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Biological timing (including circadian and interval timing) has mainly focused on rigorously controlled laboratory experiments. There are relatively few studies looking into interval timing behaviors in the wild, which could be understandable due to the complexity of the experimental design but are definitely needed in order to comprehend the adaptive value of such behavior. In this opinion paper we review some of the literature regarding timing observations under field conditions, including reports from birds and mammals, and propose a call-to-action to think about the need of a more naturalistic interpretation of time production and perception, as well as the advantage of designing more ‘natural’ settings in the laboratory.

A robust adaptation to environmental changes is vital for survival. Almost all living organisms have a circadian timing system that allows adjusting their physiology to cyclic variations in the surrounding environment. Among vertebrates, many birds are also seasonal species, adapting their physiology to annual changes in photoperiod (amplitude, length and duration). Tawny Owls (Strix aluco) are nocturnal birds of prey that use vocalization as their principal mechanism of communication. Diurnal and seasonal changes in vocalization have been described for several vocal species, including songbirds. Comparable studies are lacking for owls. In the present work, we show that male Tawny Owls present a periodic vocalization pattern in the seconds-to-minutes range that is subject to both daily (early vs. late night) and seasonal (spring vs. summer) rhythmicity. These novel theory-generating findings appear to extend the role of the circadian system in regulating temporal events in the seconds-to-minutes range to other species.

Objectives Precise temporal performance is crucial for several complex tasks. 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. Patients with Huntington's disease (HD) present deficits in cognitive and motor functions that require fine control of temporal processing. The objective of the present work was to assess temporal cognition through a peak-interval time (PI) production task in patients with HD and its potential correlation with the Unified Huntington's Disease Rating Scale (UHDRS). Materials and methods Patients with molecular diagnosis of HD and controls matched by age, sex and educational level (n=18/group) were tested for interval timing in short- (3 seconds), medium- (6 seconds) and long (12 seconds)-duration stimuli. Results Significant differences were observed in the PI task, with worse performance in HD compared to controls. Patients underestimated real time (left-shifted Peak location) for 6- and 12-second intervals (P

