of Syrian hamsters. α2 and β3 subunit levels peaked during the day in the median eminence. Finally, retinal α5 levels were maximal during the night. β1 temporal changes in the SCN and median eminence, as well as α2 variations in the median eminence were maintained under constant dark conditions, suggesting an endogenous control, while the other variations were only observed under light–dark cycle conditions.
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The neuropeptide PDF (Pigment Dispersing Factor) is important for the generation and entrainment of circadian rhythms in the fruitfly Drosophila melanogaster. Recently two pdf homologs, pdf-1 and pdf-2, and a PDF receptor, pdfr-1, have... more
The neuropeptide PDF (Pigment Dispersing Factor) is important for the generation and entrainment of circadian rhythms in the fruitfly Drosophila melanogaster. Recently two pdf homologs, pdf-1 and pdf-2, and a PDF receptor, pdfr-1, have been found in Caenorhabditis elegans and have been implicated in locomotor activity. In this work we have studied the role of the PDF neuropeptide in the circadian system of C. elegans and found that both pdf-1 and pdf-2 mutants affect the normal locomotor activity outputs. In particular, loss of pdf-1 induced circadian arrhythmicity under both light-dark (LD) and constant dark (DD) conditions. These defects can be rescued by a genomic copy of the pdf-1 locus. Our results indicate that PDF-1 is involved in rhythm generation and in the synchronization to LD cycles, since rhythmic patterns of activity rapidly disappear when pdf-1 mutants are recorded under both entrained and free running conditions. The role of PDF-2 and the PDF receptors is probably more complex and involves the interaction between the two pdf paralogues found in the nematode.
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Research Interests: Neuroscience, Enzyme Inhibitors, Ion Channels, Signal Transduction, Glutamate, and 20 moreCircadian Rhythm, Glutamate receptors, Animals, Male, Calcium Channel, Alkaloids, Signal Transduction Pathway Models, Nickel, Neuropeptide Y, Sodium channel, Tetrodotoxin, Cell communication, Action Potentials, Circadian Clock, Suprachiasmatic Nucleus, Bicuculline, Phase Shift, Maleimides, Calcium Channel Blockers, and Glutamate Receptor
ABSTRACT Precise spatiotemporal performance is required by many common tasks and represents a basic aspect of cognition. Time estimation in the second-to-minutes range–known as interval timing–involves the interaction of the basal ganglia... more
ABSTRACT Precise spatiotemporal performance is required by many common tasks and represents a basic aspect of cognition. Time estimation in the second-to-minutes range–known as interval timing–involves the interaction of the basal ganglia and the prefrontal cortex via dopaminergic-glutamatergic pathways. Neurodegenerative disorders such as Parkinson's disease (PD) and Multiple system atrophy (MSA) are characterized by basal ganglia dysfunction due to dopamine loss. Although interval timing in PD has been studied, little is known about temporal processing in MSA. In the present work, control, PD and MSA subjects (n = 8 for each group) were tested for interval timing in short (<5 seconds), medium (5-15 seconds) and long (>15 seconds) duration stimuli. MSA differed significantly from controls and PD patients in terms of decreased accuracy in the timing task. Differences between PD and MSA patients (as well as between MSA and controls) were lost after levodopa treatment. We show that time estimation for time bins between 5 and 20 seconds is affected in subjects with MSA, who had a significant tendency to underestimate time intervals as compared to controls or PD patients. Recordings of cognitive performance related to timing could be considered useful measurements of the progression of movement disorder-related pathologies.
