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Entrainment of the Circadian System of Mammals by Nonphotic Cues
Abstract
Although light is the principal zeitgeber to the mammalian circadian system, other cues can be shown to have a potent resetting effect on the clock of both adult and perinatal mammals. Nonphotic entrainment may have both biological and therapeutic significance. This review focuses on the effect of behavioral arousal as a nonphotic cue and the neurochemical circuitry that mediates arousal-induced entrainment in the adult rodent. In addition, it considers the role of nonphotic entrainment of the developing circadian system in perinatal life prior to the establishment of retinal input to the clock.
... Expression of VIP is necessary for maintaining synchrony of the expression of oscillator genes among SCN cells as well as in cells peripheral to the SCN (Aton et al., 2005;Todd et al., 2020). The SCN also receives input from brain regions other than the retina which send signals that can also act as entraining cues, and these timing-related cues are known as zeitgebers (Hastings et al., 1998;Saper, 2013). These zeitgebers drive rhythmic activity in the SCN, and that activity synchronizes the activity in downstream pathways and peripheral tissues, including the olfactory system. ...
... The SCN and OB, hubs of the circadian and olfactory systems, respectively, both display the unique feature of intrinsically-generated rhythmicity of clock genes (Reppert and Weaver, 2002;Granados-Fuentes et al., 2004b). In each case, this rhythmicity is entrained by external cues, and, in turn, the rhythmic signals produced in each area project to downstream regions to provide an entraining signal (Hastings et al., 1998;Granados-Fuentes et al., 2004aNolasco et al., 2012;Saper, 2013). The entraining signals provided by each of these systems have significant implications for behavior, and the rhythms that they provide have been found to be negatively impacted in AD, particularly in the case of the circadian system (Granados-Fuentes et al., 2011;Saper, 2013;Musiek et al., 2018;Takeuchi et al., 2023). ...
Alzheimer’s disease (AD) is the leading cause of dementia, with over 45 million patients worldwide, and poses significant economic and emotional burdens to both patients and caregivers, significantly raising the number of those affected. Unfortunately, much of the existing research on the disease only addresses a small subset of associated symptomologies and pathologies. In this review, we propose to target the earliest stages of the disease, when symptomology first arises. In these stages, before the onset of hallmark symptoms of AD such as cognitive impairments and memory loss, circadian and olfactory disruptions arise and are detectable. Functional similarities between circadian and olfactory systems provide a basis upon which to seek out common mechanisms in AD which may target them early on in the disease. Existing studies of interactions between these systems, while intriguing, leave open the question of the neural substrates underlying them. Potential substrates for such interactions are proposed in this review, such as indirect projections that may functionally connect the two systems and dopaminergic signaling. These substrates may have significant implications for mechanisms underlying disruptions to circadian and olfactory function in early stages of AD. In this review, we propose early detection of AD using a combination of circadian and olfactory deficits and subsequent early treatment of these deficits may provide profound benefits to both patients and caregivers. Additionally, we suggest that targeting research toward the intersection of these two systems in AD could uncover mechanisms underlying the broader set of symptoms and pathologies that currently elude researchers.
... Certain aspects of the potential impact of ketamine on circadian rhythms can also be examined through its effects on energy expenditure and behavior (increase in locomotor activity; see, e.g., Campbell & Feinberg, 1996;Feinberg & Campbell, 1993), both strong non-photic entraining cues for circadian rhythm. Indeed, a common feature of non-photic stimuli is their ability to arouse and increase physical activity (and thereby energy consumption) (Hastings, Duffield, Smith, Maywood, & Ebling, 1998;Mrosovsky, 1996). Notably, the effects of arousal are most pronounced at the end of the inactive phase (Hastings et al., 1998). ...
... Indeed, a common feature of non-photic stimuli is their ability to arouse and increase physical activity (and thereby energy consumption) (Hastings, Duffield, Smith, Maywood, & Ebling, 1998;Mrosovsky, 1996). Notably, the effects of arousal are most pronounced at the end of the inactive phase (Hastings et al., 1998). ...
Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid-acting antidepressant effects and summarize how diverse phenomena associated with ketamine’s antidepressant actions – such as cortical excitation, synaptogenesis, and involved molecular determinants – are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain.
... For example, 3 h of awaking with minimal locomotion can still produce large behavioral phase-advances . Geniculohypothalamic projections releasing neuropeptide Y and serotonergic innervation from the median raphe nucleus are essential for conveying nonphotic information to the SCN clock (Cutrera et al., 1994a;Janik and Mrosovsky, 1994;Meyer-Bernstein and Morin, 1996;Mrosovsky, 1996;Edgar et al., 1997;Marchant et al., 1997;Hastings et al., 1998;. ...
... For example, with the available data, it cannot be ruled out that altered photic inputs during a dark pulse in bright LL may directly be related to the diminished expression of Per genes within the SCN. Moreover, dark pulses in hamsters produce typical phase-advances in the early subjective night (Dwyer and Rosenwasser, 2000;Rosenwasser and Dwyer, 2002) while classical nonphotic cues, such as novelty-induced wheel-running, do not shift the SCN clock (Mrosovsky, 1996;Hastings et al., 1998). The IGL is a critical area for mediating nonphotic cues to the SCN clock (Mrosovsky, 1996;Marchant et al., 1997;Maywood et al., 1997). ...
... Other zeitgebers include nonphotic stimuli, such as temperature, food availability, exercise and social interactions (Buhr et al., 2010;Carneiro and Araujo, 2012;Glaser and Stanewsky, 2007;Hastings et al., 1998;Levine et al., 2002a;Mistlberger and Skene, 2005;Simoni et al., 2014), which under certain circumstances can entrain endogenous rhythmicity. For example, when nocturnal rodents are restricted to a daytime feeding schedule, through the provision of a 2-6 h meal time during their usual rest phase, they exhibit a dissociation of peripheral circadian oscillators from the SCN. ...
... The disappointing efficacy of light therapy has raised interest in other, nonphotic, zeitgebers that target peripheral circadian clocks; potential candidates include temperature (Buhr et al., 2010;Glaser and Stanewsky, 2007), food availability (Carneiro and Araujo, 2012), exercise (Atkinson et al., 2007;Edgar and Dement, 1991;Miyazaki et al., 2001) and social interactions (Hastings et al., 1998;Levine et al., 2002b;Mistlberger and Skene, 2005;Simoni et al., 2014). Although each of these zeitgebers offers a potential intervention, entrainment to a regular feeding regimen is particularly promising. ...
Molecular and cellular oscillations constitute an internal clock that tracks the time of day and permits organisms to optimize their behaviour and metabolism to suit the daily demands they face. The workings of this internal clock become impaired with age. In this review, we discuss whether such age-related impairments in the circadian clock interact with age-related neurodegenerative disorders, such as Alzheimer's disease. Findings from mouse and fly models of Alzheimer's disease have accelerated our understanding of the interaction between neurodegeneration and circadian biology. These models show that neurodegeneration likely impairs circadian rhythms either by damaging the central clock or by blocking its communication with other brain areas and with peripheral tissues. The consequent sleep and metabolic deficits could enhance the susceptibility of the brain to further degenerative processes. Thus, circadian dysfunction might be both a cause and an effect of neurodegeneration. We also discuss the primary role of light in the entrainment of the central clock and describe important, alternative time signals, such as food, that play a role in entraining central and peripheral circadian clocks. Finally, we propose how these recent insights could inform efforts to develop novel therapeutic approaches to re-entrain arrhythmic individuals with neurodegenerative disease.
... La survenue de ces symptômes contribue à détériorer la qualité de vie et le bien-être des patients. Aucun traitement actuel n'est véritablement efficace pour les combattre (Yavuzsen, Davis et al. 2005;Dy, Lorenz et al. 2008;Minton, Richardson et al. 2008 (Hastings, Duffield et al. 1998;Stephan 2002;Honma, Hashimoto et al. 2003;Roenneberg, Daan et al. 2003;Mistlberger and Skene 2004;Mistlberger and Skene 2005;Roenneberg and Merrow 2007). L'altération du fonctionnement social est aussi associée à une survie globale plus courte, indépendamment des facteurs pronostiques connus, comme je l'ai montré dans une étude effectué sur 443 patients atteints de cancer colorectal métastatique, dont la qualité de vie a été évaluée d'après leurs réponses au questionnaire EORTC QLQ-C30 (cf. ...
... la prise alimentaire et la vie sociale (Hastings, Duffield et al. 1998;Stephan 2002;Honma, Hashimoto et al. 2003;Roenneberg, Daan et al. 2003;Mistlberger and Skene 2004;Mistlberger and Skene 2005;Roenneberg and Merrow 2007). Ainsi, la corrélation entre disruption circadienne et symptômes généraux est probablement bidirectionnelle ( Figure 27). ...
The circadian timing system controls several temporal aspects of physiology and behaviour in laboratory animals and humans. The disruption of the circadian timing system results in the occurrence of alterations at various levels of organisation: central coordination, circadian physiology, molecular clocks and signalling pathways. In particular, a circadian disruption induced by long-haul flights across several time-zones or by shift work is associated with the appearance of systemic symptoms, such as fatigue, mood disorders and appetite loss. These symptoms, related to circadian disruption, are also frequently found in cancer patients, as a consequence of their neoplastic disease or its treatment. My PhD work is part of the research regarding the role of the circadian timing system in the development of the symptoms associated with cancer and its treatment, in tumor progression and in patients’ survival. Its perspective is to identify novel therapeutic options. In particular, the general objectives of this thesis consist in the definition of the relationships between symptoms and circadian function of patients before and during chemotherapy, and in the quantification of the clinical impact of circadian disruption on quality of life and survival. I have focused in particular on patients with metastatic colorectal cancer, third cancer for incidence and mortality. These studies confirm the role of the circadian timing system in the occurrence of systemic symptoms in cancer patients, without treatment or during it. This study is currently ongoing in collaboration with the NIH in the United States. In conclusion, this work leads me to propose an innovative therapeutic approach aimed at shielding and/or restoring the integrity of the circadian timing system. This novel strategy should improve the therapeutic index of chemotherapy, by increasing its efficacy and decreasing its toxicity, still reducing the occurrence of symptoms, preserving the quality of life and prolonging the survival of cancer patients. The implementation of this strategy relies on the non-invasive monitoring of biomarkers of the circadian timing system and on the personalization of chronotherapy delivery.
... This difference in methodology makes direct comparisons to many nocturnal animals difficult. Using the literature on nocturnal animals (Hastings et al. 1998) as a starting point, we will examine the neural systems mediating nonphotic phase alteration and compare these findings with those of diurnal rodents. ...
... The most common nonphotic stimuli investigated are those that induce phase advances during the subjective day in nocturnal animals (Yannielli & Harrington 2004). Serotonergic stimulation, forced arousal with a novel wheel or sleep deprivation, and application of NPY into the SCN region all induce marked phase advances in the mid-subjective day (Ellis et al. 1982;Albers et al. 1984;Hastings et al. 1998;Ehlen et al. 2001;Glass et al. 2003;Mistlberger et al. 2003;Yannielli & Harrington 2004). The question of how this class of nonphotic stimuli act in diurnal animals is especially intriguing given the relationship between the stimulus and the activity phase. ...
Diurnal animals occupy a different temporal niche from nocturnal animals and are consequently exposed to different amounts of light as well as different dangers. Accordingly, some variation exists in the way that diurnal animals synchronize their internal circadian clock to match the external 24-hour daily cycle. First, though the brain mechanisms underlying photic entrainment are very similar among species with different daily activity patterns, there is evidence that diurnal animals are less sensitive to photic stimuli compared to nocturnal animals. Second, stimuli other than light that synchronize rhythms (i.e. nonphotic stimuli) can also entrain and phase shift daily rhythms. Some of the rules that govern nonphotic entrainment in nocturnal animals as well as the brain mechanisms that control nonphotic influences on rhythms do not appear to apply to diurnal animals, however. Some evidence supports the idea that arousal or activity plays an important role in entraining rhythms in diurnal animals, either during the light (active) or dark (inactive) phases, though no consistent pattern is seen. GABAergic stimulation induces phase shifts during the subjective day in both diurnal and nocturnal animals. In diurnal Arvicanthis niloticus (Nile grass rats), SCN GABAA receptor activation at this time results in phase delays while in nocturnal animals phase advances are induced. It appears that the effect of GABA at this circadian phase results from the inhibition of period gene expression in both diurnal and nocturnal animals. Nonetheless, the resulting phase shifts are in opposite directions. It is not known what stimuli or behaviours ultimately induce changes in GABA activity in the SCN that result in alterations of circadian phase in diurnal grass rats. Taken together, studies such as these suggest that it may be problematic to apply the principles governing nocturnal nonphotic entrainment and its underlying mechanisms to diurnal species including humans.
... При цьому найбільша концентрація гормону спостерігалася з опівночі до 7 години, найнижча при 10,30 і 15 годинах. Однак Hasting M. N. і співавтори показали, що секреція адреналіну не залежить від циклу сон-неспання і від переходу з лежачого положення в положення стояче, в той час як рівень норадреналіну значно підвищується при пробудженні і зміні положення тіла [15]. ...
The article is devoted to circadian rhythms of parameters of the hemostatic systems and humoral vasoactive factors determining diurnal profile of blood pressure. Researches indicate the presence of circadian rhythms of activity of autonomic nervous system and renin-angiotensin-aldosterone system in healthy human. Plasma catecholamines maximal activity is observed during the daytime, minimal one at night. Plasma renin activity and aldosterone concentration gradually decreases during the day, reaching its minimum at 4 p.m., followed by increase overnight to a peak at 8 a.m. Angiotensin-converting enzyme diurnal pattern is characterized by monophasic curve with maximal activity in the evening and minimum at night. Physiological features of hemostasis chronobiological characteristics in patients with coronary heart disease are present. All indexes of progressing coagulation and anticoagulation blood system has shown pronounced expressive shift of hypercoagulations in patients in the evening and at night. Fluctuations of insulin and glucose levels during 24 hours are also subject to circadian rhythm, i.e. maximal concentration is observed during the daytime, minimal one at night. Such diurnal rhythms are characteristic for patients without complicated arterial hypertension. However, circadian rhythms disturbances of humoral factors may further violate the circadian profile of blood pressure. It is pointed out that chronotherapy promote further development of the principle of individual treating approach.
... The circadian system develops gradually and in laboratory rats the SCN already appears between embryonic days 14 and 17, but maturation occurs until postnatal day 10. Synchronization of the developing circadian system to the external light-dark cycle already takes place in utero by maternal cues, although it is not yet fully clear whether this is by maternal feeding, temperature, hormones or a combination of all these factors (Hastings et al., 1998;Sumova et al., 2012). Daily rhythmicity in activity of pups can be observed from around postnatal day 9 or 10 (Smith and Anderson, 1984). ...
In mammals, daily rhythms in physiology and behavior are under control of a circadian pacemaker situated in the suprachiasmatic nucleus (SCN). This master clock receives photic input from the retina and coordinates peripheral oscillators present in other tissues, maintaining all rhythms in the body synchronized to the environmental light-dark cycle. In line with its function as a master clock, the SCN appears to be well protected against unpredictable stressful stimuli. However, available data indicate that stress and stress hormones at certain times of day are capable of shifting peripheral oscillators in, e.g., liver, kidney and heart, which are normally under control of the SCN. Such shifts of peripheral oscillators may represent a temporary change in circadian organization that facilitates adaptation to repeated stress. Alternatively, these shifts of internal rhythms may represent an imbalance between precisely orchestrated physiological and behavioral processes that may have severe consequences for health and well-being.