Most living organisms have a circadian timing system adapted to optimize the daily rhythm of exposure to the environment. This circadian system modulates several behavioral and physiological processes, including the response to natural and drug rewards. Food is the most potent natural reward across species. Food-seeking is known to be mediated by dopaminergic and serotonergic transmission in cortico-limbic pathways. In the present work, we show evidence of a circadian modulation of motivation for food reward in young (4-months old) and aged (over 1.5 years old) C57BL/6 mice. Motivation was assayed through the progressive ratio (PR) schedule. Mice under a 12:12 light/dark (LD) cycle exhibited a diurnal rhythm in motivation, becoming more motivated during the night, coincident with their active phase. This rhythm was also evident under constant dark conditions, indicating the endogenous nature of this modulation. However, circadian arrhythmicity induced by chronic exposure to constant light conditions impaired the performance in the task causing low motivation levels. Furthermore, the day/night difference in motivation was also evident even without caloric restriction when using a palatable reward. All these results were found to be unaffected by aging. Taken together, our results indicate that motivation for food reward is regulated in a circadian manner, independent of the nutritional status and the nature of the reward, and that this rhythmic modulation is not affected by aging. These results may contribute to improve treatment related to psychiatric disorders or drugs of abuse, taking into account potential mechanisms of circadian modulation of motivational states. Fil: Acosta, Julieta. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bussi, Ivana Leda. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. University of Washington; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Esquivel, Macarena. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina Fil: Golombek, Diego Andrés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Agostino, Patricia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Fil: Tortello, Camila. Universidad Nacional de Quilmes. Laboratorio de Cronobiología; Argentina Fil: Tortello, Camila. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Tortello, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Agostino, Patricia V. Universidad Nacional de Quilmes. Laboratorio de Cronobiología; Argentina Fil: Agostino, Patricia V. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Agostino, Patricia V. Armada Argentina. Hospital Militar Central. Departamento de Neurología; Argentina Fil: Barbarito, Marta. Instituto Antártico Argentino; Argentina Fil: Cuiuli, Juan M. Comando Conjunto Antártico Argentino; Argentina Fil: Coll, Matías. Comando Conjunto Antártico Argentino; Argentina Fil: Golombek, Diego A. Universidad Nacional de Quilmes. Laboratorio de Cronobiología; Argentina Fil: Golombek, Diego A. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Plano, Santiago Andrés. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Plano, Santiago Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Plano, Santiago Andrés. Universidad Nacional de Quilmes. Laboratorio de Cronobiología; Argentina Fil: Vigo, Daniel Eduardo. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Vigo, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Vigo, Daniel Eduardo. Katholieke Universiteit Leuven. Faculty of Psychology and Educational Sciences; Bélgica Abstract: Time estimation is a major cognitive ability that allows humans and other animals to optimize behavioral functions. These activities require the skill to measure the elapsed time in several intervals [12], and involve multiple cognitive processes like attention, memory and decision making [47]. To assess this phenomenon, the most used procedure is interval timing [20, 25, 29, 43] which studies how a time interval is perceived, represented and estimated in a range of seconds to minutes [12]. Several studies have centered their attention on variables that can modulate time perception, such as emotion-related arousal [18, 49] and attention [46]. Other time scales of biological timing, like circadian or seasonal cycles, have also been proposed to influence interval timing [3, 21, 24]. Indeed, recent research have demonstrated the effects of the circadian clock on short-time estimation [1, 13]. Both the circadian oscillator and the sleep homeostat [11] appear to influence the rate at which the pacemaker emits pulses, evidenced in overproductions [48] . The accuracy of timing performances can also be influenced by environmental variables [22]. In this respect, the extreme photoperiod of Antarctica, with up to four months of complete darkness (polar night) is an ideal experimental setting to determine the impact of different zeitgebers on circadian human rhythms. Influences of mood state and fatigue on time production task have also been reported [23]. Both variables, together with negative affect and hostility, constitute some of the prevalent psychological symptoms during polar expeditions [8, 38]. The impact of this context on cognitive processes is variable, with reports of no changes [19, 55], increases [9] or decreases in performance [39, 42]. Thus, circadian rhythms and emotional processes have a key relevance in the cognitive functions involved in time estimation. These factors are affected by extreme photoperiodicity, isolation and confinement conditions found in Antarctica. However, there is no evidence about how time estimation unfolds in this context. Therefore, the aim of this study was to assess interval timing in a crew overwintering in Antarctica. Our hypothesis is that polar night and isolation affect the cognitive processes required to estimate time during an overwintering mission in Antarctica. Accordingly, we expect to find less accurate performances and longer intervals due to the lack of natural light exposure and to emotional variations associated with prolonged isolation and confinement.

Temporal processing in the seconds-to-minutes range, known as interval timing, is a crucial cognitive function that requires activation of cortico-striatal circuits via dopaminergic–glutamatergic pathways. In humans, both children and adults with autism spectrum disorders (ASD) present alterations in their estimation of time intervals. At present, there are no records of interval timing studies in animal models of ASD. Hence, the objective of the present work was to evaluate interval timing in a mouse model of prenatal exposure to valproic acid (VPA) – a treatment used to induce human-like autistic features in rodent models. Animals were assessed for their ability to acquire timing responses in 15-s and 45-s peak-interval (PI) procedures. Our results indicate that both female and male mice prenatally exposed to VPA present decreased timing accuracy and precision compared to control groups, as well as deviations from the scalar property. Moreover, the observed timing deficits in male VPA mice were reversed after early social enrichment. Furthermore, catecholamine determination by HPLC-ED indicated significant differences in striatal dopaminergic, but not serotonergic, content in female and male VPA mice, consistent with previously identified alterations in dopamine metabolism in ASD. These deficits in temporal processing in a mouse model of autism complement previous results in humans, and provide a useful tool for further behavioral and pharmacological studies. Fil: Acosta, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina Fil: Campolongo, Marcos Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina Fil: Depino, Amaicha Mara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Golombek, Diego Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina Fil: Agostino, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina

Environmental cycles on Earth display different periodicities, including daily, tidal or annual time scales. Virtually all living organisms have developed temporal mechanisms to adapt to such changes in environmental conditions. These biological timing structures – ranging from microsecond to seasonal timing – may have intrinsic properties and even different clock machinery. However, interaction among these temporal systems may have evolutionary advantages, for example, when species are exposed to changing climatic conditions or when they expand their geographical range to different latitudes or altitudes. Here, we present and discuss a model that accounts for the circadian regulation of both ultradian (less than 24-h) and infradian (more than 24-h) cycles, and for the interaction among the three time scales. We show two clear examples of such interaction, between the circadian clock and the seasonal regulation of the hypothalamic-pituitary-thyroid axis, and between the circadian clock and the hypothalamic-nigrostriatal ultradian modulation. This remarkable interplay among the otherwise considered isolated rhythms has been demonstrated to exist in diverse organisms, suggesting an adaptive advantage of multiple scales of biological timing.

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 (15 s) 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 s 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 Fil: Hogl, Birgit. Universidad de Innsbruck; Austria Fil: Agostino, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina Fil: Peralta, Maria Cecilia. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina Fil: Gershanik, Oscar Samuel. Fundación Favaloro; Argentina Fil: Golombek, Diego Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina

Duration discrimination within the seconds-to-minutes range, known as interval timing, involves the interaction of cortico-striatal circuits via dopaminergic-glutamatergic pathways. Besides interval timing, most (if not all) organisms exhibit circadian rhythms in physiological, metabolic and behavioral functions with periods close to 24 h. We have previously reported that both circadian disruption and desynchronization impaired interval timing in mice. In this work we studied the involvement of dopamine (DA) signaling in the interaction between circadian and interval timing. We report that daily injections of levodopa improved timing performance in the peak-interval procedure in C57BL/6 mice with circadian disruptions, suggesting that a daily increase of DA is necessary for an accurate performance in the timing task. Moreover, striatal DA levels measured by reverse-phase high-pressure liquid chromatography indicated a daily rhythm under light/dark conditions. This daily variation was affected by inducing circadian disruption under constant light (LL). We also demonstrated a daily oscillation in tyrosine hydroxylase levels, DA turnover (3,4-dihydroxyphenylacetic acid/DA levels), and both mRNA and protein levels of the circadian component Period2 (Per2) in the striatum and substantia nigra, two brain areas relevant for interval timing. None of these oscillations persisted under LL conditions. We suggest that the lack of DA rhythmicity in the striatum under LL - probably regulated by Per2 - could be responsible for impaired performance in the timing task. Our findings add further support to the notion that circadian and interval timing share some common processes, interacting at the level of the dopaminergic system.

Circadian rhythms are endogenous and need to be continuously entrained (synchronized) with the environment. Entrainment includes both coupling internal oscillators to external periodic changes as well as synchrony between the central clock and peripheral oscillators, which have been shown to exhibit different phases and resynchronization speed. Temporal desynchronization induces diverse physiological alterations that ultimately decrease quality of life and induces pathological situations. Indeed, there is a considerable amount of evidence regarding the deleterious effect of circadian dysfunction on overall health or on disease onset and progression, both in human studies and in animal models. In this review we discuss the general features of circadian entrainment and introduce diverse experimental models of desynchronization. In addition, we focus on metabolic, immune and cognitive alterations under situations of acute or chronic circadian desynchronization, as exemplified by jet-lag and shiftwork schedules. Moreover, such situations might lead to an enhanced susceptibility to diverse cancer types. Possible interventions (including light exposure, scheduled timing for meals and use of chronobiotics) are also discussed. Fil: Golombek, Diego Andrés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Casiraghi, Leandro Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Agostino, Patricia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Paladino, Natalia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Duhart, José Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Plano, Santiago Andrés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Chiesa, Juan José. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Interval timing within the seconds-to-minutes range involves the interaction of the prefrontal cortex and basal ganglia via dopaminergic–glutamatergic pathways. Because the secreted protein brain-derived neurotrophic factor (BDNF) is able to modulate dopamine release as well as glutamatergic activity, we hypothesized that BDNF may be important for these timing mechanisms. Recently, the calcium-responsive transcription factor (CaRF) was identified as an important modulator of BDNF expression in the cerebral cortex. In this study, a strain of Carf knockout mice was evaluated for their ability to acquire the ‘Start’ and ‘Stop’ response thresholds under sequential and simultaneous training conditions, using multiple (15-second and 45-second) or single (30-second) target durations in the peak-interval procedure. Both Carf+/− and Carf−/− mice were impaired in their ability to acquire timed response thresholds relative to Carf+/+ mice. Additionally, control mice given microinjections of BDNF antisense oligodeoxynucleotide to inhibit protein expression in the prefrontal cortex showed timing impairments during acquisition similar to Carf mice. Together, these results suggest that the inhibitory processes required to update response thresholds and exert temporal control of behavior during acquisition may be dependent on CaRF regulation of genes including Bdnf in cortico-striatal circuits.