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We endeavored to determine whether three behavioral effects of melatonin in rodents, i.e., depression of locomotor activity in hamsters, analgesia in mice, and impairment of 3-mercaptopropionic acid (3-MP) convulsions, exhibited the time... more
We endeavored to determine whether three behavioral effects of melatonin in rodents, i.e., depression of locomotor activity in hamsters, analgesia in mice, and impairment of 3-mercaptopropionic acid (3-MP) convulsions, exhibited the time dependency known to occur for several neuroendocrine effects of the hormone. Activity was monitored and registered by means of an optical actometer, and analgesia was assessed by the hot-plate procedure. Locomotor activity, analgesia, and seizure susceptibility were maximal at the beginning of the scotophase and minimal at noon. The effects of melatonin on the three parameters peaked at early night. The administration of the benzodiazepine antagonist flumazenil, although unable by itself to modify locomotor activity, pain, or seizure threshold, blunted the activity of melatonin. These results suggest that the time-dependent effects of melatonin on specific rodent behaviors may be mediated by central synapses employing gamma-aminobutyric acid (GABA) as an inhibitory transmitter.
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The endogenous circadian pacemaker in mammals is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Various cues can reset circadian rhythm phase, thereby entraining the internal rhythm to the environmental cycle, and these... more
The endogenous circadian pacemaker in mammals is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Various cues can reset circadian rhythm phase, thereby entraining the internal rhythm to the environmental cycle, and these effects can be investigated using an in vitro method to measure phase shifts of the SCN. Although pituitary adenylate cyclase activat- ing peptide (PACAP) is localized
This study was performed to examine the circadian variations in body temperature and locomotor activity in two rat models of liver damage and portal-systemic col- lateralization, it is, cirrhosis by common bile duct ligature and ...
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KN-62, an inhibitor of CaM kinase II, attenuated phase shifts induced by low intensity light pulses and reduced light-induced phosphorylation of the transcription factor, CREB, in the suprachiasmatic nucleus. The calmodulin inhibitor,... more
KN-62, an inhibitor of CaM kinase II, attenuated phase shifts induced by low intensity light pulses and reduced light-induced phosphorylation of the transcription factor, CREB, in the suprachiasmatic nucleus. The calmodulin inhibitor, W-7, had similar effects: neither drug produced a complete block of photic responses. The results support the hypothesis that circadian responses to light are mediated in part by CaM kinase activity and CREB, and suggest that other signal transduction pathways also take part.
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In mammals, the mechanism for the generation of circadian rhythms and entrainment by light-dark (LD) cycles resides in the hypothalamic suprachiasmatic nuclei (SCN), and the principal signal that adjusts this biological clock with... more
In mammals, the mechanism for the generation of circadian rhythms and entrainment by light-dark (LD) cycles resides in the hypothalamic suprachiasmatic nuclei (SCN), and the principal signal that adjusts this biological clock with environmental timing is the light:dark cycle. Within the SCN, rhythms are generated by a complex of molecular feedback loops that regulate the transcription of clock genes, including per and cry. Posttranslational modification plays an essential role in the regulation of biological rhythms; in particular, clock gene phosphorylation by casein kinase I , both epsilon (CKIepsilon) and delta (CKIdelta), regulates key molecular mechanisms in the circadian clock. In this paper, we report for the first time that CKI activity undergoes a significant circadian rhythm in the SCN (peaking at circadian time 12, the start of the subjective night), and its pharmacological inhibition alters photic entrainment of the clock, indicating that CKI may be a key element in this pathway.
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CONSEJO NACIONAL DE INVESTIGACIONES CIENTIFICAS Y TECNICAS (CONICET) [AR/AR]; Av. Rivadavia 1906 3 "F", -, Buenos Aires, C1033AAJ (AR) (All Except US). UNIVERSIDAD NACIONAL DE QUILMES [AR/AR]; Roque Sáenz Peña 352, Bernal, ...