... By contrast, the SCN is primarily entrained by light. For example, the SCN is largely unresponsive to glucocorticoids 3 , although there is evidence that non-photic stimuli including exercise also contribute to SCN entrainment [4][5][6][7][8] . However, the SCN is sensitive to caffeine [9][10][11] , suggesting that there exists an endogenous adenosine-based regulatory pathway that is of profound importance to circadian timekeeping. ...
The accumulation of adenosine is strongly correlated with the need for sleep and the detection of sleep pressure is antagonised by caffeine. Caffeine also affects the circadian timing system directly and independently of sleep physiology, but how caffeine mediates these effects upon the circadian clock is unclear. Here we identify an adenosine-based regulatory mechanism that allows sleep and circadian processes to interact for the optimisation of sleep/wake timing in mice. Adenosine encodes sleep history and this signal modulates circadian entrainment by light. Pharmacological and genetic approaches demonstrate that adenosine acts upon the circadian clockwork via adenosine A 1 /A 2A receptor signalling through the activation of the Ca ²⁺ -ERK-AP-1 and CREB/CRTC1-CRE pathways to regulate the clock genes Per1 and Per2 . We show that these signalling pathways converge upon and inhibit the same pathways activated by light. Thus, circadian entrainment by light is systematically modulated on a daily basis by sleep history. These findings contribute to our understanding of how adenosine integrates signalling from both light and sleep to regulate circadian timing in mice.
... Furthermore, brief arousing episodes induced by an intraperitoneal injection of saline were even able to produce phase-shifts without substantial locomotor activity, though the magnitude of shifts remained much smaller (Hastings et al., 1998). Antle and Mistlberger (2000) showed in Syrian hamsters that the phase-shifting effects of intense locomotor activity can be fully mimicked by keeping animals awake by gentle handling, with minimal levels of motor activity . ...
The master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus provides a temporal pattern of sleep and wake that - like many other behavioural and physiological rhythms - is oppositely phased in nocturnal and diurnal animals. The SCN primarily uses environmental light, perceived through the retina, to synchronize its endogenous circadian rhythms with the exact 24 h light/dark cycle of the outside world. The light responsiveness of the SCN is maximal during the night in both nocturnal and diurnal species. Behavioural arousal during the resting period not only perturbs sleep homeostasis, but also acts as a potent non-photic synchronizing cue. The feedback action of arousal on the SCN is mediated by processes involving several brain nuclei and neurotransmitters, which ultimately change the molecular function of SCN pacemaker cells. Arousing stimuli during the sleeping period differentially affect the circadian system of nocturnal and diurnal species, as evidenced by the different circadian windows of sensitivity to behavioural arousal. In addition, arousing stimuli reduce and increase light resetting in nocturnal and diurnal species, respectively. It is important to address further the question of circadian impairments associated with shift work and trans-meridian travel not only in the standard nocturnal laboratory animals, but also in diurnal animal models.
... The light-dark cycle (LD) by its recurrent and regular oscillation is the main zeitgeber of circadian rhythms. However, environmental scenarios have a broad temporal representation, in which social relations mediated by auditory and olfactory cues can also act as significant nonphotic zeitgebers (Hastings et al. 1998;Mistlberger and Skene 2004). ...
The input of environmental time cues and expression of circadian activity rhythms may change with aging. Among nonphotic zeitgebers, social cues from conspecific vocalizations may contribute to the stability and survival of individuals of social species, such as nonhuman primates. We evaluated aging-related changes on social synchronization of the circadian activity rhythm (CAR) in a social diurnal primate, the common marmoset. The activity of 18 male marmosets was recorded by actiwatches in two conditions. (1) Experimental – 4 young adult (5 ± 2 yrs of age) and 4 older (10 ± 2 yrs of age) animals maintained under LD 12/12 h and LL in a room with full insulation for light but only partial insulation for sound from vocalizations of conspecifics maintained outdoors in the colony; and (2) Control – 10 young adult animals maintained outdoors in the colony (5 animals as a control per age group). In LL, the CAR of young adults showed more stable synchronization with controls. Among the aged marmosets, two free-ran with τ > 24 h, whereas the other two showed relative coordination during the first 30 days in LL, but free-ran thereafter. These differences were reflected in the “social” phase angles (ψon and ψoff) between rhythms of experimental and control animal groups. Moreover, the activity patterns of aged animals showed lower social synchrony with controls compared to young adults, with the time lags of the time series between each experimental group and control group being negative in aged and positive in young adult animals (t-test, p < 0.05). The index of stability of the CAR showed no differences according to age, while the intradaily variability of the CAR was higher in the aged animals during LD-resynchronization, who took additional days to resynchronize. Thus, the social modulation on CAR may vary with age in marmosets. In the aged group, there was a lower effect of social synchronization, which may be associated with aging-related changes in the synchronization and generation of the CAR as well as in system outputs.
... Over the course of evolution, the circadian rhythm (CR) of organisms-which is an endogenous rhythm with a cycle close to 24 h (Aschoff, 1981)-has remained highly consistent (Sahar & Sassone-Corsi, 2009). However, endogenous CRs are also affected by exogenous photic (Schmoll, Tendo, Aspinall, & Dhillon, 2011) or nonphotic (Hastings, Duffield, Smith, Maywood, & Ebling, 1998) entrainment. The activity rhythm of organisms is synchronized to the 24-h light/dark (LD) cycle, which is the normal (N)CR, but exogenous factors such as shift work or jetlag (Stevens et al., 2007;Zimmet et al., 2019) can desynchronize the body's activity rhythm, resulting in CR disorder (CRD) (Bass, 2012). ...
The present study investigated the effects of circadian rhythm disorder (CRD) on the hippocampus of SHR and WKY rats. Male SHR rats (n = 27) and WKY rats (n = 27) were randomly divided into six groups: SHR and WKY normal (N)CR, SHR and WKY CRD 16/8 (CRD16/8), and SHR and WKY CRD 12/12 (CRD12/12). Activity patterns were adjusted using different photoperiods over 90 days and any changes were recorded. Rats were tested in the Morris water maze and in a novel object recognition experiment; serologic analysis, magnetic resonance imaging (diffusion tensor imaging + arterial spin labeling), hippocampal Nissl staining, Fluoro-Jade B staining, and immunohistochemistry were also performed. The results showed that both types of inverted photoperiod reduced CR amplitude and prolonged the circadian period. CRD and hypertension reduced memory performance and novel object recognition and preference. The decreases in memory and preference indices were greater in rats in the CRD12/12 group compared to the CRD16/8 group. CRD and hypertension decreased fractional anisotropy values, the number of neurons and astrocytes in the hippocampus, and the expression of brain-derived neurotrophic factor and synapsin 1; it also enhanced the degeneration of neurons and microglia and reduced blood flow in the hippocampus, and increased nuclear factor κB, caspase, neuron-specific enolase, and interleukin-6 levels. These findings reveal a biological basis for the link between CRD and cognitive decline, which has implications for CRD caused by shift work and other factors.
... In addition to retina-dependent photoentrainment, light-independent neural circuits likewise directly influence SCN neurons to regulate circadian phase. The most prominent non-photic entrainment cues in mammals are behavioral arousal induced by sleep deprivation, animal handling, or exposure to a novel running wheel [41,42]. Serotonin and NPY are known to directly change SCN molecular rhythms and induce phase shifts of circadian activity during the subjective day, when the SCN is least sensitive to light and most sensitive to non-photic entrainment cues [43][44][45][46]. ...
Circadian rhythms, or biological oscillations of approximately 24 hours, impact almost all aspects of our lives by regulating the sleep-wake cycle, hormone release, body temperature fluctuation, and timing of food consumption. The molecular machinery governing these rhythms is similar across organisms ranging from unicellular fungi to insects, rodents, and humans. Circadian entrainment, or temporal synchrony with one's environment, is essential for survival. In mammals, the central circadian pacemaker is located in the suprachiasmatic nucleus (SCN †) of the hypothalamus and mediates entrainment to environmental conditions. While the light:dark cycle is the primary environmental cue, arousal-inducing, non-photic signals such as food consumption, exercise, and social interaction are also potent synchronizers. Many of these stimuli enhance dopaminergic signaling suggesting that a cohesive circadian physiology depends on the relationship between circadian clocks and the neuronal circuits responsible for detecting salient events. Here, we review the inner workings of mammalian circadian entrainment, and describe the health consequences of circadian rhythm disruptions with an emphasis on dopamine signaling.
... By contrast, non-photic inputs produce phase shifts in the SCN that differ significantly from those produced by light [see Fig. 1 in (Albers et al., 2017)]. These signals produce large phase advances in behavioural rhythms during the day and small phase delays during the night (Mrosovsky, 1988;Reebs & Mrosovsky, 1989;Mead et al., 1992;Hastings et al., 1998;Lone & Sharma, 2011;Polidarova et al., 2011). These non-photic phase shifts of the circadian system have also been studied in humans (Redlin & Mrosovsky, 1997;Mistlberger & Skene, 2005). ...
Neuronal oscillations of the brain, such as those observed in the cortices and hippocampi of behaving animals and humans, span across wide frequency bands, from slow delta waves (0.1 Hz) to ultra-fast ripples (600 Hz). Here, we focus on ultra-slow neuronal oscillators in the hypothalamic suprachiasmatic nuclei (SCN), the master daily clock that operates on interlocking transcription-translation feedback loops to produce circadian rhythms in clock gene expression with a period of near 24 hours (<0.001 Hz). This intracellular molecular clock interacts with the cell's membrane through poorly understood mechanisms to drive the daily pattern in the electrical excitability of SCN neurons, exhibiting an up-state during the day and a down-state at night. In turn, the membrane activity feeds back to regulate the oscillatory activity of clock gene programs. In this review, we emphasise the circadian processes that drive daily electrical oscillations in SCN neurons, and highlight how mathematical modelling contributes to our increasing understanding of circadian rhythm generation, synchronisation and communication within this hypothalamic region and across other brain circuits.
... This possibility of potential contribution of nonspecific arousal to non-photic stimuli was already mentioned in early experiments on non-photic resetting (Mrosovsky, 1988;Rusak et al., 1989). Furthermore, brief arousing episodes induced by an intraperitoneal (i.p.) injection of saline also produce phase-shifts without substantial locomotor activity, though the magnitude of shifts remains much smaller (Hastings et al., 1998). Antle and Mistlberger (2000) showed in Syrian hamsters that the phase-shifting effects of intense locomotor activity can be fully mimicked by keeping animals awake by gentle handling, with minimal activity . ...
Located in the hypothalamic suprachiasmatic nucleus (SCN), the master clock generates rhythms of behavioural and metabolic processes in mammals. For example, daily rhythms of sleep-wake, fasting-feeding, plasma glucose concentration, glucose tolerance and insulin sensitivity are regulated by the SCN clock. Light is the primary synchronizer of SCN pacemaker though many light-independent factors such as behavioural arousal and metabolic cues also have phase and period resetting properties. The aim of thesis was to study different aspects of the interactions between behavioural arousal, circadian rhythms and glucose metabolism. In the first part, we extended the study of brain control of glucose metabolism by investigating the central action of gastrin-releasing peptide (GRP), a neuropeptide synthesized in the SCN, on glucose metabolism. Our result indicates that central GRP induces long-lasting hyperglycemia. We also showed that acute sleep deprivation leads to impaired glucose tolerance. In the second part, we demonstrated that behavioural arousal induced by sleep deprivation or caffeine treatment enhances photic-entrainment of the SCN clock in the diurnal Sudanian grass rat, Arvicanthis ansorgei. These circadian responses in a diurnal species are opposite to the earlier findings in nocturnal rodents and may have biomedical applications.
... In fact, several non-photic stimuli capable of inducing phase shifts appear to do so by increasing locomotor activity and possibly general arousal. Examples of non-photic phase shifting stimuli include spontaneous running on a novel wheel, several hours of gentle handling, and saline injections Mrosovsky, 1995;Hastings et al., 1998). In contrast to a number of other non-photic phase shifting stimuli, NPY injected into the SCN does not induce phase shifts by increasing arousal (Mrosovsky, 1995;Biello et al., 1994). ...
Virtually every neuron within the suprachiasmatic nucleus (SCN) communicates via GABAergic signaling. The extra-cellular levels of GABA within the SCN are determined by a complex interaction of synthesis and transport, as well as synaptic and non-synaptic release. The response to GABA is mediated by GABAA receptors that respond to both phasic and tonic GABA release and that can produce excitatory as well as inhibitory cellular responses. GABA also influences circadian control through the exclusively inhibitory effects of GABAB receptors. Both GABA and neuropeptide signaling occur within the SCN although the functional consequences of the interactions of these signals are not well understood. This review considers the role of GABA in the circadian pacemaker, in the mechanisms responsible for the generation of circadian rhythms, in the ability of non-photic stimuli to reset the phase of the pacemaker, and in the ability of the day-night cycle to entrain the pacemaker.
... Environmental time cues (called zeitgebers) relevant to the maintenance of a stable temporal organization comprise, besides the light/dark cycle, feeding times, timing of physical exercise and probably very relevantly, social interaction (Hastings et al., 1998). Contemporary society is full of such traps especially in the scenery of globalization (Crary, 2014), so it is not surprising that we witness today, for instance, a growing number of sleep complaints, tips of the iceberg of a disturbed temporal organization. To be able to understand and eventually help individuals in such disorders one must retrace the ways in the near and remote past of their lives so as to identify what may have become temporal traps for them. ...
In the inspiring and friendly environment of the ninth International Summer School on Mind, Brain and Education, titled Body, Brain and Personal Identity: Historical and Contemporary Perspectives, and directed by Antonio M. Battro, Kurt W. Fischer and Fernando Vidal, I presented the provisional results of my investigation of the impact of neurotechnology on the speechless subjects’ ability to communicate. In particular, I focused on the possible use of neurotechnology to communicate with comatose patients.
... Para un amplio número de especies la luz o el ciclo luz-oscuridad representa el zeitgeber (dador de tiempo o sincronizador) más poderoso, aunque otros estímulos pueden ser sincronizadores en ausencia de luz. Si el efecto del sincronizador es similar al de la luz se lo denomína fótico, en caso contrario, si su efecto es diferente, el sincronizador es no-fótico, por ejemplo: pulsos de oscuridad, actividad locomotora forzada, estímulos novedosos o interacciones sociales (Hastings, et al. 1998;Mrosovsky, 1996). ...
Diversas variables bioquímicas, fisiológicas y comportamentales de los
seres vivos presentan ritmos. Gran parte de estos ritmos son circadianos y están
comandados por un oscilador principal alojado en los núcleos supraquiasmáticos
(NSQ) del hipotalamo. La base molecular del oscilador circadiano implica la
participación de genes y proteínas reloj las que conforman un circuito
retroalimentado. El ambiente, y en especial la luz, puede interaccionar con el
sistema circadiano y modificar los ritmos a nivel molecular. Una parte fundamental
de la cronobiología estudia cómo se establece esta interacción y como se modifica
la hora del reloj biológico. Sabemos que en mamíferos la luz modifica la hora del
reloj solo en la fase de actividad de los individuos, provocando adelantos del ritmo
cuando se aplica al comienzo de la actividad y retardos del ritmo cuando se
muestra en el final de la etapa de actividad, y por consiguiente no tiene efecto
durante la etapa de reposo.