Existing evidence suggests that interval timing, processing of temporal information in the hundredth of milliseconds-to-minutes range, recruits broad brain regions such as cortico-striatal circuits via dopaminergic-glutamatergic pathways. In this review, we summarize recent findings on the neurobiological basis of interval timing with a special focus on dopaminergic modulations of temporal information. Two properties of interval timing - accuracy and precision - are used to examine recent results from manipulations of dopaminergic signaling and the resulting distortions in temporal processing. Fil: Agostino, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina Fil: Cheng, Ruey-Kuang. Institute Of Molecular And Cellular Biology A*star; Singapur

Temporal perception is fundamental to environmental adaptation in humans and other animals. To deal with timing and time perception, organisms have developed multiple systems that are active over a broad range of order of magnitude, the most important being circadian timing, interval timing and millisecond timing. The circadian pacemaker is located in the suprachiasmatic nuclei (SCN) of the hypothalamus, and is driven by a self-sustaining oscillator with a period close to 24h. Time estimation in the second-to-minutes range--known as interval timing--involves the interaction of the basal ganglia and the prefrontal cortex. In this work we tested the hypothesis that interval timing in mice is sensitive to circadian modulations. Animals were trained following the peak-interval (PI) procedure. Results show significant differences in the estimation of 24-second intervals at different times of day, with a higher accuracy in the group trained at night, which were maintained under constant dark (DD) conditions. Interval timing was also studied in animals under constant light (LL) conditions, which abolish circadian rhythmicity. Mice under LL conditions were unable to acquire temporal control in the peak interval procedure. Moreover, short time estimation in animals subjected to circadian desynchronizations (modeling jet lag-like situations) was also affected. Taken together, our results indicate that short-time estimation is modulated by the circadian clock.

Circadian rhythms rely on the interaction of highly conserved transcription-translation loops. Casein kinase I epsilon (CK1epsilon) post-transcriptionally regulates circadian rhythms by phosphorylating clock genes, and the tau mutation, an arginine to cysteine substitution at residue 128, results in a short circadian period, abnormal entrainment to light cycles, and potentiated resetting responses to light. Each of these effects could be attributed to changes in the regulation of the core molecular circadian loops. We now demonstrate that the mutation results in a heightened sensitivity to light, suggesting that CK1epsilon also regulates the photic entrainment pathway.

Nocturnal light pulses induce phase shifts in circadian rhythms and activate cFos expression in the suprachiasmatic nuclei (SCN). We have studied the role of nitric oxide (NO) in the intercellular communication within the dorsal and ventral portions of the SCN in Syrian hamsters. Administration of the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide blocked photic phase advances in a dose-dependent manner and inhibited light-induced cFos-ir, without affecting light-induced circadian phase delays. These results suggest that NO may act as an intercellular messenger in the SCN, mediating light-induced phase advances.