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The abuse of benzodiazepine (BZP) and Z drugs has become, due to the tolerance and dependence they produce, a serious public health problem. Thirty years ago, we demonstrated in experimental animals the interaction of melatonin with... more
The abuse of benzodiazepine (BZP) and Z drugs has become, due to the tolerance and dependence they produce, a serious public health problem. Thirty years ago, we demonstrated in experimental animals the interaction of melatonin with central BZD receptors, and in 1997 we published the first series of elderly patients who reduced BZP consumption after melatonin treatment. Almost every single neuron in the hypothalamic suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system, contains γ-aminobutyric acid (GABA) and many results in animals point out to a melatonin interaction with GABA-containing neurons. In addition, central-type BZD antagonism, that obliterates GABAA receptor function, blunted most behavioral effects of melatonin including sleep. Melatonin is involved in the regulation of human sleep. This is supported by the temporal relationship between the rise of plasma melatonin levels and sleep propensity as well as by the sleep-promoting effects of exogenousl...
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MAP kinases (MAPKs) play a key role in photic entrainment signaling in the suprachiasmatic nuclei (SCN), the mammalian circadian clock. The control of MAPKs is a fine balance between specific kinases (MEKs) and phosphatases (MKPs), whose... more
MAP kinases (MAPKs) play a key role in photic entrainment signaling in the suprachiasmatic nuclei (SCN), the mammalian circadian clock. The control of MAPKs is a fine balance between specific kinases (MEKs) and phosphatases (MKPs), whose orchestration in the SCN is still unresolved. We have found MKP1/2 and MKP3 immunoreactive-cells in the hamster SCN, whose levels are rapidly increased in response to transient light stimulation in the subjective night (CT 18), when light is able to entrain the clock. Moreover, the expression level of MKP3 varies under light-dark cycles and constant darkness, peaking at noon, when MAPKs are in their activated state and begin their inactivation. These results show a different perspective on MAPKs in the SCN, which includes its regulation by a complex net of phosphatases.
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GABA is the major inhibitory neurotransmitter in the mammalian brain, and has been implicated in the regulation of a variety of behavioral functions, including biological rhythms. The focus of this minireview is the rhythmic variation of... more
GABA is the major inhibitory neurotransmitter in the mammalian brain, and has been implicated in the regulation of a variety of behavioral functions, including biological rhythms. The focus of this minireview is the rhythmic variation of the central GABAergic system, comprising fluctuations of GABA levels and turnover, GABA receptor affinity and postsynaptic activity on the chloride ionophore in rodent's brain. Neurochemical rhythms correlated with diurnal and circadian changes in several behaviors associated with the GABA(A) receptor, e.g., anxiolysis-related behavior. GABA is considered to be the principal neurotransmitter of the mammalian circadian system, being present in the suprachiasmatic nuclei and the intergeniculate leaflet. Pharmacological manipulations of GABA(A) receptors phase shift circadian rhythms and alter circadian responses to light. Administration of putative modulators of GABA function, like melatonin or neuroactive steroids, affects the timing of biologica...
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Mammalian circadian rhythms originate in the hypothalamic suprachiasmatic nuclei (SCN), from which rhythmic neural activity can be recorded in vitro. Application of neurochemicals can reset this rhythm. Here we determine cellular... more
Mammalian circadian rhythms originate in the hypothalamic suprachiasmatic nuclei (SCN), from which rhythmic neural activity can be recorded in vitro. Application of neurochemicals can reset this rhythm. Here we determine cellular correlates of the phase-shifting properties of neuropeptide Y (NPY) on the hamster circadian clock in vitro. Drug or control treatments were applied to hypothalamic slices containing the SCN on the first day in vitro. The firing rates of individual cells were sampled on the second day in vitro. Control slices exhibited a peak in firing rate in the middle of the day. Microdrop application of NPY to the SCN phase advanced the time of peak firing rate. This phase-shifting effect of NPY was not altered by block of sodium channels with tetrodotoxin or block of calcium channels with cadmium and nickel, consistent with a direct postsynaptic site of action. Pretreatment with the glutamate receptor antagonists (DL-2-amino-5-phosphonovaleric acid and 6-cyano-7-nitroq...