En este trabajo de tesis indagamos sobre la vía de señalización de MAPK a
nivel de NSQ en hámsteres dorados. Específicamente estudiamos las MAPK más
conocidas: ERK, JNK y p38, tanto en condiciones de aislamiento ambiental como
en condiciones de sincronización lumínica. El estudio abarcó a los moduladores
directos de MAPK: tanto las MAPK fosfatasas (inactivadores o MKPs), como las
MAPK quinasas (activadores o MEKs). Además, con el fin de entender el grado
de importancia de las MAPK en el sistema circadiano realizamos una intervención
a nivel molecular alterando su patrón normal de activación en forma transciente. El
estudio se realizó por medio de la transformación in-vivo de activadores mutantes,
con actividad constitutiva y alta, de la vía de MAPK. Corriente arriba de MAPK
estudiamos los posibles moduladores extracelulares implicados en la
sincronización de los ritmos. En particular evaluamos la acción de la neurotrofina
NGF y del neuropéptido NPY sobre la activación de ERK- MAPK a nivel de NSQ.
Corriente abajo de las MAPK realizamos estudios sobre sus posibles sustratos y la
relación con el sistema circadiano.
Los resultados indican que las MAPK poseen un ritmo circadiano de
activación tanto en condiciones de oscuridad constante como en condiciones de
iluminación, con máximos durante las horas de reposo. Además, pulsos de 5
minutos de luz saturante alcanza para disparar la activación de las tres MAPK en
la etapa de actividad y no en la etapa de reposo de los hámsteres. Además vimos
como MKP1/2 y MKP3 se expresan en los NSQ, con especial vigor luego de la
estimulación fótica en horarios nocturnos, cuando la luz también induce una
fosforilación rápida y transiente de las MAPKs, e induce un cambio de fase de los
ritmos circadianos. Por otro lado encontramos expresión de MEK1/2 y MEK 3/6
en los NSQ indicando que los niveles de fosforilación de las MAPKs pueden
establecerse a partir de un balance entre la actividad de sus activadores y
desactivadotes, MEKs y MKPs respectivamente. En particular encontramos una
oscilación diaria en el estado de activación de MEK3/6, con niveles máximos
durante la fase de reposo. En cambio no encontramos variación a lo largo del día
en los niveles de actividad de MEK1/2.
Siguiendo con el estudio de las MAPK vimos que la alteración de los
patrones normales de fosforilación de ERK-MAPK en los NSQ de hámsteres
resulta en una inhibición significativa de los adelantos de fase de los ritmos
circadianos (actividad locomotora en rueda) inducidos por pulso de luz en la noche
tardía. Esta inhibición fue revertida, luego de restablecerse el ritmo circadiano
normal en los niveles de pp-ERK.
En este trabajo, además, implicamos funcionalmente a NGF en el sistema
circadiano. Vimos que en hámsteres la aplicación de NGF directamente sobre los
NSQ provoca un cambio de fase del ritmo circadiano de la actividad locomotora en
rueda. Dicho cambio es similar al producido por la luz, ya sea en magnitud, en
dirección y en la fase dependencia; de esta manera decimos que los efectos de
NGF son de tipo fótico. Además, los efectos de NGF en simultáneo con un pulso
de luz sobre los cambios de fase de la actividad locomotora en rueda de
hámsteres no son aditivos. Esto, sumado a la similitud de la PRC de la luz y de
NGF, sugiere que ambos estímulos comparten la vía de señalización en algún
punto. De acuerdo con esta hipótesis encontramos que la estimulación con NGF
es capaz de inducir la expresión de FOS en forma similar a lo observado con la
estimulación con luz. Por otro lado la activación de ERK-MAPK en los NSQ luego
de la administración de NGF muestra patrones similares a los obtenidos luego de
la misma estimulación fótica. Otro de los moduladores estudiados fue NPY y los
resultados muestran un aumento en los niveles de p-ERK1/2 una hora después de
aplicado dicho estímulo durante la fase de reposo de los animales.
Por otra parte encontramos un posible candidato capaz de comportarse
como sustrato de MAPKs y estar implicado en la sincronización fótica de los ritmos
a nivel de NSQ. El análisis muestra que la expresión de ATF2 posee un ritmo
diario en los NSQ, con un máximo nivel durante el día. Los animales colocados en
oscuridad constante muestran también una oscilación en los niveles de expresión
de ATF2 pero en antifase respecto a lo observado bajo condiciones de luzoscuridad.
Además, un pulso de luz alcanza para disparar la expresión de ATF2
durante el día.
Con la información obtenida hasta el momento podemos colocar a las
MAPK en una posición central en la regulación de los ritmos circadianos a nivel de
NSQ, tanto en la sincronización fótica y no-fótica, como en el control endógeno del
propio reloj biológico. Por supuesto que las preguntas no se han agotado, y falta
un largo camino por recorrer en la caracterización completa de la dinámica de
expresión y activación de la vía de MAPKs en los NSQ.
En síntesis, a partir de nuestros resultados podemos pensar que las MAPK
están involucradas en los mecanismos de sincronización fótica y que además
pueden integrar diferentes vías de señalización aferentes al reloj circadiano en los
NSQ de mamíferos.
... In the SCN, the nearly 24-h (i.e., circadian) rhythms produced by these clockgenes are synchronized to the exact 24-h rhythms in the outer world by their sensitivity to (sun)light (Dibner et al., 2010). The synchronizing stimuli for peripheral clocks in non-SCN tissues are less clear, in addition to nervous and humoral signals from the SCN, behavioral signals such as body temperature, energy metabolism and (feeding) activity also likely play a role (Hastings et al., 1998;Dibner et al., 2010). ...
... Exercise effects on sleep quality might be explained by the chronobiotic properties of exercise (i.e., the ability to synchronize circadian rhythms of physiology and behavior). The chronobiotic properties of exercise have been well established in various animal models (for reviews, see Mrosovsky, 1996;Hastings et al., 1998), however, the science is less definitive in humans (reviewed in Skene, 2004, 2005). ...
Given the world’s aging population, the staggering economic impact of dementia, the lack of effective treatments, and the fact a cure for dementia is likely many years away – there is an urgent need to develop interventions to prevent or at least delay dementia’s progression. Thus, lifestyle approaches to promote healthy aging are an important line of scientific inquiry. Good sleep quality and physical activity (PA) are pillars of healthy aging, and as such, are an increasing focus for intervention studies aimed at promoting health and cognitive function in older adults. However, PA and sleep quality are difficult constructs to evaluate empirically. Wrist-worn actigraphy (WWA) is currently accepted as a valid objective measure of sleep quality. The MotionWatch 8© (MW8) is the latest WWA, replacing the discontinued Actiwatch 4 and Actiwatch 7. In the current study, concurrent measurement of WWA and indirect calorimetry was performed during 10 different activities of daily living for 23 healthy older adults (aged 57–80 years) to determine cut-points for sedentary and moderate-vigorous PA – using receiver operating characteristic curves – with the cut-point for light activity being the boundaries between sedentary and moderate to vigorous PA. In addition, simultaneous multi-unit reliability was determined for the MW8 using inter-class correlations. The current study is the first to validate MW8 activity count cut-points – for sedentary, light, and moderate to vigorous PA – specifically for use with healthy older adults. These cut-points provide important context for better interpretation of MW8 activity counts, and a greater understanding of what these counts mean in terms of PA. Hence, our results validate another level of analysis for researchers using the MW8 in studies aiming to examine PA and sleep quality concurrently in older adults.
... In general, for these markers sampling can occur at any time-point during the day or after an overnight fast. However, environmental factors, such as light exposure and food intake might affect the levels of these markers, since they provide input for the internal time-keeping system [8][9][10][11]. Several markers are well known for their diurnal variation, for example cortisol and melatonin [12]. Importantly, heterogeneity in diurnal variation and disturbance of circadian rhythms among a study population might increasingly occur as a result of our increasing 24/7 economy and related variation in exposure to environmental factors (such as light and food). ...
Introduction:
Many molecular epidemiology studies focusing on high prevalent diseases, such as metabolic disorders and cancer, investigate metabolic and hormonal markers. In general, sampling for these markers can occur at any time-point during the day or after an overnight fast. However, environmental factors, such as light exposure and food intake might affect the levels of these markers, since they provide input for the internal time-keeping system. When diurnal variation is larger than the inter-individual variation, time of day should be taken into account. Importantly, heterogeneity in diurnal variation and disturbance of circadian rhythms among a study population might increasingly occur as a result of our increasing 24/7 economy and related variation in exposure to environmental factors (such as light and food).
Aim:
The aim of the present study was to determine whether a set of often used biomarkers shows diurnal variation in a setting resembling large molecular epidemiology studies, i.e., non-fasted and limited control possibilities for other environmental influences.
Results:
We show that markers for which diurnal variation is not an issue are adrenocorticotropic hormone, follicle stimulating hormone, estradiol and high-density lipoprotein. For all other tested markers diurnal variation was observed in at least one gender (cholesterol, cortisol, dehydroepiandrosterone sulfate, free fatty acids, low-density lipoprotein, luteinizing hormone, prolactin, progesterone, testosterone, triglycerides, total triiodothyronine and thyroid-stimulating hormone) or could not reliably be detected (human growth hormone).
Discussion:
Thus, studies investigating these markers should take diurnal variation into account, for which we provide some options. Furthermore, our study indicates the need for investigating diurnal variation (in literature or experimentally) before setting up studies measuring markers in routine and controlled settings, especially since time-of-day likely matters for many more markers than the ones investigated in the present study.
... In the SCN, the nearly 24-h (i.e., circadian) rhythms produced by these clockgenes are synchronized to the exact 24-h rhythms in the outer world by their sensitivity to (sun)light (Dibner et al., 2010). The synchronizing stimuli for peripheral clocks in non-SCN tissues are less clear, in addition to nervous and humoral signals from the SCN, behavioral signals such as body temperature, energy metabolism and (feeding) activity also likely play a role (Hastings et al., 1998;Dibner et al., 2010). ...
Our current 24-h society requires an increasing number of employees to work nightshifts with millions of people worldwide working during the evening or night. Clear associations have been found between shiftwork and the risk to develop metabolic health problems, such as obesity. An increasing number of studies suggest that the underlying mechanism includes disruption of the rhythmically organized body physiology. Normally, daily 24-h rhythms in physiological processes are controlled by the central clock in the brain in close collaboration with peripheral clocks present throughout the body. Working schedules of shiftworkers greatly interfere with these normal daily rhythms by exposing the individual to contrasting inputs, i.e., at the one hand (dim)light exposure at night, nightly activity and eating and at the other hand daytime sleep and reduced light exposure. Several different animal models are being used to mimic shiftwork and study the mechanism responsible for the observed correlation between shiftwork and metabolic diseases. In this review we aim to provide an overview of the available animal studies with a focus on the four most relevant models that are being used to mimic human shiftwork: altered timing of (1) food intake, (2) activity, (3) sleep, or (4) light exposure. For all studies we scored whether and how relevant metabolic parameters, such as bodyweight, adiposity and plasma glucose were affected by the manipulation. In the discussion, we focus on differences between shiftwork models and animal species (i.e., rat and mouse). In addition, we comment on the complexity of shiftwork as an exposure and the subsequent difficulties when using animal models to investigate this condition. In view of the added value of animal models over human cohorts to study the effects and mechanisms of shiftwork, we conclude with recommendations to improve future research protocols to study the causality between shiftwork and metabolic health problems using animal models.
... Performing physical exercise intensively stimulates one's arousal level by increasing sympathetic activity, which is suggested to enhance the nonphotic effect of a shift schedule 59) . In addition, exercise-induced physiological changes such as hyperthermia may possibly influence the entrainment of circadian rhythms 60) . ...
This review introduces a variety of human circadian rhythms including physiological processes and mental and physical performances, with reference to real-life situations. Circadian rhythms play a role in physiological processes, such as core body temperature and plasma mela-tonin, which are recognized as the body clock. As humans are diurnal organisms, mental performance declines primarily at night, secondarily in the early afternoon; this is consistent with risks of traffic and industrial accidents. Physical performance is composed of various fitness components and generally reaches its peak and nadir at around evening and early morning, respectively. Exceptions to this are body balance control and accuracy, both of which require brain function. Although maximal oxygen consumption (V ・ O 2 max) measured in the laboratory shows a constant value independent of the time of day, actual endurance capacity might be determined by core body temperature at the beginning of exercise, thermoregulatory response, and environmental temperature and humidity, all of which vary with the time of day. As the most powerful factor affecting the human circadian clock is bright light, physical exercise may be one factor entraining the human circadian pacemaker. However, experimental evidence has suggested that exercise itself has little or no influence on shifting the human master clock. Although further studies are required, recent studies have demonstrated that physical exercise at a certain time of day specifically improves physical performance at the same time, which might be independent of the master clock.
... Retinal light stimulation results in secretion of the neurotransmitters glutamate and pituitary adenylate cyclaseactivating peptide (PACAP) from the RHT terminal, stimulating their receptors in the SCN neurons and leading to the upregulation of some immediate early genes and Per1 and 2 (105). In addition to the photic input via the RHT, nonphotic inputs reach the SCN via afferent neuropeptide Y (NPY)containing projections from the intergeniculate leaflet and serotonergic inputs from the midbrain raphe (39,91). In the mammalian brain, the SCN mainly projects to the paraventricular nucleus of the hypothalamus (PVN), the subparaventricular zone (sPVZ), the dorsomedial nucleus of the hypothalamus (DMH), the paraventricular nucleus of the thalamus (PVT), and the intergeniculate leaflet (IGL) (89) utilizing classic neurotransmitters, such as glutamate and ␥-aminobutyric acid (GABA), and neuropeptides, including vasoactive intestinal peptide (VIP), vasopressin (VP), and gastrin-releasing peptide (GRP) (114). ...
The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to the environment by light, peripheral clocks are entrained by various factors, of which feeding/fasting is the most important. Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake, can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and type 2 diabetes. Diets high in fat or sugar have been shown to alter circadian clock function. This review discusses the recent findings concerning the influence of nutrients, in particular fatty acids and glucose, on behavioral and molecular circadian rhythms and will summarize critical studies describing putative mechanisms by which these nutrients are able to alter normal circadian rhythmicity, in the SCN, in non-SCN brain areas, as well as in peripheral organs. As the effects of fat and sugar on the clock could be through alterations in energy status, the role of specific nutrient sensors will be outlined, as well as the molecular studies linking these components to metabolism. Understanding the impact of specific macronutrients on the circadian clock will allow for guidance towards the composition and timing of meals optimal for physiological health, as well as putative therapeutic targets to regulate the molecular clock.
Copyright © 2014, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
... The chronobiotic properties of exercise have been well established in various animal models (typically using wheel running in rodents; for reviews see Mrosovsky, 1996;Hastings et al., 1998). Whether or not exercise has chronobiotic properties in humans is difficult to determine given the challenges associated with isolating the effect of exercise vs. other factors such as light, food, and social influences (for reviews see Skene, 2004, 2005). ...
As of 2010, the worldwide economic impact of dementia was estimated at $604 billion USD; and without discovery of a cure or effective interventions to delay disease progression, dementia’s annual global economic impact is expected to surpass $1 trillion USD as early as 2030. Alzheimer’s disease (AD) is the leading cause of dementia accounting for over 75% of all cases. Toxic accumulation of amyloid beta (Aβ), either by overproduction or some clearance failure, is thought to be an underlying mechanism of the neuronal cell death characteristic of AD—though this amyloid hypothesis has been increasingly challenged in recent years. A compelling alternative hypothesis points to chronic neuroinflammation as a common root in late-life degenerative diseases including AD. Apolipoprotein-E (APOE) genotype is the strongest genetic risk factor for AD: APOE-ε4 is proinflammatory and individuals with this genotype accumulate more Aβ, are at high risk of developing AD, and almost half of all AD patients have at least one ε4 allele. Recent studies suggest a bidirectional relationship exists between sleep and AD pathology. Sleep may play an important role in Aβ clearance, and getting good quality sleep vs. poor quality sleep might reduce the AD risk associated with neuroinflammation and the ε4 allele. Taken together, these findings are particularly important given the sleep disruptions commonly associated with AD and the increased burden disrupted sleep poses for AD caregivers. The current review aims to: (1) identify individuals at high risk for dementia who may benefit most from sleep interventions; (2) explore the role poor sleep quality plays in exacerbating AD type dementia; (3) examine the science of sleep interventions to date; and (4) provide a road map in pursuit of comprehensive sleep interventions, specifically targeted to promote cognitive function and delay progression of dementia.