Mammalian circadian rhythms are generated by a master clock located in the suprachiasmatic nuclei and entrained by light-activated signaling pathways. In hamsters, the mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase, cGMP and its related kinase (PKG). It is not completely known whether interference with this pathway affects entrainment of the clock, including adaptation to changing light schedules. Here we report that cGMP-specific phosphodiesterase 5 is present in the hamster suprachiasmatic nuclei, and administration of the inhibitor sildenafil (3.5 mg/kg, i.p.) enhances circadian responses to light and decreases the amount of time necessary for reentrainment after phase advances of the light–dark cycle. These results suggest that sildenafil may be useful for treatment of circadian adaptation to environmental changes, including transmeridian eastbound flight schedules.

Interval timing is a complex cognitive process that involves the estimation of time within the seconds-to-minutes range. This temporal processing depends on cortico-striatal interactions, as well as an optimal dopaminergic function. On the other hand, the circadian system controls physiological and behavioral functions with periods close to 24 hr. We have previously reported that short-time perception in mice is influenced by the circadian pacemaker, with dopamine signaling as a link between both temporal systems. In this work we evaluated the involvement of melatonin in the circadian modulation of interval timing, as well as the interaction between this hormone and dopamine levels in the striatum. We report that melatonin-depleted rats, by pinealectomy, present an impairment in their ability to estimate a short (24 s) target duration in the peak-interval procedure. Moreover, melatonin administration in drinking water restores interval timing precision in pinealectomized rats. We also show that circadian desynchronization causes a transient impairment in the timing task. In addition, melatonin administration affects interval timing only when rats are trained and tested during the night. Furthermore, we report that melatonin depletion increases striatal dopamine availability, which is reverted by external melatonin administration. Taken together, our findings add further support to the notion that the circadian system modulates interval timing, probably by using melatonin as an output to regulate dopaminergic functions in brain areas that are important for interval timing mechanisms.

Mammalian circadian rhythms are generated by a hypothalamic suprachiasmatic nuclei (SCN) clock. Light pulses synchronize body rhythms by inducing phase delays during the early night and phase advances during the late night. Phosphorylation events are known to be involved in circadian phase shifting, both for delays and advances. Pharmacological inhibition of the cGMP-dependent kinase (cGK) or Ca2+/calmodulin-dependent kinase (CaMK), or of neuronal nitric oxide synthase (nNOS) blocks the circadian responses to light in vivo. Light pulses administered during the subjective night, but not during the day, induce rapid phosphorylation of both p-CAMKII and p-nNOS (specifically phosphorylated by CaMKII). CaMKII inhibitors block light-induced nNOS activity and phosphorylation, suggesting a direct pathway between both enzymes. Furthermore, SCN cGMP exhibits diurnal and circadian rhythms with maximal values during the day or subjective day. This variation of cGMP levels appears to be related to temporal changes in phosphodiesterase (PDE) activity and not to guanylyl cyclase (GC) activity. Light pulses increase SCN cGMP levels at circadian time (CT) 18 (when light causes phase advances of rhythms) but not at CT 14 (the time for light-induced phase delays). cGK II is expressed in the hamster SCN and also exhibits circadian changes in its levels, peaking during the day. Light pulses increase cGK activity at CT 18 but not at CT 14. In addition, cGK and GC inhibition by KT-5823 and ODQ significantly attenuated light-induced phase shifts at CT 18. This inhibition did not change c-Fos expression SCN but affected the expression of the clock gene per in the SCN. These results suggest a signal transduction pathway responsible for light-induced phase advances of the circadian clock which could be summarized as follows: Glu-Ca2+-CaMKII-nNOS-GC-cGMP-cGK-->-->clock genes. This pathway offers a signaling window that allows peering into the circadian clock machinery in order to decipher its temporal cogs and wheels.

Circadian rhythms of physiology and behavior are generated by biological clocks that are synchronized to the cyclic environment by photic or nonphotic cues. The interactions and integration of various entrainment pathways to the clock are poorly understood. Here, we show that the Ras-like G protein Dexras1 is a critical modulator of the responsiveness of the master clock to photic and nonphotic inputs. Genetic deletion of Dexras1 reduces photic entrainment by eliminating a pertussis-sensitive circadian response to NMDA. Mechanistically, Dexras1 couples NMDA and light input to Gi/o and ERK activation. In addition, the mutation greatly potentiates nonphotic responses to neuropeptide Y and unmasks a nonphotic response to arousal. Thus, Dexras1 modulates the responses of the master clock to photic and nonphotic stimuli in opposite directions. These results identify a signaling molecule that serves as a differential modulator of the gated photic and nonphotic input pathways to the circadian timekeeping system.