Research Interests: Neuroscience, Enzyme Inhibitors, Ion Channels, Signal Transduction, Glutamate, and 20 moreCircadian Rhythm, Glutamate receptors, Animals, Male, Calcium Channel, Alkaloids, Signal Transduction Pathway Models, Nickel, Neuropeptide Y, Sodium channel, Tetrodotoxin, Cell communication, Action Potentials, Circadian Clock, Suprachiasmatic Nucleus, Bicuculline, Phase Shift, Maleimides, Calcium Channel Blockers, and Glutamate Receptor
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Circadian rhythms are entrained by light-activated signal transduction pathways in the biological clock. Among these, circadian and photic control of mouse suprachiasmatic ERK MAP kinase activation has been reported. In this paper we... more
Circadian rhythms are entrained by light-activated signal transduction pathways in the biological clock. Among these, circadian and photic control of mouse suprachiasmatic ERK MAP kinase activation has been reported. In this paper we extend these results to hamsters and to the two other major members of the MAPK family: JNK and p38. The three kinases are rhythmically phosphorylated under light-dark and constant conditions, with maximal values during the day or subjective day. Light pulses during the subjective night induce rapid activation of the three enzymes, suggesting that the three MAP kinases might be implicated in mammalian photic entrainment.
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The orexigenic peptide ghrelin stimulates both food intake and growth hormone release and is synthesized in the stomach and in hypothalamic areas involved in feeding control. The suprachiasmatic nuclei of the hypothalamus (SCN) control... more
The orexigenic peptide ghrelin stimulates both food intake and growth hormone release and is synthesized in the stomach and in hypothalamic areas involved in feeding control. The suprachiasmatic nuclei of the hypothalamus (SCN) control most circadian rhythms, although there is evidence that some oscillators, such as food-entrainable oscillators, can drive activity rhythms even after SCN ablation. Ghrelin levels exhibit a circadian rhythm and closely follow feeding schedules, making this peptide a putative candidate for food-related entraining signals. We examined the response of the SCN to ghrelin treatments in vitro, by means of electrophysiological and bioluminescence recordings, and in vivo, by assessing effects on the phase of locomotor activity rhythms. Ghrelin applied at circadian time 6 in vitro to cultured SCN slices induced an approximately 3 h phase advance. In addition, ghrelin phase advanced the rhythm of PER2::LUC (Period2::Luciferase) expression in cultured SCN explants from mPer2(Luc) transgenic mice. In vivo, intraperitoneal administration of ghrelin or a synthetic analog, growth hormone-releasing protein-6 (GHRP-6), to ad libitum fed animals failed to alter circadian phase. When injected after 30 h of food deprivation, GHRP-6 induced a phase advance compared with saline-injected animals. These results indicate that ghrelin may play a role in the circadian system by exerting a direct action on the SCN and that the system as a whole may become sensitive to ghrelin and other feeding-related neuropeptides under conditions of food restriction.
Research Interests: Neuroscience, Ghrelin, Mice, Circadian Rhythm, Female, and 8 moreAnimals, Male, The, Eating, Rats, Peptide hormones, Suprachiasmatic Nucleus, and Motor activity
Research Interests: Genetics, Caenorhabditis elegans, Drosophila melanogaster, Multidisciplinary, Mutation, and 18 moreMovement, Circadian Rhythm, Animals, Temperature Compensation, Light, Temperature, Animal Model, Genetic Screening, Periodicity, PLoS one, Body Temperature, Biological clock, Infrared, Time Factors, Locomotor Activity, Ease of Use, Biological clocks, and Motor activity
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The aim of the present study was to determine whether melatonin-induced depression of locomotor activity in hamsters is time-dependent and to analyze the inhibitory effects of the central-type benzodiazepine (BZP) antagonist Ro 15-1788 on... more
The aim of the present study was to determine whether melatonin-induced depression of locomotor activity in hamsters is time-dependent and to analyze the inhibitory effects of the central-type benzodiazepine (BZP) antagonist Ro 15-1788 on melatonin-induced depression of locomotor behavior. Activity was monitored and registered by means of an optical actometer. Two phases of locomotor behavior were found. The initial phase, found both at noon and during the evening, exhibited an absence of diurnal variability, while a second long-lasting phase of activity exhibited a peak at early night. The IP injection of melatonin (minimal effective dose: 100 micrograms/kg) inhibited the early phase of activity at 1200 or 2000 h. Inhibition of the late phase of activity was found at 2000 or 0400 h, but not at midnight. When assessed at 2000 h, melatonin depression of the early phase of locomotor activity attained significance after 5 days of injection, while its effect on the late phase of activity attained significance during the second day of injection. The administration of Ro 15-1788, although unable by itself to modify locomotor activity, significantly attenuated the inhibitory effects of melatonin. These results indicate the existence of a time-dependency for melatonin activity on locomotor behavior similar to that known to occur for other effects of the hormone, and further support a link between melatonin and the activity of central type BZP receptors.