... This daily oscillation of the spontaneous firing frequency has been well established from in vivo (Inouye and Kawamura, 1979;Sato and Kawamura, 1984;Kurumiya and Kawamura, 1988) and in vitro extracellular recordings (Green and Gillette, 1982;Groos and Hendriks, 1982;Shibata et al., 1982;Bos and Mirmiran, 1990). The rhythmic firing is converted to a major output from the SCN to other brain regions (Inouye and Kawamura, 1979), and is translated into synchronization of the animal's metabolic, behavioral and hormonal activity to the external light-dark cycle (for reviews, see Hastings et al., 1998;van Esseveldt et al., 2000). Putative neurotransmitters and modulators, such as amino acids, peptides and nitric oxide (NO), have been shown to shift the phase of the SCN rhythm (which is primarily set by light inputs in the living animal) if applied in vitro. ...
... The neurotransmitters listed above also play key roles in regulating the timing of circadian rhythms (Albrecht, 2012). Underlying mechanisms of non-photic entrainment, or synchronization of rhythms to cues like exercise or stress, remain largely understudied even though they block the effects of light and reset clock phase both in rodents and humans (Hastings et al. 1998;Mistlberger & Skene, 2005). For example, both melatonin and NPY induce large phase advances of locomotor behaviour and spike rate rhythms during the day and hyperpolarize the resting membrane potential in a potassium-sensitive manner (Jiang et al. 1995;Hall et al. 1999;Scott et al. 2010). ...
Key points
Many time‐of‐day cues are mediated by G protein‐coupled signals within the clock centre (the suprachiasmatic nucleus, SCN) of the mammalian brain.
The role of G protein‐coupled inwardly rectifying potassium (GIRK) channels in SCN function and entrainment has yet to be determined.
GIRK channels are necessary for proper day‐time SCN neuronal resting membrane potential, neuropeptide Y signalling, and re‐entrainment to phase advances of the light–dark (LD) cycle.
GIRK channel activation is sufficient to mimic non‐photic phase shifts of the molecular clock.
GIRK channels act as an essential part of the non‐photic entrainment system, and could play a critical role in diseases such as epilepsy or addiction that have strong circadian comorbidities.
Abstract
G protein signalling within the central circadian oscillator, the suprachiasmatic nucleus (SCN), is essential for conveying time‐of‐day information. We sought to determine whether G protein‐coupled inwardly rectifying potassium channels (GIRKs) modulate SCN physiology and circadian behaviour. We show that GIRK current and GIRK2 protein expression are greater during the day. Pharmacological inhibition of GIRKs and genetic loss of GIRK2 depolarized the day‐time resting membrane potential of SCN neurons compared to controls. Behaviourally, GIRK2 knockout (KO) mice failed to shorten free running period in response to wheel access in constant darkness and entrained more rapidly to a 6 h advance of a 12 h:12 h light–dark (LD) cycle than wild‐type (WT) littermate controls. We next examined whether these effects were due to disrupted signalling of neuropeptide Y (NPY), which is known to mediate non‐photic phase shifts, attenuate photic phase shifts and activate GIRKs. Indeed, GIRK2 KO SCN slices had significantly fewer silent cells in response to NPY, likely contributing to the absence of NPY‐induced phase advances of PER2::LUC rhythms in organotypic SCN cultures from GIRK2 KO mice. Finally, GIRK channel activation is sufficient to cause a non‐photic‐like phase advance of PER2::LUC rhythms on a Per2 Luc +/− background. These results suggest that rhythmic regulation of GIRK2 protein and channel function in the SCN contributes to day‐time resting membrane potential, providing a mechanism for the fine tuning responses to non‐photic and photic stimuli. Further investigation could provide insight into disorders with circadian disruption comorbidities such as epilepsy and addiction, in which GIRK channels have been implicated.
... Although light is the dominant zeitgeber and the SCN is the light-entrainable oscillator (LEO), some evidence suggests that the central clock could also be influenced by non-photic inputs including behavior, nutritional intake, restricted exercise and social contact (Hastings et al., 1998;Challet, 2010). Thus, the SCN may be considered as an element of a neuronal network in which signals are received from, and sent to other brain regions, including nuclei from the limbic cortex, the basal forebrain, the hypothalamus, the brainstem and the midline thalamus (Moga and Moore, 1997). ...
Experimental and epidemiological evidence reveal the profound influence that industrialized modern society has imposed to human social habits and physiology during the past 50 years. This drastic change in lifestyle is thought to be one of the main causes of modern diseases including obesity, type 2 diabetes, mental illness such as depression, sleep disorders, and certain types of cancer. These disorders have been associated to disruption of the circadian clock, an intrinsic time-keeper molecular system present in virtually all cells and tissues. The circadian clock is a key element in homeostatic regulation by controlling a large array of genes implicated in cellular metabolism. Importantly, intimate links between epigenetic regulation and the circadian clock exist and are likely to prominently contribute to the plasticity of the response to the environment. In this review, we summarize some experimental and epidemiological evidence showing how environmental factors such as stress, drugs of abuse and changes in circadian habits, interact through different brain areas to modulate the endogenous clock. Furthermore we point out the pivotal role of the deacetylase SIRT1 as a molecular effector of the environment in shaping the circadian epigenetic landscape.
... In nocturnal mammals, some of the strongest non-photic effects involve manipulations that induced initiation of locomotor activity, at times when the animal would normally be resting, i.e. the subjective day 83,100,101 . When mice were provided with 'novel running wheels' during the subjective day, they usually become active, started digging and scratching their body, started scent marking, and pushing grains 83 . ...
The spatial and temporal aspects of the geophysical environment act as prominent selection forces for the evolution of life on this planet. The spatial features of the environment open up a choice of spatial niches and the temporal aspects on the other hand provide opportunities for adopting different temporal niches. Hence, both the spatial and the temporal properties of the environment together enhance the possibility for living organisms to exploit a given ecological niche at a given time of the day. The temporal selection pres- sures of the geophysical environment are composed of a number of abiotic factors such as light/dark cycles, temperature cycles, humidity cycles, and a range of biotic factors such as inter-individual interactions, inter- actions with preys, predators and parasites. Although the study of temporal organization in living organisms is relatively a recent phenomenon in bio logy, we now have access to a fair amount of know ledge about it in a number organisms ranging from cyanobacteria to humans. In this review, we shall focus mainly on three core questions related to timekeeping in living organ- isms: How are circadian clocks made to osci llate at desired frequencies?; What are the geophysical cycles that fine-tune circadian clocks?; Why are circadian clocks circadian? Life on earth has evolved around two key variables, space and time. The spatial features of each organism's biotic and abiotic environments are to a certain extent a fami liar concept to all of us, but the temporal features remain more abstract and often go unnoticed at least by an unfami l- iar observer 1 . It is only now becoming progressively clear that adaptation to the temporal str uctures of the geophysical environment is at least as important as adaptation to sp atial factors, more so for organisms living in periodically flu c- tuating environments
... The light-dark cycle is the main zeitgeber acting on the mammalian circadian system. Nevertheless, non-photic cues can have an important resetting effects on the clock (Hastings et al., 1998). Social cues can entrain or phase-shift free-running rhythms in humans (Aschoff et al., 1971;Honma et al., 1995). ...
The light/dark cycle is the main zeitgeber acting on the mammalian circadian system; nevertheless, distinct environments, such as those with and without electricity may provoke important resetting effects on the clock. The aim of this study was to describe sleep/wake patterns of adolescents living in two Brazilian rural regions. In the first population, 120 adolescents participated in the study, 35 of whom did not have electricity at home. They filled out a questionnaire which included questions concerning their sleep habits. It was found that electricity at home influenced sleep patterns. Adolescents with electricity at home had later wake-up times on school days (p < 0.05) and on weekends (p < 0.05), and tendencies towards later bedtimes on school days (0.05 < p < 0.10) and weekends (0.05 < p < 0.10). In the second population, 461 adolescents filled out the same questionnaire, 66 of whom did not have television at home. ANOVA showed that having TV at home was related to later bedtimes during school days (p < 0.05) and weekends (p < 0.05). These results support the idea that sleep patterns are influenced by technological advances.
... While this review has focused on possible serotonergic mediation of nonphotic inputs to the SCN pacemaker, another body of evidence has accumulated indicating that NPY plays a vital role in this process. These data have recently been reviewed elsewhere (e.g., Hastings et al, 1998;Harrington & Mistlberger, 1999), but the core observations are as follows: 1. NPY injected into the SCN area induces phase shifts similar in timing and magnitude to those induced by wheel running (Albers & Ferris, 1984;Biello et al., 1994). 2. Antibody to NPY injected into the SCN blocks phase shifts to wheel running . ...
Endogenous depression is often accompanied by alterations in core parameters of circadian rhythms, and antidepressant treatments, including serotonergic drugs, sleep deprivation and exercise, alter circadian phase or period in humans or animal models. Antidepressants may act in part through the circadian system, and behavioral antidepressants through a common serotonergic path to the clock. This review evaluates the evidence from animal models that serotonin (5-HT) mediates phase-shifting effects of behavioral stimuli on circadian rhythms. In rodents, 'exercise' stimulated during the rest phase of the rest-activity cycle induces large phase shifts of circadian rhythms. These shifts can be mimicked by short-term sleep deprivation without intense activity. During wheel running or sleep deprivation, 5-HT release in the suprachiasmatic nucleus (SCN) circadian clock is significantly elevated. Lesions of 5-HT afferents to the SCN attenuate phase shifts or entrainment induced by activity in response to some stimuli (e.g., triazolam injections in hamsters, treadmill running in mice) but not others (e.g., novel wheel confinement in hamsters). Antagonists selective to 5HT1, 2 or 7 receptors do not attenuate shifts induced by wheel running, although 5-HT2/7 antagonists do partially block shifts to saline injections. 5-HT agonists (e.g., 8-OH-DPAT) induce large shifts in vitro, but much smaller shifts in vivo, particularly if administered directly to the SCN. Procedures for inducing 5-HT supersensitivity in vivo result in larger shifts to 8-OH-DPAT. 5-HT stimuli may affect the clock by direct and indirect pathways, particularly through the thalamic intergeniculate leaflet, and the role of these pathways may differ across species. At the level of the SCN, 5-HT likely acts through 5-HT7 receptors on neurons and possibly also glial cells. These receptors may be useful targets for the development of antidepressant drugs. In aggregate, the literature provides mixed support for the hypothesis that exercise or behavioral arousal shift the circadian clock by a 5-HT pathway; the role of indirect pathways, interactions with other transmitters, cellular adaptations to denervation, glial cells, and species differences remain to be more fully clarified. Serotonergic and behavioral stimuli provide an intriguing route to elucidate the circadian clockworks and their possible role in depression.
... Environmental time cues (called zeitgebers) relevant to the maintenance of a stable temporal organization comprise, besides the light/dark cycle, feeding times, timing of physical exercise and probably very relevantly, social interaction (Hastings et al., 1998). Contemporary society is full of such traps especially in the scenery of globalization (Crary, 2014), so it is not surprising that we witness today, for instance, a growing number of sleep complaints, tips of the iceberg of a disturbed temporal organization. To be able to understand and eventually help individuals in such disorders one must retrace the ways in the near and remote past of their lives so as to identify what may have become temporal traps for them. ...
http://www.mbe-erice.org/papers/2015-mbe-erice-10years-web.pdf
... During early postnatal development rodents blinded or maintained in constant light or dark demonstrate rhythms synchronized with their foster mother (Reppert et al., 1984;Hastings et al., 1998;Ohta et al., 2002), suggesting the relevance of non-photic stimuli as entraining agents during this period also. Recently, Ohta et al. (2002Ohta et al. ( , 2003, in a study of non-photic entrainment in blinded neonatal rats, found that maternal deprivation is an effective non-photic stimulus for entraining the SCN at the molecular level, perhaps not surprising considering the intensive maternal care typically shown by this species and its significance for the young. ...
A notable and phylogenetically conserved characteristic of organisms is the demonstration of endogenous 24-h (circadian) rhythms across a wide range of behavioral, physiological and molecular processes. The extensive efforts to understand how such rhythms are generated and sustained have focused on their coupling to the daily light – dark cycle, that is, on their entrainment by photic cues. Although understandable given that this is the most predictable environmental information, it is increasingly clear that recurrent, non-photic events such as the periodic availability of food also regulate circadian systems and via mechanisms different to photic cues. One of the challenges facing circadian rhythms research is to understand how organisms respond to the wealth of diurnally fluctuating information around them and integrate this to generate a coherent and adaptive system of circadian function. Here we briefly review what is known about the influence of non-photic stimuli on the circadian system. We then consider the value but inherent difficulties of a developmental approach. After considering the advantages offered by the neonatal rabbit, we close by emphasizing the importance of developing models more closely tied to the animal's natural, evolved lifestyle if sense is to be made of the diversity of information rapidly accumulating on circadian processes.
... In nocturnal mammals, some of the strongest non-photic effects involve manipulations that induced initiation of locomotor activity, at times when the animal would normally be resting, i.e., the subjective day (Smith et al., 1992;Mrosovsky, 1996;Hastings et al., 1998). When mice were provided with 'novel running wheels' during the subjective day, they usually become active, started digging and scratching their 214 R. Chidambaram et al. body, started scent marking, and pushing grains (Mrosovsky, 1988). ...
The effect of 'novel running wheels' on circadian clocks of the nocturnal field mouse Mus booduga was investigated during free-running and entrained conditions. In order to find out whether daily access to novel running wheels can entrain the locomotor activity rhythms experimental animals (n = 6) were provided with 'novel running wheels' at a fixed time of the day. The control animals (n = 5) were handled similar to the experimental animals but were not given access to novel running wheels. The results show that daily access to novel running wheels entrained the free-running locomotor activity rhythm of these mice. The post-entrainment free-running period (τ) of the experimental animals was significantly shorter than the pre-entrainment τ, whereas the pre- and post-treatment τ of the control animals did not differ significantly. In separate set of experiments, the effect of access to novel running wheels on the rate of re-entrainment was studied after a 6 h phase advance/delay in 24 h (12:12 h) light/dark (LD) cycles. Experimental animals were given access to novel running wheels for 3-h, 1 h after the 'lights-off' only on the first day of the 'new LD cycles'. Experimental animals took fewer cycles to re-entrain to 6-h phase advanced LD cycles compared to the control animals. After a phase delay in the LD cycles by 6h, the experimental animals took more number of cycles to re-entrain compared to the control animals. These results thus suggest that access to novel running wheel can act as a Zeitgeber for the circadian clocks of the nocturnal mouse M. booduga, and can also modify the rates of re-entrainment to phase shifted LD cycles, in a time-dependent manner.