Mammalian circadian rhythms are generated by the hypothalamic suprachiasmatic nuclei and finely tuned to environmental periodicities by neurochemical responses to the light-dark cycle. Light reaches the clock through a direct retinohypothalamic tract, primarily through glutamatergic innervation, and its action is probably regulated by a variety of other neurotransmitters. A key second messenger in circadian photic entrainment is calcium, mobilized through membrane channels or intracellular reservoirs, which triggers the activation of several enzymes, including a calcium/calmodulin-dependent protein kinase and nitric oxide synthase. Other enzymes activated by light are mitogen-activated- and cGMP-dependent protein kinase; all of the above have been reported to be involved in the circadian responses to nocturnal light pulses. These mechanisms lead to expression of specific clock genes which eventually set the phase of the clock and of clock-controlled circadian rhythms.

The activities of several proteases in the hamster suprachiasmatic nuclei were measured at different time points throughout the daily or circadian cycle. No variation for metalloproteinase A (MMP-2) activity was found, while metalloproteinase B (MMP-9) was rhythmic and maximally active during the night. In addition, diurnal variations for two low molecular weight proteases were determined, with peaks during the light phase. This rhythmicity appears to be under exogenous control, since constant darkness abolished fluctuations throughout the circadian cycle. These results suggest that protein degradation in the hamster circadian clock is regulated in a diurnal fashion.

The circadian system controls the daily rhythms of a variety of physiological processes. Most organisms show physiological, metabolic and behavioral rhythms that are coupled to environmental signals. In humans, the main synchronizer is the light/dark cycle, although non-photic cues such as food availability, noise, and work schedules are also involved. In a continuously operating hospital, the lack of rhythmicity in these elements can alter the patient’s biological rhythms and resilience. This paper presents a Theory of Inpatient Circadian Care (TICC) grounded in circadian principles. We conducted a literature search on biological rhythms, chronobiology, nursing care, and middle-range theories in the databases PubMed, SciELO Public Health, and Google Scholar. The search was performed considering a period of 6 decades from 1950 to 2013. Information was analyzed to look for links between chronobiology concepts and characteristics of inpatient care. TICC aims to integrate multidisciplinary knowledge of biomedical sciences and apply it to clinical practice in a formal way. The conceptual points of this theory are supported by abundant literature related to disease and altered biological rhythms. Our theory will be able to enrich current and future professional practice. Fil: Camargo Sanchez, Andrés. Universidad de Ciencias Aplicadas y Ambientales; Colombia Fil: Niño, Carmen L.. Universidad de Ciencias Aplicadas y Ambientales; Colombia Fil: Sánchez, Leonardo. Universidad de Ciencias Aplicadas y Ambientales; Colombia Fil: Echeverri, Sonia. Fundacion Santa Fe de Bogota; Colombia Fil: Gutiérrez, Diana P.. Fundacion Santa Fe de Bogota; Colombia Fil: Duque, Andrés F.. Marly Clinic; Colombia Fil: Pianeta, Oscar. Universidad de Ciencias Aplicadas y Ambientales; Colombia Fil: Jaramillo Gómez, Jenny A.. Universidad Nacional de Colombia; Colombia Fil: Pilonieta, Martin A.. Universidad Nacional de Colombia; Colombia Fil: Cataño, Nhora. Universidad Nacional de Colombia; Colombia Fil: Arboleda, Humberto. Universidad Nacional de Colombia; Colombia Fil: Agostino, Patricia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Alvarez Baron, Claudia P.. University of Wisconsin; Estados Unidos Fil: Vargas, Rafael. Pontificia Universidad Javeriana; Colombia

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 a common neurochemical substrate for timing mechanisms in the brain has been related to dopamine-reward systems, circadian modulation of interval timing suggests an interaction of different frequencies in cerebral temporal processes.