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Neural timing mechanisms range from the millisecond to diurnal, and possibly annual, frequencies. Two of the main processes under study are the interval timer (seconds-to-minute range) and the circadian clock. The molecular basis of these... more
Neural timing mechanisms range from the millisecond to diurnal, and possibly annual, frequencies. Two of the main processes under study are the interval timer (seconds-to-minute range) and the circadian clock. The molecular basis of these two mechanisms is the subject of intense research, as well as their possible relationship. This article summarizes data from studies investigating a possible interaction between interval and circadian timing and reviews the molecular basis of both mechanisms, including the discussion of the contribution from studies of genetically modified animal models. While there is currently no common neurochemical substrate for timing mechanisms in the brain, circadian modulation of interval timing suggests an interaction of different frequencies in cerebral temporal processes.
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Circadian rhythms govern a wide variety of physiological and metabolic functions in most organisms through neural networks, hormones and gene expression. In this work, we studied the circadian variation in metabolic variables of adult C.... more
Circadian rhythms govern a wide variety of physiological and metabolic functions in most organisms through neural networks, hormones and gene expression. In this work, we studied the circadian variation in metabolic variables of adult C. elegans such as food consumption, pharyngeal contractions, defecation and oxygen consumption. Feeding behavior was clearly rhythmic under LD conditions, with a non-significant trend under DD conditions. In addition, a daily and circadian variation in muscle contraction of the pharynx was observed. Oxygen consumption also showed a circadian fluctuation with a maximum in the middle of the night (a peak was found around ZT18/CT18). Furthermore, defecation behavior also showed a daily variation in the N2 strain (wild type). This work demonstrates that in the adult nematode C. elegans metabolic variables vary daily. In summary, our results will allow us to take full advantage of this widely used animal model (including research in genetics, ageing and developmental biology) for studies in Chronobiology.
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The effects of Chagas disease on the mammalian circadian system were studied in Trypanosoma cruzi-infected C57-B16J mice. Animals were inoculated with CAI or RA strains of T. cruzi or vehicle, parasitism confirmed by blood specimen... more
The effects of Chagas disease on the mammalian circadian system were studied in Trypanosoma cruzi-infected C57-B16J mice. Animals were inoculated with CAI or RA strains of T. cruzi or vehicle, parasitism confirmed by blood specimen visualization and locomotor activity rhythms analyzed by wheel-running recording. RA-strain infected mice exhibited significantly decreased amplitude of circadian rhythms, both under light-dark and constant dark conditions, probably due to motor deficiencies. CAI-treated animals showed normal locomotor activity rhythms. However, in these mice, reentrainment to a 6h phase shift of the LD cycle took significantly longer than controls, and application of 15min light pulses in DD produced smaller phase delays of the rhythms. All groups exhibited light-induced Fos expression in the suprachiasmatic nuclei. We conclude that the main effect of T. cruzi infection on the circadian system is an impairment of the motor output from the clock toward controlled rhythms, together with an effect on circadian visual sensitivity.