Alzheimer's disease (AD) is considered to be the most typical form of dementia that provokes irreversible cognitive impairment. Along with cognitive impairment, circadian rhythm dysfunction is a fundamental factor in aggravating AD. A link among circadian rhythms, sleep, and AD has been well-documented. The etiopathogenesis of circadian system disruptions and AD serves some general characteristics that also open up the possibility of viewing them as a mutually reliant path. In this review, we have focused on different factors that are related to circadian rhythm dysfunction. The various pathogenic factors, such as amyloid-beta, neurofibrillary tangles, oxidative stress, neuroinflammation, and circadian rhythm dysfunction may all contribute to AD. In this review, we also tried to focus on melatonin which is produced from the pineal gland and can be used to treat circadian dysfunction in AD. Aside from amyloid beta, tau pathology may have a notable influence on sleep. Conclusively, the center of this review is primarily based on the principal mechanistic complexities associated with circadian rhythm disruption, sleep deprivation, and AD, and it also emphasizes the potential therapeutic strategies to treat and prevent the progression of AD.
Serotonin (5‐HT) reuptake inhibitors, such as fluoxetine, are the most prescribed antidepressant for maternal depression. In this sense, it exposes mothers and the brains of infants to increased modulatory and trophic effects of serotonergic neurotransmission. 5‐HT promotes essential brain changes throughout its development, which include neuron migration, differentiation, and organization of neural circuitries related to emotional, cognitive, and circadian behavior. Early exposure to the SSRIs induces long‐term effects on behavioral and neural serotonergic signalization. We have aimed to evaluate the circadian rhythm of locomotor activity and the neurochemical content, neuropeptide Y (NPY) and 5‐HT in three brain areas: intergeniculate leaflet (IGL), suprachiasmatic nuclei (SCN) and raphe nuclei (RN), at two zeitgebers (ZT6 and ZT18), in male and female rat’s offspring early exposed (developmental period GD13‐GD21) to fluoxetine (20mg/kg). First, we have conducted daily records of the locomotor activity rhythm using activity sensors coupled to individual cages over four weeks. We have lastly evaluated the immunoreactivity of NPY in both SCN and IGL, and as well the 5‐HT expression in the dorsal and medial RN. In summary, our results showed that (1) prenatal fluoxetine affects phase entrainment of the rest/activity rhythm at ZT6 and ZT18, more in male than female specimens, and (2) modulates the NPY and 5‐HT expression. Here, we show male rats are more susceptible to phase entrainment and the NPY and 5‐HT misexpression compared to female ones. The sex differences induced by early exposure to fluoxetine in both the circadian rhythm of locomotor activity and the neurochemical expression into SCN, IGL, and midbrain raphe are an important highlight in the present work. Thus, our results may help to improve the knowledge on neurobiological mechanisms of circadian rhythms and are relevant to understanding the “broken brains” and behavioral abnormalities of offspring early exposed to antidepressants. Fluoxetine during pregnancy affects the serotonergic system of males and females. Males are more susceptible to change in the circadian rhythm period. Fluoxetine during pregnancy affects NPY expression more in males than in females
This chapter reviews how non-photic cues like temperature, food, anxiety and induced activity lead to circadian rhythm entrainment in mammals. Generally speaking, when dealing with entrainment by different photic and non-photic zeitgebers, we are only able to show that a certain type of stimulus can or cannot entrain the circadian system, therefore, the comparison is difficult to be quantified for the purpose of interpretation. For example, the effect of temperature as a zeitgeber could be different when used alone or when used in anti-phase with the light-dark cycle. Timed feeding and anxiety can also cause non-photic entrainment of circadian rhythms, with a potentially strong selective benefits for prey species like mice and rats.
Although significant work has been done on non-photic entrainment, there are still many open questions to date. Here we will describe different aspects of non-photic entrainment of the circadian system in mammals, with focus on certain open questions especially when nocturnal and diurnal animals are compared.
Many African mole-rats (Bathyergidae) exhibit distinct circadian rhythms, despite the fact that they are strictly subterranean and are very infrequently exposed to light. We investigated the circadian system of Emin’s mole-rats (Heliophobius emini) by exposing 13 individuals to different lighting regimes. The mole-rats were subjected to a standard 12-h light:12-h dark light cycle, followed by a constant darkness (DD) cycle to evaluate entrainment and endogenous rhythms of locomotor activity. After allowing the mole-rats to re-entrain to a 12L:12D light cycle, the light cycle was inverted to examine the duration of re-entrainment following a drastic change in the light cycle. Furthermore, we investigated the effect of different ambient temperatures on the locomotor activity of the mole-rats, and they were thus subjected to a 12D:12L light cycle at 20°C, 25°C, and 30°C. Lastly, mole-rats were presented with a long-day (16L:8D) and a short-day (8L: 16D) light cycle to look at the effect on preferred active time. The animals showed a preference for diurnal activity with 9 mole-rats entraining to the light cycle, and maintaining clear endogenous rhythms throughout DD. Subjects were excessively slow to re-entrain their activity to the inverted light cycle. When subjected to different ambient temperatures, individuals showed marked increases in average activity at 20°C, with the lowest average activity occurring at 30°C. The mole-rats maintained their diurnal preference regardless of day length, condensing their activity during the short-day light cycle, while extending their active period during the long-day cycle. These results suggest that Emin’s mole-rats are able to perceive light and entrain their locomotor activity to light cycles, albeit weakly. In addition, ambient temperature influenced the level of overall activity, indicating that these animals may use behavioral thermoregulation to maintain a constant body temperature.
It has long been hypothesized that exposure to bright light was required to entrain the non-24-h period of the human biological clock to the Earth’s 24.0-h day. We report here supplemental data from a previously published study (1) showing that even when exposed to light levels during wakefulness that are equivalent to candlelight (averaging only ∼1.5 lux in the angle of gaze), imposition of a periodic schedule of activity, sleep, meals and other routine daily activities is usually sufficient to maintain circadian entrainment to the 24.0-h day, but not to a 23.5-h or 24.6-h day. Our results indicate that either very dim light is biologically active in humans with regard to circadian photoreception and/or that the sleep-wake/rest-activity cycle itself can exert a greater influence on circadian entrainment than previously recognized. As we reported previously (1), our results also demonstrate functionally that in normally entrained, sighted adults the average intrinsic circadian period must be very near to 24 h. These results have major implications for understanding the mechanism by which the human biological clock is synchronized to environmental time and the pathophysiology of disorders of circadian regulation.
Orcadian rhythms are those daily cycles of behaviour and physiology that persist with an intrinsic period of approximately 24 hours when the individual is held in temporal isolation, devoid of cyclical environmental cues (Aschoff, 1981; Pittendrigh, 1993). They are expressed across divergent phyla (Dunlap 1999) and, in mammals, at every level of tissue organisation, from cells, through tissues to the whole organism. They are a fundamental aspect of eukaryotic organisation, and consequently have the most profound biological and clinical relevance (Hastings 1998). The spontaneous expression of circadian rhythms implies the existence of an internal biological clock or oscillator. To be biologically adaptive this internal clockwork has to be synchronised (entrained) to the solar day, so that internal time matches external time. This article will review recent developments in the analysis of the neural and molecular basis to circadian timing in mammals, and then consider how this core clockwork is entrained by light and by other environmental cues.
Modern medicine emphasizes the concept of homeostasis, constancy of the intern milieu. Accordingly, it is assumed that biological functions and processes are relatively stable during the 24 h and other time periods and that the exacerbation of disease and risk of severe clinical events are of equal probability each hour of the day and night, day of month, and month of year. Also, it is taken for granted that the kinetics and effects of medications are independent of the time of day when they are ingested, inhaled, injected, or infused. The concept of homeostasis as proposed by Claude Bernard in France in the 19th century and elaborated upon by Walter Cannon in the United States early in the 20th century was deduced from studies performed primarily during the daytime. In their eras, the assessment of biological parameters repeatedly at more than a single time of day was not generally feasible. The laboratory techniques of yesteryear necessitated the withdrawal of very large volumes of blood to determine the concentration of hormones and other constituents. Moreover, instrumentation enabling around-the-clock measurement of physiologic variables had not yet been invented. Today, modern laboratory methods require sometimes minute amounts of blood, and ambulatory devices facilitate the monitoring of a variety of variables, such as activity, body temperature, blood pressure, heart rate, and brain activity, continuously throughout the 24 h. The findings of investigations employing this technology invariably reveal that biological functions and processes are anything but constant. Rather, they document a prominent genetically based time structure consisting of rhythms with periods as short as a second or less to as long as a year (1–3). The majority of practitioners and even academic investigators know very little about biological rhythms. This chapter first discusses the fundamental properties of biological rhythms and biological timekeeping. It provides an in-depth discussion of the role of circadian (24-h) rhythms in blood pressure (BP) regulation and day—night patterns in common cardiovascular (CV) diseases.
The suprachiasmatic nucleus (SCN) is a prominent feature of the anterior hypothalamus. In virtually all mammals, the SCN is a compact group of small neurons dorsal to the optic chiasm along most of its length and just lateral to the periventricular nucleus and third ventricle (Figure 1). The SCN was recognized in early cytoarchitectonic studies (Brockhaus, 1942; Gurdjian, 1927), but its function remained obscure until the early 1970s. Perhaps the first hint was a report by Pate (1937), who observed what must be considered transneuronal atrophy of the SCN after eye removal in the cat. The issue of retinohypothalamic projections in mammals was contentious in that era and the great neuroanatomist W. J. H. Nauta concluded in the late 1960s that there were no compelling data to support such a projection. This conclusion, however, was contrary to the situation in lower vertebrates, where a projection from the retina to the suprachiasmatic area was well established (Ebbeson, 1970). As often happens, new technical advances provided the basis for new understanding. The discovery of anterograde transport by Weiss and colleagues (Weiss, 1972) was dependent upon the fact that tritiated amino acids are incorporated into proteins in neuronal perikarya and then transported through axons to sites of terminal arbors. This phenomenon formed the basis for an axoplasmic tracing method to analyze connections in brain (Cowan, Gottlieb, Hendrickson, Price, & Woolsey, 1972) and this was applied to the study of retinal projections, providing new evidence for a retinohypothalamic tract in mammals (Hendrickson, Wagoner, & Cowan, 1972; Moore, 1973; Moore & Lenn, 1972). In these studies, silver grains were found distributed over the ventral SCN, strongly suggesting that terminals of retinal axons were present in that location. This was confirmed by the electron microscopic finding of degenerating axon terminals synapsing on SCN neuron dendrites after eye removal (Moore & Lenn, 1972). These data, then, provided definitive evidence for a retinohypothalamic tract terminating in the SCN.
The mammalian clock genes clock, BMAL1, and Periods, were cloned and demonstrated to localize in the suprachiasmatic nucleus (SCN), the mammalian circadian center. In the present study, we examined the daily mRNA expression profiles of these genes by quantitative in situ hybridization. Clock was constantly expressed in the mouse SCN in any circadian time, although mammalian Periods and BMAL1 were expressed in time-dependent manner: peaks of Periods appeared in the daytime but those of BMAL1 appeared in the nighttime. Digoxigenin-in situ hybridization demonstrated that all of these clock genes were expressed in most SCN cells. These findings suggest that clock genes were expressed in the SCN with the different expression profiles.
Although light is the principal Zeitgeber in mammals, non-photic stimuli have also been described as affecting the properties of a circadian pacemaker. In the present experiment we tested the effect of 4 types of non-photic stimuli (heat and cold pulses, dexamethasone injection and access to a running-wheel) on the circadian rhythm of the motor activity of blinded Wistar rats. The Phase Response Curve and the Tau Response Curve for each stimulus were obtained. Our results show no clear effect of non-photic stimuli on the circadian rhythm of the rat, and thus, question the capacity of these animals to respond to single pulses other than light, and consequently the importance of these type of stimuli in this species.
Many people regularly wake up early in the morning on week days; however, during weekends, they stay awake late into the night and wake up late, thus representing a phase delay in their locomotor activity and sleeping pattern. We suggest that these phase delays on weekends may affect the spatial memory performance at the first couple of days in the following week. In the present study, we aimed to investigate the effects of the weekend phase delays on spatial memory performance of the Wistar albino rats at the beginning of the coming week by using Morris water maze. Control and phase delay groups were performed for both juvenile and adult rats in males and females. After eight weeks of the experimental phase delays, Morris water maze experiments were performed. Locomotor activity rhythms of the rats were also examined. The adult rats showed better learning performances in the total distance travelled and latency than the juvenile ones. However, juvenile rats entered and spent more time in the correct quadrant than adult ones. Phase delays reduced the velocity of the rats. The interaction effects among the phase delays, generation and sex were also significant. The findings of the present study showed that the phase delays at the weekends as well as their interaction with sex and generation are important on the learning performances of the Wistar albino rats.
The influence of a previously synchronised conspecific of the same sex on the circadian activity rhythm resynchronisation rate to the LD cycle was assessed in five adult male marmosets during a 6 h LD cycle delay, followed by a 6 h advance, in the absence and presence of a donor. After phase delay with donor, activity onset and offset were resynchronised in fewer days. During the transients, the occurrence of a mid-activity delay, an activity increase in the L-phase and a decrease in the D-phase indicates a faster resynchronisation. After phase advance, activity onset resynchronised promptly and the number of transients for the offset and mid-activity during the transients did not differ. Daily activity increased at phase shifts. Social cues may influence photic synchronisation in marmosets, probably due to direct effects of socially-induced arousal on the circadian pacemaker or by indirect effects, thus increasing photic input or masking.
In this review, we describe six lines of evidence that reveal a modulatory role for serotonin (5-HT) in the regulation of the response of suprachiasmatic nucleus (SCN) neurons to retinal illumination in the Syrian hamster. Electrical stimulation of the median raphe nucleus, sufficient to elicit the release of 5-HT in the SCN, inhibits light-induced phase shifts of the hamster circadian activity rhythm. Two 5-HT receptors capable of mediating the effects of 5-HT on photic responses, the 5-HT7 receptor and the 5-HT1B receptor, are present in the hamster SCN. Light-induced phase shifts are attenuated by systemic and local administration of two 5-HT receptor agonists, 8-OH-DPAT, and TFMPP, and these agents attenuate photic phase shifts by acting on pharmacologically distinct receptors. Furthermore, both compounds also attenuate light-induced Fos expression and photic suppression of pineal melatonin content, indicating that serotonergic modulation of photic signal transduction in the SCN is not limited to the regulation of circadian phase. Finally, both 8-OH-DPAT and TFMPP inhibit RHT neurotransmission in the hypothalamic slice preparation. Further, TFMPP fails to attenuate responses to exogenous glutamate on retinorecipient SCN neurons, consistent with a presynaptic site of action for the drug. Based on these data, we propose that 5-HT modulates RHT neurotransmission in the SCN through at least two distinct mechanisms: (1) via activation of 5-HT7 receptors probably located on retinorecipient neurons; and (2) via activation of presynaptic 5-HT1B receptors leading to reduced release of glutamate from RHT terminals in the SCN.
In this chapter we review clinical and experimental evidence linking biological rhythms and affective state, and explore possible mechanisms underlying these relationships. Alterations in circadian rhythmicity have been observed in association with mood disorders (Anderson and Wirz-Justice 1991; Wirz-Justice 1995) as well as in putative animal models of depression and/or altered affective state (Rosenwasser 1992). However, much of the evidence for covariation of chronobiological and affective parameters is correlative, and the causal bases for such observations have not been fully elucidated.
Aerobic running exercise in six Ss changed endogenous core body temperature and melatonin rhythm phases by 2-3 hours between early morning running and early evening running conditions.
The expression patterns of 13 GABAA receptor subunit encoding genes (alpha 1-alpha 6, beta 1-beta 3, gamma 1-gamma 3, delta) were determined in adult rat brain by in situ hybridization. Each mRNA displayed a unique distribution, ranging from ubiquitous (alpha 1 mRNA) to narrowly confined (alpha 6 mRNA was present only in cerebellar granule cells). Some neuronal populations coexpressed large numbers of subunit mRNAs, whereas in others only a few GABAA receptor-specific mRNAs were found. Neocortex, hippocampus, and caudate-putamen displayed complex expression patterns, and these areas probably contain a large diversity of GABAA receptors. In many areas, a consistent coexpression was observed for alpha 1 and beta 2 mRNAs, which often colocalized with gamma 2 mRNA. The alpha 1 beta 2 combination was abundant in olfactory bulb, globus pallidus, inferior colliculus, substantia nigra pars reticulata, globus pallidus, zona incerta, subthalamic nucleus, medial septum, and cerebellum. Colocalization was also apparent for the alpha 2 and beta 3 mRNAs, and these predominated in areas such as amygdala and hypothalamus. The alpha 3 mRNA occurred in layers V and VI of neocortex and in the reticular thalamic nucleus. In much of the forebrain, with the exception of hippocampal pyramidal cells, the alpha 4 and delta transcripts appeared to codistribute. In thalamic nuclei, the only abundant GABAA receptor mRNAs were those of alpha 1, alpha 4, beta 2, and delta. In the medial geniculate thalamic nucleus, alpha 1, alpha 4, beta 2, delta, and gamma 3 mRNAs were the principal GABAA receptor transcripts. The alpha 5 and beta 1 mRNAs generally colocalized and may encode predominantly hippocampal forms of the GABAA receptor. These anatomical observations support the hypothesis that alpha 1 beta 2 gamma 2 receptors are responsible for benzodiazepine I (BZ I) binding, whereas receptors containing alpha 2, alpha 3, and alpha 5 contribute to subtypes of the BZ II site. Based on significant mismatches between alpha 4/delta and gamma mRNAs, we suggest that in vivo, the alpha 4 subunit contributes to GABAA receptors that lack BZ modulation.
The expression patterns of 13 GABA A receptor subunit encoding genes (α1-α6, β1-β3, γ1-γ3,δ) were determined in adult rat brain by in situ hybridization. Each mRNA displayed a unique distribution, ranging from ubiquitous (α1 mRNA) to narrowly confined (α6 mRNA was present only in cerebellar granule cells). Some neuronal populations coexpressed large numbers of subunit mRNAs, whereas in others only a few GABAA receptor-specific mRNAs were found. Neocortex, hippocampus, and caudate-putamen displayed complex expression patterns, and these areas probably contain a large diversity of GABAA receptors. In many areas, a consistent coexpression was observed for α1 and β2 mRNAs, which often colocalized with γ2 mRNA. The α1β2, combination was abundant in olfactory bulb, globus pallidus, inferior colliculus, substantia nigra pars reticulata, globus pallidus, zona incerta, subthalamic nucleus, medial septum, and cerebellum. Colocalization was also apparent for the α2 and β3 mRNAs, and these predominated in areas such as amygdala and hypothalamus. The α3 mRNA occurred in layers V and VI of neocortex and in the reticular thalamic nucleus. In much of the forebrain, with the exception of hippocampal pyramidal cells, the α4 and δ transcripts appeared to codistribute. In thalamic nuclei, the only abundant GABAA receptor mRNAs were those of α1, α4, β02, and δ. In the medial geniculate thalamic nucleus, α1, α4, β02, δ and γ3 mRNAs were the principal GABAA receptor transcripts. The α5 and β1, mRNAs generally colocalized and may encode predominantly hippocampal forms of the GABAA receptor. These anatomical observations support the hypothesis that α1,β2γ2 receptors are responsible for benzodiazepine I (BZ I) binding, whereas receptors containing α2,α3, and α5 contribute to subtypes of the BZ II site. Based on significant mismatches between α4/δ and γ mRNAs, we suggest that in vivo, the α4 subunit contributes to GABAA receptors that lack BZ modulation.
The study investigated whether nonphotic cues that alter the phase of overt circadian rhythms do so by causing instantaneous shifts in the underlying, light-sensitive clock. Wheel-running activity in Syrian hamsters was studied under free-running conditions of constant dim red light as an overt marker of circadian phase, the daily onset of activity being defined as circadian time 12 (CT 12). Exposure to a 15 min pulse of bright light at CT 12.20 caused a phase delay in activity onset, whereas pulses delivered at CT 11.20 had no effect upon the overt rhythm. Correlated with their effect on behavior, light pulses delivered at CT 12.20 induced expression of c-fos-like immunoreactivity in the retinorecipient regions of the suprachiasmatic nuclei of the hypothalamus (SCN), whereas pulses delivered at CT 11.20 had no effect upon the expression of c-fos. Expression of this immediate-early gene therefore provided a second marker of circadian phase, because its induction by light is closely correlated with the onset of subjective night (CT 12). To establish a suitable protocol for nonphotic shifts of the activity rhythm, animals were handled and received a subcutaneous injection of saline at different circadian phases. Injections at CT 8 or CT10 caused an immediate bout of wheel-running activity, and a consequent phase advance in the activity rhythm as assessed by the earlier onsets of activity in successive days. Handling and injections at other circadian phases were without effect. Despite shifting the overt rhythm, these procedures at CT 10 did not lead to the expression of c-fos in the SCN.(ABSTRACT TRUNCATED AT 250 WORDS)
This paper reviews the discovery and characterization of a behavioural system for entrainment of circadian rhythms. This behavioural system depends on non-photic inputs but interacts with the light-entrainment system. Non-photic stimuli can be powerful quantitatively: behavioural events can shift rhythms by several hours. Non-photic entrainment offers scope for rephasing biological rhythms in circumstances where light input from the environment is inadequate.
Pulses of darkness can phase-shift the circadian activity rhythms of hamsters, Mesocricetus auratus, kept in constant light. Dark pulses under these conditions alter photic input to the circadian system, but they also commonly trigger wheel-running activity. This paper investigates the contribution of running activity to the phase-shifting effects of dark pulses. A first experiment showed that running activity by itself can phase-shift rhythms in constant light. Hamsters were induced to run by being confined to a novel wheel for 3-5 h. When this was done at circadian times (CT) 0, 6, and 9, the mean steady-state phase-shifts were 0.6 h, 3.5 h, and 2.3 h, respectively. The latter two values are at least as large as those previously obtained with dark pulses of similar durations and circadian phases. A second experiment showed that restricting the activity of hamsters during 3-h dark pulses at CT 9 reduces the amplitude of the phase-shifts. Unrestrained animals phase-advanced by 1.1 h, but this shift was halved in animals whose wheel was locked, and completely abolished in animals confined to nest boxes during the dark pulse. Activity restriction in itself (without dark pulses) had only minimal phase-delaying effects on free-running rhythms when given between ca. CT 10 and CT 13. These results support the idea that, in hamsters at least, dark pulses affect the circadian system mostly by altering behavioural states rather than by altering photic input to the internal clock.
In a natural environment, body rhythms are adapted to the regular alternation of night and day, and the slower seasonal cycles. Current social organization (inter alia) leads to specific mismatches between our internal physiology and our environment. Shift-work and rapid travel across several time-zones leads to forced desynchronization of internal rhythms from the external environment and from each other, with consequent problems of behavior (e.g. sleep), physiology (e.g. gut function) and performance (e.g. accident rate). Similar disorganization of daily rhythms is seen in the aged, some blind subjects and in certain pathological situations, such as delayed sleep phase insomnia, some psychiatric disorders, possibly some cancers and other pathology.
• Results of biological and psychosocial studies of depression completed in the last decade have stimulated the need for new hypotheses that synthesize these findings in a unified etiologic theory. The importance of disruption of biological rhythms on the one hand, and psychosocial losses on the other, in the causation of depressive episodes suggest one possible unifying hypothesis. The concept of loss of "social zeitgebers," ie, persons, social demands, or tasks that set the biological clock, may provide the link between biological and psychosocial theories of etiology. We suggest that a disruption of social rhythms, which may result in instability in biological rhythms, could be responsible for triggering the onset of a major depressive episode in vulnerable individuals.
This chapter focuses on the role of retinal afferents, serotonin, and melatonin in circadian entrainment in the Syrian hamster. The Syrian hamster (Mesocricetus auratus) has been used extensively in the studies of the formal properties and the neurobiology of circadian and seasonal timing. The chapter also discusses some recent studies that have used the Syrian hamster to investigate the neurochemical mechanisms by which the circadian clock is entrained. In common with other mammals, including humans, there are three neural inputs to the hamster SCN that are thought to be involved in synchronization of the clock. The powerful resetting effect of light on the circadian clock can be demonstrated by exposing free-running hamsters to brief pulses of light. The phase response curve (PRC), which describes the relationship between the circadian time at which the light is presented and the resulting phase-shift, is well characterized for the Syrian hamster. This interaction between the pathways may be especially significant during early neonatal life when the developing SCN switches from non-photic (maternal) to photic cues as the principal entraining stimuli.
Photic entrainment of circadian rhythms occurs as a consequence of daily, light-induced adjustments in the phase and period of the suprachias-matic nuclei (SCN) circadian clock. Photic information is acquired by a unique population of retinal photoreceptors, processed by a distinct subset of retinal ganglion cells, and conveyed to the SCN through the retinohypotha-lamic tract (RHT). RHT neurotransmission is mediated by the release of the excitatory amino acid glutamate and appears to require the activation of both NMDA- and non-NMDA-type glutamate receptors, the expression of immediate early genes (IEGs), and the synthesis and release of nitric oxide. In addition, serotonin appears to regulate the response of the SCN circadian clock to light through postsynaptic 5-HT1A or 5-ht7 receptors, as well as presynaptic 5-HT1B heteroreceptors on RHT terminals.
It is well established that the circadian clock of the suprachiasmatic nuclei (SCN) is entrained by light. More recently, the potent effects of arousing, non-photic cues on the clock have been recognized. The neural mediators of non-photic entrainment are yet to be identified. To examine the contribution of the thalamic intergeniculate leaflet (IGL) and its NPY-immunopositive projection, the geniculo-hypothalamic tract to non-photic entrainment by arousal, male Syrian hamsters received lesions of the IGL (IGLX) which ablated NPY-immunoreactivity in the SCN. Their circadian responses to both photic and non-photic cues were then tested. Lesions resulted in a delay in the timing of activity onset following lights out, but had no effect on the behavioural or cellular circadian responses to phase-advancing light pulses presented at circadian time (CT) CT19 (where CT12 represents the time of activity onset). Injection with a benzodiazepine (chlordiazepoxide, 100 mg/kg) at CT6 suppressed wheel-running, increased general locomotion of intact controls and induced large phase advances of the circadian rhythm of wheel-running. Chlordiazepoxide also inhibited wheel-running in lesioned animals, but there was no significant increase in general locomotion and the lesioned animals did not phase advance. Serial arousal by injection of saline at intervals of 23.5 h for 6 days entrained the circadian rhythm of wheel-running of intact hamsters and was associated with an increase in general locomotor activity. Entrainment by serial arousal was abolished by IGLX. However, the lesioned animals did show a clear behavioural response to every presentation of the non-photic cue. These results show that the IGL is a necessary component of the neural pathways mediating both arousal- and benzodiazepine-induced non-photic entrainment.
The light/dark (L/D) cycle is a major synchronizer of human circadian rhythms. In the absence of a strong L/D cycle, synchrony with 24 hours can nevertheless be maintained in a socially structured environment, as shown in Polar regions (Broadway et al. 1987) and by some blind subjects (Czeisler et al. 1995a). The relative contribution of other time cues to entrainment in dim light has not been fully explored. The present study investigated the behaviour of melatonin (assessed as 6-sulphatoxymelatonin); rectal temperature; activity and sleep (actigraphy and logs) in constant dim light (L/L) with access to a digital clock. 6 normal healthy males were maintained as a group in partial temporal isolation with attenuated sound and ambient temperature for 21 days. All 6 subjects showed free-running periodicity for 6-sulphatoxymelatonin and 5/6 subjects for temperature, activity and sleep offset. The average period (tau) was 24.26±0.049, substantially shorter than in previous experiments with a self selected L/D cycle but similar to a recent study conducted in very dim light. One subject maintained a rigid sleep/wake cycle throughout whilst his 6-sulphatoxymelatonin rhythm free-ran. Total sleep time, from actigraph data, did not change but sleep efficiency decreased during the experiment. The subjects did not show group synchronization. These results confirm previous data indicating the importance of the L/D cycle in human entrainment and underline the lesser role of social cues and knowledge of clock time. This particular approach will permit the administration of timed medication to sighted humans under free-running conditions.
Recent studies have shown that light-induced phase shifts of the circadian rhythm of locomotor activity are associated with c-fos expression in the suprachiasmatic nucleus (SCN) and intergeniculate leaflet (IGL) of the lateral geniculate nucleus of rodents. In order to determine whether c-fos expression is necessary for the phase shifting effects of a non-photic stimulus, we assessed Fos-like immunoreactivity (Fos-lir) in the SCN and IGL at various times after an injection of the short-acting benzodiazepine, triazolam, at circadian time (CT) 6; i.e. at a time when triazolam induces an acute increase in locomotor activity and maximal phase advances in the circadian rhythm of locomotor activity. Specific Fos-lir staining was not observed in the SCN or IGL regions of any animals treated with triazolam or vehicle at any time point examined. These results indicate that exposure to an activity-inducing stimulus at circadian times when this stimulus induces phase shifts does not induce Fos protein synthesis in the SCN or IGL regions.
The development of circadian rhythms and the neuronal mechanisms underlying their generation (particularly the suprachiasmatic nucleus of the hypothalamus) were reviewed. Based on perinatal animal studies and data from human foetuses and/or preterm infants it was concluded that human circadian rhythms are present as early as at 30 weeks of gestation. The significance of the mother and/or the environment regarding the entrainment of the “endogenous” foetal biological clock was emphasized.
D1 dopamine receptor localization was examined by immunohistochemistry using a polyclonal anti-peptide antibody which (i) immunoprecipitated a protein fragment encoded by a D1 receptor cDNA and (ii) on Western blots of solubilized striatal and hippocampal membranes recognized two proteins of approximately 50 kDa and 75 kDa, corresponding to reported sizes of D1 receptor proteins. Immunoreactivity overlapped with dopamine-containing pathways, patterns of D1 receptor binding, and mRNA expression. Staining was concentrated in prefrontal, cingulate, parietal, piriform, entorhinal, and hippocampal cortical areas and subcortically in the basal ganglia, amygdala, septal area, substantia inominata, thalamus, hypothalamus, and neurohypophysis. Prominent labeling was seen in the thalamic reticular nucleus, a region known to integrate ascending basal forebrain inputs with thalamocortical and corticothalamic pathways and in fiber bundles interconnecting limbic areas. In striatal neuropil, staining appeared in spines (heads and necks), at postsynaptic sites in dendrites, and in axon terminals; in the pars reticulata of the substantia nigra, labeling was prevalent in myelinated and unmyelinated axons and dendrites. These data provide direct evidence for the regional and subcellular distribution of D1 receptor protein in the brain and for its pre- and postsynaptic localization in the basal ganglia. The prominent immunoreactivity seen in the limbic system and thalamic reticular nucleus supports an important role for this receptor subtype in mediating integrative processes involved with learning, memory, and cognition.
The effects of 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone and ipsapirone on wheel-running activity in hamsters were investigated in comparison with those of GABAA receptor agonist muscimol and benzodiazepine triazolam. Intraperitoneal administration of 8-OH-DPAT, buspirone, ipsapirone, muscimol and triazolam at circadian time (CT) 8 (CT 12; onset of activity) induced a significant phase advance of wheel-running activity under constant light conditions. However, administration of these drugs at other CT points did not induce phase changes. The administration of trifluoromethylphenylpiperazine (TFMPP), a 5-HT1B receptor agonist, at CT8 produced a small phase advance. The phase advance induced by 8-OH-DPAT was blocked by pretreatment with (-)-pindolol, a 5-HT1A receptor antagonist. In addition, 8-OH-DPAT, buspirone and SM3997 accelerated the rate of re-entrainment to an 8-h phase advance in the light-dark cycle. These observations suggest that 5-HT1A receptors in the brain participate in the regulation of the circadian rhythm of wheel-running activity in hamsters.
The localization of neurons containing mRNA of the gamma 2-subunit of GABAA receptors was examined in the rat central nervous system with in situ hybridization histochemistry using an oligonucleotide probe to the sequence of the gamma 2-subunit. Neurons containing the gamma 2-subunit mRNA were widely but unevenly distributed in the brain. The location of gamma 2-subunit mRNA-containing neurons differed from those containing alpha- or beta-subunits. According to our results brain regions can be divided into three categories: one containing only gamma 2-subunit, one containing mRNA of at least one subunit other than gamma 2 and one containing more than one other subunit but not the gamma 2-subunit. The distribution of strongly labeled nuclei partly coincided with that of glutamate decarboxylase, suggesting that the GABAA receptor gamma 2-subunit would be involved in an autoreceptive mechanism of the GABAergic transmission.
The existence of an activatable dopamine system within the hypothalamic suprachiasmatic nuclei (SCN), the site of a biological clock, was investigated in rats during fetal life. In situ hybridization studies revealed that D1-dopamine receptor mRNA was highly expressed in the fetal SCN and not expressed in other hypothalamic regions. Cocaine injected into pregnant rats or directly into rat fetuses on day 20 of gestation selectively activated c-fos gene expression in the fetal SCN; cocaine did not induce c-fos expression elsewhere in the fetal brain or in the maternal SCN. This cocaine-induced activation of c-fos expression in fetal SCN was mediated in part through D1-dopamine receptors, as the cocaine-induced activation was partially blocked by the D1-dopamine receptor antagonist SCH 23390. In addition, the selective D1-dopamine receptor agonist SKF 38393 induced high levels of c-fos expression in the fetal SCN. The presence of an activatable dopamine system within the fetal SCN provides a mechanism through which maternal signals could entrain the fetal biological clock and through which maternally administered psychotropic drugs could alter normal development of the circadian timing system.
The 5-HTergic neurons in the mesencephalic raphe nuclei provide a robust projection to the hypothalamic suprachiasmatic nucleus (SCN), the site of a putative neuronal circadian pacemaker. Although it has been suggested that 5-HT neurons may play a role in the circadian timing system, this role has not yet been specified. Prosser et al. (Brain Res., 534 (1990) 336-339) reported that 1 h treatments with quipazine induce robust phase shifts in vitro, and that this effect depends upon the circadian time of treatment. However, quipazine is a non-specific 5-HT agonist. Besides, it is reported that the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetraline hydrobromide (8-OH-DPAT) affected a circadian rhythm of hamster wheel-running activity. In the present study we investigated whether the 5-HT1A agonist 8-OH-DPAT can reset the phase of the SCN clock when it is isolated in vitro. The present results show that 1 h treatments with 8-OH-DPAT induce robust phase advances in vitro when it was administered during the subjective day. This result suggests that 5HT1A receptor functioning may play a role in modulating the phase of SCN clock, especially during the subjective day.
This study investigated the relative potency of melatonin and arousal as Zeitgebers in the non-photic phase shifting of circadian rhythmicity in the adult Syrian hamster. Animals held under dim red light (DD) exhibited robust free-running rhythms of wheel-running activity. Melatonin (1 mg/kg) or ethanolic saline vehicle, delivered manually by subcutaneous injection after removing the animal from its cage, resulted in phase advances of the activity rhythm. This effect was phase dependent, injections at CT 8 and 10 being effective (CT 12 = anticipated activity onset), whereas injection at CT 2, 6, 14 and 20 did not cause a shift. There was no significant difference between the magnitude or timing of phase shifts in response to injections of saline or melatonin. To determine whether the observed shifts were related to arousal of the animals induced by handling, a second group held under DD were fitted with chronic s.c. cannulae so that melatonin solution or vehicle could be delivered remotely at projected CT 10. Neither solution had any effect upon the free-running rhythm. However, when these animals received manual s.c. injection of saline or melatonin solution, they exhibited phase advances similar to those observed in Expt. 1. These results fail to support the hypothesis that melatonin can exert a chemically specific, acute phase-shifting action in the adult Syrian hamster. They do, however, demonstrate the potent effect of arousing stimuli upon the circadian clock in this species.
Application of a new rapid perfusion (up to 4.8 ml/s) technique to 45Ca-labeled ventricular cells from adult rat heart has defined a discrete intracellular calcium (Ca) compartment with the following characteristics: 1) its exchange is absolutely dependent on operation of the Na-Ca exchanger, i.e., its isotopic content remains constant during washout in the absence of Na and Ca and is released only upon addition of Na and Ca to the perfusate. 2) At an extracellular Ca concentration of 1.0 mM it contains 350 mumol/kg dry wt cells and exchanges with half time of 650 ms. Ca flux from the compartment is 385 mumol.kg dry wt-1.s-1 or 20% of the total nonperfusion limited flux from the cells. 3) Its content is decreased 19% by 10 mM caffeine but not diminished by exposure of the cells to 10(-6) M ryanodine and not accessible to lanthanum (La) displacement. 4) Only limited exchange occurs when only Na or Ca is present and exchange is virtually eliminated by substitution of extracellular Li for extracellular Na. 5) Replacement of Na and Ca to the perfusate after various periods of removal produces no contraction (despite immediate Ca release from the cell). The results define a discrete intracellular Ca compartment which exchanges only via the Na-Ca exchanger. It is not La accessible, not in the ryanodine- or caffeine-sensitive portions of the sarcoplasmic reticulum, not in the mitochondria nor at the myofilaments, but may reside at inner sarcolemmal leaflet binding sites.
Phase-response curves (PRCs) have been reported for a wide variety of agents that induce phase shifts in the circadian rhythm of locomotor activity in the golden hamster. Many of these PRCs appear to be quite similar to one another. Because of the important role that the interpretation of PRCs has played in understanding the dynamics of the mammalian circadian pacemaker, a review of PRCs for the golden hamster reported from 1964 to 1991 was conducted to systematically summarize the common characteristics among these PRCs. Plots of phases associated with the peak of the advance portions, or of phases associated with the transitions between the delay and advance portion of the PRCs, revealed bimodal distributions of PRCs 11-13 h apart. Mardia-Watson-Wheeler circular test statistics indicated that the PRCs were distributed as two distinct populations. PRCs were either characteristic of those for light pulses (L-PRCs), or of those for dark pulses (D-PRCs). Taken with anatomical and physiological evidence, these data suggest that either one or two final common pathways may exist to mediate the phase-shifting effects of different stimuli.
Administration of benzodiazepines at appropriate times in the circadian cycle induce phase-shifts in circadian locomotor activity. The possibility that benzodiazepine-induced shifts are mediated at the level of the suprachiasmatic nuclei (SCN), identified as the circadian pacemaker in mammals, was examined electrophysiologically. Extracellular recordings were made from Syrian hamster (Mesocricetus auratus) hypothalamic SCN neurones in vitro to assess (1) the effects of gamma-aminobutyric acid (GABA) on SCN neuronal activity and (2) the effects of benzodiazepines (chlordiazepoxide and flurazepam) on GABA-evoked responses. Of 93 SCN cells tested, 86 were suppressed by iontophoresed GABA (20 mM) in a current(dose)-dependent manner, while 6 were unaffected; suppression was found during both the projected light and dark phases of the circadian cycle. Application of bicuculline methiodide alone elevated mean discharge activity, while GABA-evoked suppressions were blocked by bicuculline (n = 9/11 cells). Iontophoresis of chlordiazepoxide or flurazepam (20 mM; 1-10 nA) alone produced a current(dose)-dependent prolonged suppression of cell firing which was antagonised by bicuculline. These results indicate that benzodiazepine/GABA-evoked responses are at least partially mediated by GABAA receptors within the SCN and suggest that SCN may be a possible locus for the action of benzodiazepines in their induction of phase-shifts in circadian function.
Administration of the benzodiazepine triazolam at the appropriate time in the circadian cycle has been shown to induce phase shifts in hamster circadian rhythms. These phase shifts can be blocked by geniculo-hypothalamic tract (GHT) ablation or by restraint of activity. The present study examined the effects of the benzodiazepine chlordiazepoxide on running-wheel activity rhythms of hamsters. The phase-advancing effect of intraperitoneal injections of chlordiazepoxide administered at circadian time 6 (CT 6) was dose-dependent. Average shifts ranged from 6 min at a dose of 0.05 mg/kg to 135 min at a dose of 200 mg/kg. Four of twenty hamsters did not show a phase shift to any dose tested. Phase advance shifts to chlordiazepoxide (CT 6; 100 mg/kg) were blocked by GHT lesions. Chlordiazepoxide injections at doses which induced phase shifts were often followed by sedation. These results indicate that chlordiazepoxide is similar to triazolam, in that its ability to induce phase shifts at circadian time 6 is blocked by GHT lesions.
Circadian rhythm entrainment has long been thought to depend exclusively on periodic cues in the external environment. However, evidence now suggests that appropriately timed vigorous activity may also phase shift the circadian clock. Previously it was not known whether levels of exercise/activity associated with spontaneous behavior provided sufficient feedback to phase shift or synchronize circadian rhythms. The present study investigated this issue by monitoring the sleep-wake, drinking, and wheel-running circadian rhythms of mice (Mus musculus) during unrestricted access to running wheels and when free wheel rotation was limited to either 12- or 6-h intervals with a fixed period of 24 h. Wheel rotation was controlled remotely. Mice spontaneously ran in wheels during scheduled access, and free-running sleep-wake and drinking circadian rhythms became entrained to scheduled exercise in 11 of 15 animals. However, steady-state entrainment was achieved only when exercise commenced several hours into the subjective night. The temporal placement of running during entrainment was related (r = 0.7003, P less than 0.02) to free-running period before entrainment. Mice with a free-running period less than 23.0 h did not entrain but exhibited relative coordination between free-running variables and the wheel availability schedule. Thus the circadian timekeeping system responds to temporal feedback arising from the timing of volitional exercise/activity, suggesting that the biological clock not only is responsive to periodic geophysical events in the external environment but also derives physiological feedback from the spontaneous activity behaviors of the organism.
gamma-Aminobutyric acid (GABA) and exogenous benzodiazepines are thought to play a role in the neural regulation of circadian rhythms. Because binding sites for the benzodiazepines and GABAA ligands are functionally coupled as part of the GABAA/benzodiazepine receptor complex (GABAA/BZR), we analyzed the localization of GABA neurons and GABAA/BZR within 3 nuclei involved in circadian rhythm regulation using autoradiographic and immunohistochemical techniques. Glutamic acid decarboxylase-immunoreactive axons are present in the suprachiasmatic nuclei (SCN), intergeniculate leaflet (IGL), and dorsal raphe nucleus (DR). Immunoreactivity for the GABAA/BZ receptor complex is absent from the SCN and the IGL whereas the DR shows a dense, uniform immunoreactivity. Semiquantitative analysis of autoradiograms for [3H]diazepam and [3H]flunitrazepam binding reveals a moderate level of binding in the SCN, a low level of binding in the IGL, and the highest level of the DR. Based on both the pattern of benzodiazepine binding and of receptor immunoreactivity the DR would appear to be a likely target site for GABAA and benzodiazepine action. The SCN would also appear to be a possible target site. The results suggest the IGL is not a site for direct GABAA and benzodiazepine action, but do not exclude a role for the IGL in the neural circuitry mediating GABA and benzodiazepine interactions with the circadian system.
The role of the serotonergic system in the regulation of hamster circadian rhythms was analyzed using intraventricular injection of the selective neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). Sixty days after 5,7-DHT administration, immunoreactive serotonin in the forebrain, particularly the suprachiasmatic nuclei and intergeniculate leaflets, was severely depleted in 16 animals, moderately depleted in four and only slightly affected in four. 5,7-DHT produced an immediate and sustained advance of the onset of running wheel activity relative to the 24 h light-dark (LD) cycle. Activity onset occurred 0.7 +/- 0.07 h before lights out among 5,7-DHT-treated animals compared with 0.18 +/- 0.04 h after lights out for vehicle-infused controls. This new, advanced phase angle of entrainment was maintained throughout the 60-day period of the study while the animals remained in a LD cycle, including after an 8-h phase advance of the light cycle. 5,7-DHT treatment also delayed the offset of wheelrunning in 16 of 24 animals and reduced the likelihood of a smooth pattern of reentrainment to the shifted LD cycle. The drug treatment did not affect circadian period in constant darkness, the rate of reentrainment to an 8-h phase advance or the amount of wheelrunning activity per day. In addition, 5,7-DHT treatment had no effect on the ability of triazolam, a short-acting benzodiazepine, to accelerate the rate of reentrainment to an 8-h phase advance. These observations show that ascending projections of midbrain raphe serotonin neurons participate in the regulation of the circadian activity phase but are not required for triazolam-induced acceleration of reentrainment to a phase-advanced LD cycle.
In two experiments, triazolam (2.5 and 1.5 mg/animal) failed to significantly enhance the rate of reentrainment of hamsters (Mesocricetus auratus) to an 8-hr advance of their light-dark cycle. Evidently the phase-shifting effects of triazolam are not robust. The animals did not run much in their wheels in response to the drug in these two experiments. In a third experiment, triazolam (0.5 and 2.5 mg/animal) produced phase advances of activity rhythms of hamsters in the dark. In this experiment, running in response to the drug was greater. Hamsters given triazolam but confined to their nest boxes over the next few hours did not show phase shifts. The phase-shifting effects of triazolam (when they do occur) appear to be mediated through activity increases. Triazolam-treated hamsters became ataxic in all three of these experiments. Suggestions that triazolam may be useful in ameliorating rhythm disturbances in people should be treated with a caution.
An immunocytochemical analysis with 33 antisera was undertaken to investigate the localization of 25 different neurotransmitter-related antigens in the hypothalamic suprachiasmatic nucleus in the rat. To obtain estimates of relative densities of immunoreactive axons a stereological approach was used involving counting of intersections of immunoreactive axons with a superimposed semi-circle test grid. All neurotransmitter-related antigens found in perikarya within the suprachiasmatic nucleus, including those stained with antisera against bombesin, gastrin-releasing peptide, neurophysin, vasopressin, somatostatin, gamma-aminobutyrate, glutamate decarboxylase and vasoactive intestinal polypeptide were also found in axons within the nucleus. A greater number of these immunoreactive axons was found within the nucleus than in the adjacent anterior hypothalamus. The size of all immunoreactive axons in the suprachiasmatic nucleus was consistently small; immunoreactive axons were found ramifying widely in the nucleus, often ending with terminal boutons near perikarya immunoreactive for the same antigen. All neurotransmitter-related substances found in perikarya of the suprachiasmatic nucleus were also found in axons crossing over the midline to innervate the contralateral nucleus, providing an anatomical substrate for a high degree of communication between the paired nuclei. Axons immunoreactive for other putative transmitters including serotonin arising outside the nucleus were also found in high densities within the nucleus and crossing over the midline between the nuclei. Immunoreactivity for some transmitters was found in axons of similar densities within and outside the nucleus, including antisera against tyrosine hydroxylase; a small number of dopamine beta-hydroxylase and a few phenylethanolamine N-methyltransferase-immunoreactive axons were found in the SCN, suggesting that dopamine, norepinephrine and epinephrine may occur in a limited number of axons in the nucleus. Small numbers of axons immunoreactive with antisera raised against cholecystokinin, prolactin, substance P, thyrotropin-releasing hormone and choline acetyltransferase were found within the suprachiasmatic nucleus. Axons immunoreactive for luteinizing hormone-releasing hormone, adrenocorticotropic hormone, alpha-melanocyte-stimulating hormone and neurotensin were rarely found within the suprachiasmatic nucleus; axons immunoreactive for luteinizing hormone-releasing hormone, adrenocorticotropic hormone, cholecystokinin and tyrosine hydroxylase were found in both horizontal and coronal sections in the area between the left and right suprachiasmatic nuclei.(ABSTRACT TRUNCATED AT 400 WORDS)
The adjustment of hamsters to advanced light-dark (LD) cycles can be greatly accelerated by scheduling a single 3-hr bout of extra activity in a novel running wheel, starting about 7 hr before the time when the animals become active in the preceding LD cycle. The present experiments were designed to provide stronger evidence that this effect depends on a shift in the pacemaker rather than on masking. It was shown that when hamsters were put into continuous darkness (DD) 1 day after the exercise-accelerated phase shift, their free-running rhythms took off from a time nearer to the onset of darkness in the new LD cycle than in the preceding LD cycle. An incidental finding was that in DD the free-running period of the hamsters with the accelerated phase shifts was longer than that of the control animals. Further evidence that the 3-hr exercise pulse had produced a greater phase advance than that occurring in undisturbed control animals was obtained by giving a light pulse at the same clock time to all animals after they had been in DD for 8 days. The animals that had previously exercised for the additional 3-hr phase-advanced in response to the light pulse, while the undisturbed control animals phase-delayed.
A dogma in the field of circadian rhythms is that in order to keep accurate time, pacemakers that generate such rhythms must be relatively independent of changes in the external and internal environment. While it is true that the period of circadian oscillators is conserved within a narrow range, regardless of alterations in the external and internal environment, numerous perturbations have now been found that can change the period and/or induce a phase shift in circadian pacemakers. Many of these perturbations also alter the overall level of activity and/or metabolic state of the organism. In 1960, Aschoff suggested that alterations in the "level of excitement" may induce changes in circadian clocks. Although little attention has been given to this hypothesis over the past three decades, recent findings support its validity and open new avenues for studying the function and organization of circadian clock systems.
Neurotransmission effected by GABA (gamma-aminobutyric acid) is predominantly mediated by a gated chloride channel intrinsic to the GABAA receptor. This heterooligomeric receptor exists in most inhibitory synapses in the vertebrate central nervous system (CNS) and can be regulated by clinically important compounds such as benzodiazepines and barbiturates. The primary structures of GABAA receptor alpha- and beta-subunits have been deduced from cloned complementary DNAs. Co-expression of these subunits in heterologous systems generates receptors which display much of the pharmacology of their neural counterparts, including potentiation by barbiturates. Conspicuously, however, they lack binding sites for, and consistent electrophysiological responses to, benzodiazepines. We now report the isolation of a cloned cDNA encoding a new GABAA receptor subunit, termed gamma 2, which shares approximately 40% sequence identity with alpha- and beta-subunits and whose messenger RNA is prominently localized in neuronal subpopulations throughout the CNS. Importantly, coexpression of the gamma 2 subunit with alpha 1 and beta 1 subunits produces GABAA receptors displaying high-affinity binding for central benzodiazepine receptor ligands.
The suprachiasmatic nucleus (SCN) receives photic input via a direct retinohypothalamic tract (RHT) and an indirect geniculohypothalamic tract (GHT). The neurons giving rise to the GHT are in the intergeniculate leaflet (IGL) of the lateral geniculate nucleus (LGN) and contain neuropeptide-Y (NPY) immunoreactivity. The present study used the neurotoxin, N-methyl aspartate (NMA), to examine the effects of lesions of the LGN on circadian wheelrunning in the hamster. The results are compared to those from control lesioned animals and animals with parasigittal cuts through the hypothalamus. The effectiveness of the lesions was examined with NPY immunohistochemistry of the SCN and IGL. NMA injections destroyed the neurons of the IGL and the adjacent ventral and dorsal divisions of the LGN and greatly reduced NPY immunoreactivity in the SCN. The results of the rhythm studies were: 1) NMA injection into the LGN area produced phase advances if the injection occurred within the 12 hr preceding activity onset and delays or no effect if injected during the 12 hr after activity onset; 2) the NMA lesions reduced the rate of reentrainment to 6 hr shifts in the LD 14:10 photoperiod and advanced the entrained phase angles by about 10 min; 3) the knife cuts advanced the entrained phase angles by about 30 min; 4) neither NMA lesions nor knife cuts altered circadian period in constant dim light. Our results indicate that the GHT is not required for entrainment or normal expression of circadian rhythmicity, but that the GHT does exert an influence on entrainment.
A number of environmental and pharmacological stimuli capable of inducing phase shifts and/or period changes in the circadian clock of mammals have now been identified. Agents that can alter circadian clocks provide a means for investigating the cellular and neural mechanisms responsible for their generation, regulation and entrainment. Two stimuli that have been used to probe the basis of circadian rhythmicity are pulses of darkness on a background of constant light and injections of short-acting benzodiazepines, such as triazolam. Surprisingly, these two very different stimuli have remarkably similar phase-shifting effects on the circadian clock of hamsters. The observation that a short-term increase in locomotor activity occurs when the circadian activity rhythm of hamsters is shifted by dark pulses or triazolam injections, coupled with the finding that activity bouts themselves are capable of shifting this rhythm, raises the possibility that dark pulses or triazolam alter the circadian clock by inducing acute hyperactivity. Here we demonstrate that the phase-advancing and phase-delaying effects of dark pulses or triazolam on the circadian activity rhythm can be totally suppressed by immobilization of the animals during treatment. These results indicate that behavioural events mediate the phase-shifting effects of both dark pulses and triazolam on the circadian activity rhythm and question present hypotheses regarding the pathways by which light-dark information and pharmacological agents influence circadian pacemakers.
The suprachiasmatic nucleus (SCN) of the hypothalamus contains a neural oscillatory system which regulates many circadian rhythms in mammals. Immunohistochemical evidence indicates that a relatively high density of GABAergic neurons exist in the suprachiasmatic region. Since intraperitoneal injections of the benzodiazepine, triazolam, have been shown to induce phase shifts in the free-running circadian rhythm of locomotor activity in the golden hamster, the extent to which microinjections of muscimol, a specific agonist for gamma-aminobutyric acid (GABA), may cause phase-shifts in hamster activity rhythms was investigated. Stereotaxically implanted guide cannulae aimed at the region of the SCN were used to deliver repeated microinjections in individual animals. A phase-response curve (PRC) generated from microinjections of muscimol revealed that the magnitude and direction of permanent phase-shifts in the activity rhythm were associated with the time of administration. The PRC generated for muscimol was characterized by maximal phase-advances induced 6 h before activity onset and by maximal phase-delays which occurred 6 h after activity onset. The PRC for muscimol had a shape similar to a PRC previously generated for the short-acting benzodiazepine, triazolam. Single microinjections of different doses of muscimol given 6 h before activity onset induced phase-advances in a dose-dependent fashion. Histological analysis revealed that phase shifts induced by the administration of muscimol were associated with the proximity of the injection site to the SCN area. These data indicate that a GABAergic system may exist within the suprachiasmatic region as part of a central biological clock responsible for the regulation of the circadian rhythm of locomotor activity in the golden hamster.
Destruction of the maternal suprachiasmatic nuclei (SCN) early in gestation disrupts maternal communication of time-of-day information to the rat fetus. In the present study, we demonstrated that periodic feeding (food cue) to SCN-lesioned pregnant rats entrains the fetal biological clock. The phase of the drinking behavior rhythm was examined in pups reared in constant darkness, beginning at weaning. In several control (uncued) litters, pup phases at weaning were scattered. In other control litters where within-litter coordination of phase was observed, the average litter phase was unpredictable. In contrast, drinking rhythms of pups whose dams had received food cue during gestation were synchronized within- and between-litters, suggesting that prenatal food cue entrained the fetuses. The effect of food cue occurs prenatally, as similar results were obtained when offspring of SCN-lesioned, cued dams were fostered to lesioned, uncued dams on the day of birth. The present results, along with data from this and other laboratories, suggest that redundant mechanisms communicate time-of-day information to the fetus.
The effects of periodic, restricted feeding (RF) for two hours at a fixed time of day on the circadian rhythms of locomotor activity were examined in CS and C57BL/6J mice, kept under continuous dim, red lights (LLdim). In C57BL/6J mice, free-running rhythms were not affected by an RF schedule, although anticipatory behavior prior to the food access period was observed. On the other hand, the free-running rhythms of CS mice did entrain to an RF schedule, exhibiting anticipatory behavior. The free-running rhythms of none of the control animals in either strain exhibited any effects resulting from the periodic disturbances occurring concurrently with the performance of RF. These results indicate that the circadian pacemaker couples with the food entrainable oscillator (FEO) in CS mice, but that such coupling may not exist, or may be very weak, in C57BL/6J mice.
The suprachiasmatic nuclei (SCN) contain the major pacemaker for mammalian circadian rhythms. The SCN receive photic input both directly, via the retinohypothalamic tract (RHT), and indirectly, via the geniculohypothalamic tract (GHT), which originates in cells in the intergeniculate leaflet (IGL) and anterior portions of the ventral lateral geniculate nucleus (vLGN). We tested whether electrical stimulation of the GHT would induce phase shifts in wheel-running activity rhythms of Syrian hamsters housed in continuous darkness or continuous illumination. In both lighting conditions, electrical stimulation of the GHT induced mainly phase advances when given during the late subjective day and small phase delays when given during the late subjective night and early subjective day. Stimulation in the thalamus outside the GHT failed to produce similar phase shifts. Repeated daily stimulation had only a weak entraining effect on the activity rhythm. Activation of GHT neurons appears to influence the pacemaker for activity rhythms in a phase-dependent manner.
The hormone melatonin is secreted primarily from the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone, through an action in the brain, appears to be involved in the regulation of various neural and endocrine processes that are cued by the daily change in photoperiod. This article reviews the pharmacological characteristics and function of melatonin receptors in the central nervous system, and the role of melatonin in mediating physiological functions in mammals. Melatonin and melatonin agonists, at picomolar concentrations, inhibit the release of dopamine from retina through activation of a site that is pharmacologically different from a serotonin receptor. These inhibitory effects are antagonized by the novel melatonin receptor antagonist luzindole (N-0774), which suggests that melatonin activates a presynaptic melatonin receptor. In chicken and rabbit retina, the pharmacological characteristics of the presynaptic melatonin receptor and the site labeled by 2-[125I]iodomelatonin are identical. It is proposed that 2-[125I]iodomelatonin binding sites (e.g., chicken brain) that possess the pharmacological characteristics of the retinal melatonin receptor site (order of affinities: 2-iodomelatonin greater than 6-chloromelatonin greater than or equal to melatonin greater than or equal to 6,7-di-chloro-2-methylmelatonin greater than 6-hydroxymelatonin greater than or equal to 6-methoxymelatonin greater than N-acetyltryptamine greater than or equal to luzindole greater than N-acetyl-5-hydroxytryptamine greater than 5-methoxytryptamine much greater than 5-hydroxytryptamine) be classified as ML-1 (melatonin 1). The 2-[125I]iodomelatonin binding site of hamster brain membranes possesses different binding and pharmacological characteristics from the retinal melatonin receptor site and should be classified as ML-2. In summary, the recent advances in the pharmacological characterization of melatonin receptors in the central nervous system will further stimulate the search for potent and selective melatonin receptor agonists and antagonists, and should aid in our understanding of the mechanism of action of melatonin in mammalian brain.
In vitro autoradiography with 125I-labeled melatonin was used to examine melatonin binding sites in human hypothalamus. Specific 125I-labeled melatonin binding was localized to the suprachiasmatic nuclei, the site of a putative biological clock, and was not apparent in other hypothalamic regions. Specific 125I-labeled melatonin binding was consistently found in the suprachiasmatic nuclei of hypothalami from adults and fetuses. Densitometric analysis of competition experiments with varying concentrations of melatonin showed monophasic competition curves, with comparable half-maximal inhibition values for the suprachiasmatic nuclei of adults (150 picomolar) and fetuses (110 picomolar). Micromolar concentrations of the melatonin agonist 6-chloromelatonin completely inhibited specific 125I-labeled melatonin binding, whereas the same concentrations of serotonin and norepinephrine caused only a partial reduction in specific binding. The results suggest that putative melatonin receptors are located in a human biological clock.
A single injection of the short-acting benzodiazepine, triazolam, can induce permanent phase shifts in the circadian rhythm of locomotor activity in free-running hamsters, with the direction and magnitude of the phase shifts being dependent on the circadian time of treatment. The shape of the "phase-response curve" to triazolam injections is totally different from that for light pulses. These findings raise the possibility that repeated injections of triazolam on a circadian basis might be capable of entraining the circadian pacemaker underlying the activity rhythm of hamsters and that the entrainment pattern might differ from that observed in animals entrained to light pulses. To test this hypothesis, blind hamsters received intraperitoneal injections of triazolam (or vehicle) every 23.34, 23.72, 24.00 or 24.66 h for 19-20 days, and the effect of these injections on the period of the rhythm of wheel-running behavior was determined during and after treatment. Repeated injections of 0.1 mg triazolam at these time intervals resulted in the entrainment of the activity rhythm in 36 of 40 animals, whereas 0 of 40 animals entrained to vehicle injections. Importantly, the phase relationship between triazolam injections and the circadian activity rhythm was dependent on the period of drug treatment and could be predicted from the phase-response curve to single injections of triazolam. These phase relationships are dramatically different from those observed between the activity rhythm and 1-h light pulses presented at similar circadian intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
I am invited to lunch In a Chinese restaurant, Something I love, By a patient whom I don't know so well, A former Jewish Bombardier, Whose arthritic leg I cannot cure, but Who wants to tell me How and why and when it happened, Though he warns me That the pain may be Too much for me, As his memories, carefully stored, Catalogued, encoded, will be Deciphered in a Chinese boatman's eatery. A host who too was bombed In that place called Nam, Now serves me and my patient, Who wants not so much to heal the damaged limb, As to let me know his wounded spirit, Torn long ago by Shrapnel over Hamburg or Bremen, But never over Belsen or Dachau; For that was not allowed, But now I fear, as he suspected, To hear next week His tale, To know his pain To relive my childhood fantasies In his reality.
Several pharmacological treatments, including application of an excitatory neurotoxin to the lateral geniculate nucleus (LGN) and systemic administration of triazolam, a clinically effective benzodiazepine, can elicit large phase shifts in a circadian rhythm according to the time of administration. The hypothesis that the LGN might mediate the effect of triazolam on circadian clock function was tested. Bilateral lesions of the LGN, which destroyed the connection from the intergeniculate leaflet to the suprachiasmatic nucleus, blocked phase-shift responses to triazolam. The requirement of an intact LGN for triazolam to shift circadian phase suggests that the LGN may be a site through which stimuli gain access to the circadian clock to modulate rhythm phase and entrainment.
Three daily injections of the short-acting benzodiazepine, triazolam, induced pronounced phase shifts in the onset of both the circadian surge in pituitary LH release and the circadian rhythm of locomotor activity in ovariectomized hamsters treated with estrogen. Both the magnitude and the direction of the phase shifts in these two rhythms were similar. These results indicate that a master circadian clock underlying diverse behavioral and endocrine rhythms can be reset by treatment with triazolam.