Publisher Summary Both cAMP and cGMP mediate a wide range of physiological functions, such as regulation of specific cAMP or cGMP phosphodiesterases, protein kinases, ion channels, and several neuronal signal transduction mechanisms. Regulation of CN synthesis and degradation appears to be different in various brain regions, and is modified by several physiological and pathological conditions. cAMP is widely distributed in the CNS. The localization of adenylyl cyclase (AC), the enzyme that produces cAMP, has been studied in the rat brain. The cAMP/PKA signaling pathway has a crucial role in learning in animals as diverse as Aplysia , Drosophila , and mammals, and is involved in activity-dependent forms of synaptic plasticity, such as long-term potentiation (LTP). This pathway culminates in the phosphorylation and activation of critical transcription factors. Cyclic AMP-responsive element-binding protein (CREB) is perhaps the best characterized stimulus-induced transcription factor. It is well established that NO/cGMP/PKG plays a role in long-term depression. The family of cyclic nucleotide-regulated channels comprises two groups: the cyclic nucleotide-gated (CNG) channels, and the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. CNG cation channels are ion channels whose activation is mediated by the direct binding of cGMP or cAMP to the channel protein. In mammals, the mechanism for the generation and entrainment of circadian rhythms resides in the hypothalamic suprachiasmatic nuclei (SCN), and the principal signal that adjusts this biological clock with environmental timing is the light–dark cycle. In conclusion, there are a great number of physiological pathways in which cAMP and cGMP are involved in the central nervous system.

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.

Entrainment of mammalian circadian rhythms requires the activation of specific signal transduction pathways in the hypothalamic suprachiasmatic nuclei (SCN). We have tested the participation of heme oxygenase (HO) in the SCN, by assessing HO specific activity at different time points and photic conditions. HO activity was determined by the conversion of hemin to bilirubin. HO enzymatic activity in the SCN was significantly higher during the night than during the day; this difference persisted when animals were placed under constant darkness, suggesting an endogenous circadian control. HO inhibition by Zn-protoporphyrin did not affect light-induced phase shifts in vivo, suggesting that the enzyme is not necessary for light input to the clock.

Mammalian circadian rhythms are entrained by light pulses that induce phosphorylation events in the suprachiasmatic nuclei (SCN). Ca(2+)-dependent enzymes are known to be involved in circadian phase shifting. In this paper, we show that calcium/calmodulin-dependent kinase II (CaMKII) is rhythmically phosphorylated in the SCN both under entrained and free-running (constant dark) conditions while neuronal nitric oxide synthase (nNOS) is rhythmically phosphorylated in the SCN only under entrained conditions. Both p-CaMKII and p-NOS (specifically phosphorylated by CaMKII) levels peak during the day or subjective day. Light pulses administered during the subjective night, but not during the day, induced rapid phosphorylation of both enzymes. Moreover, we found an inhibitory effect of KN-62 and KN-93, both CaMKII inhibitors, on light-induced nNOS activity and nNOS phosphorylation respectively, suggesting a direct pathway between both enzymes which is at least partially responsible of photic circadian entrainment.

Biological clocks are genetically encoded oscillators that allow organisms to keep track of their environment. Among them, the circadian system is a highly conserved timing structure that regulates several physiological, metabolic and behavioural functions with periods close to 24 h. Time is also crucial for everyday activities that involve conscious time estimation. Timing behaviour in the second-to-minutes range, known as interval timing, involves the interaction of cortico-striatal circuits. In this review, we summarize current findings on the neurobiological basis of the circadian system, both at the genetic and behavioural level, and also focus on its interactions with interval timing and seasonal rhythms, in order to construct a multi-level biological clock. Fil: Golombek, Diego Andrés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bussi, Ivana Leda. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Agostino, Patricia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Whether and how music is involved in evoking emotions is a matter of considerable debate. In the target article, Juslin & Västfjäll (J&V) argue that music induces a wide range of both basic and complex emotions that are shared with other stimuli. If such a link exists, it would provide a common basis for considering the interactions among music, emotion, timing, and time perception.

The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil) also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions.