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ABSTRACT: The current study investigated whether candidate cognitive endophenotypes may be used to validate a schizo-obsessive subtype. Using within-subject random effect regression analyses and cross-trait cross-relative analyses, we evaluated the association between obsessive-compulsive symptoms (OCSs) and cognitive performance in 984 patients with nonaffective psychosis (22.5% with OCSs), 973 unaffected siblings (7.7% with OCSs), 851 parents (4.2% with OCSs), and 573 controls (4.5% with OCSs). No significant within-subject associations between OCSs and cognitive functioning were found for patients and siblings. Severity of OCSs was associated with worse set-shifting ability in parents and worse processing speed in controls, but effect sizes were small (0.10 and 0.05 respectively). Cross-trait cross-relative analyses yielded no significant results. Contrary to our expectations, neither within-subject analyses nor cross-relative analyses yielded a clear association between OCSs and cognitive performance. Results do not support a schizo-obsessive subtype associated with cognitive impairment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Mammalian circadian rhythms are driven by the circadian pacemaker of the suprachiasmatic nucleus (SCN) and are synchronized to the external 24-hour light/dark cycle. After advance time zone transitions (eastbound jet lag), overt circadian rhythms require several days to adjust. The retarded adaptation may protect against acute imbalance of different brain systems. Abrupt circadian rhythm changes may trigger migraine attacks, possibly because migraineurs have an inadequate adaptation mechanism. The novel R192Q knock-in migraine mouse model carries mutated Ca(v)2.1 calcium channels, causing increased presynaptic calcium influx and neurotransmitter release. We investigated whether these mice have an abnormal adjustment to phase advance shifts. METHODS: We examined phase resetting to 6-hour advance shifts of the light/dark cycle with behavioral and electroencephalographic recordings in R192Q and wild-type mice. We recorded excitatory postsynaptic currents in the SCN, and electrical impulse frequency in vitro and in vivo. RESULTS: R192Q mice showed a more than twofold enhanced adjustment of behavioral wheel-running activity and electroencephalographic patterns, as well as enhanced shifts of electrical activity of SCN neurons in vivo. No differences were found for in vitro recordings of the electrical impulse frequency in SCN slices. INTERPRETATION: R192Q migraine mice lack the physiological retardation in circadian adaptation to phase advance shifts. The opposite findings in vivo and in vitro exclude involvement of the retinal input pathway or the phase-shifting capacity of the SCN. Thus, the physiological inhibitory process appears to be mediated by Ca(v)2.1 channel-dependent afferent signaling from extra-SCN brain areas to the SCN. [ABSTRACT FROM AUTHOR]

Eveningness has been associated with both disturbed sleep and depression. It is unclear, however, if deprived sleep explains evening types' vulnerability to depression. The role of pre-sleep rumination in these associations also remains understudied. The present study assessed the relationship between eveningness and sleep quality, as well as the possible mediating effect of pre-sleep rumination and the moderating effect of a history of depression, under naturalistic conditions. Eighty-eight Dutch-speaking participants (87.5% females, 21.4 ± 3.7 years) were selected on the basis of their non-intermediate chronotype using the Morningness Eveningness Questionnaire (evening types (n = 53); morning types (n = 35)). Depression status was assessed through a diagnostic interview (healthy (n = 61); remitted depressed (n = 27)). Participants' sleep characteristics were monitored via actigraphy and sleep diaries for seven consecutive days and nights. Pre-sleep rumination was measured via a self-report questionnaire. Evening types had longer subjective and actigraphic sleep onset latency than morning types. Pre-sleep rumination did not mediate the former associations but predicted longer subjective sleep onset latency. Furthermore, the relationship between chronotype and subjective sleep onset latency was moderated by depression history. Remitted depressed evening types reported longer sleep onset latency than healthy evening and morning types, possibly posing the former at a higher risk for depressive relapse. Overall, the current findings address the need to further investigate the physiological signature of circadian rhythms and sleep latency. This could serve as a foundation for the development of prevention and early intervention programs, tailored for mood and sleep disorders., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Circadian clock function declines with ageing, which can aggravate ageing-related diseases such as type 2 diabetes and neurodegenerative disorders. Understanding age-related changes in the circadian system at a systemic level can contribute to the development of strategies to promote healthy ageing. The goal of this study was to investigate the impact of ageing on 24-h rhythms in amine metabolites across four tissues in young (2 months of age) and old (22-25 months of age) mice using a targeted metabolomics approach. Liver, plasma, the suprachiasmatic nucleus (SCN; the location of the central circadian clock in the hypothalamus) and the paraventricular nucleus (PVN; a downstream target of the SCN) were collected from young and old mice every 4 h during a 24-h period (n = 6-7 mice per group). Differential rhythmicity analysis revealed that ageing impacts 24-h rhythms in the amine metabolome in a tissue-specific manner. Most profound changes were observed in the liver, in which rhythmicity was lost in 60% of the metabolites in aged mice. Furthermore, we found strong correlations in metabolite levels between the liver and plasma and between the SCN and the PVN in young mice. These correlations were almost completely abolished in old mice. These results indicate that ageing is accompanied by a severe loss of the circadian coordination between tissues and by disturbed rhythmicity of metabolic processes. The tissue-specific impact of ageing may help to differentiate mechanisms of ageing-related disorders in the brain versus peripheral tissues and thereby contribute to the development of potential therapies for these disorders., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Cancer survivors can experience long lasting fatigue resulting in a lower quality of life. How chemotherapy treatment contributes to this fatigue is poorly understood. Previously we have shown in a mouse model of cancer related fatigue that doxorubicin treatment induces fatigue-like symptoms related to disturbed circadian rhythms. However, the specific components of the circadian regulatory circuitry affected by doxorubicin treatment remained unclear. Therefore we investigated the role of the central circadian clock, the suprachiasmatic nucleus (SCN), in chemotherapy-induced fatigue., Methods: We measured circadian controlled behavior and multiunit neuronal activity in the SCN in freely moving mice exhibiting fatigue-like behavior after doxorubicin treatment under both light-dark (LD) and constant dark (DD) conditions. Additionally, we assessed the expression of inflammation related genes in spleen and kidney as potential inducers of CRF., Results: Doxorubicin treatment significantly reduced both the running wheel activity and time spent using the running wheel for over five weeks after treatment. In contrast to the pronounced effects on behavior and neuronal activity of doxorubicin on circadian rhythms, peripheral inflammation markers only showed minor differences, five weeks after the last treatment. Surprisingly, the circadian SCN neuronal activity under both LD and DD conditions was not affected. However, the circadian timing of neuronal activity in peri-SCN areas (the brain areas surrounding SCN) and circadian rest-activity behavior was strongly affected by doxorubicin, suggesting that the output of the SCN was altered. The reduced correlation between the SCN neuronal activity and behavioral activity after doxorubicin treatment, suggests that the information flow from the SCN to the periphery was disturbed., Conclusion: Our preclinical study suggests that chemotherapy-induced fatigue disrupts the circadian rhythms in peripheral brain areas and behavior downstream from the SCN, potentially leading to fatigue like symptoms. Our data suggest that peripheral inflammation responses are less important for the maintenance of fatigue. Chronotherapy that realigns circadian rhythms could represent a non-invasive way to improve patient outcomes following chemotherapy., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

A robust endogenous clock is required for proper function of many physiological processes. The suprachiasmatic nucleus (SCN) constitutes our central circadian clock and allows us to adapt to daily changes in the environment. Aging can cause a decline in the amplitude of circadian rhythms in SCN and peripheral clocks, which contributes to increased risk of several chronic diseases. Strengthening clock function would therefore be an effective strategy to improve health. A high-throughput chemical screening has identified clock-enhancing molecule 3 (CEM3) as small molecule that increases circadian rhythm amplitude in cell lines and SCN explants. It is, however, currently not known whether CEM3 acts by enhancing the amplitude of individual single-cell oscillators or by enhancing synchrony among neurons. In view of CEM3's potential, it is of evident importance to clarify the mode of action of CEM3. Here, we investigated the effects of CEM3 on single-cell PERIOD2::LUCIFERASE rhythms in mouse SCN explants. CEM3 increased the amplitude in approximately 80%-90% of the individual cells in the SCN without disrupting the phase and/or period of their rhythms. Noticeably, CEM3's effect on amplitude is independent of the cell's initial amplitude. These findings make CEM3 a potential therapeutic candidate to restore compromised amplitude in circadian rhythms and will boost the development of other molecular approaches to improve health., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

The mammalian circadian clock is located in the suprachiasmatic nucleus (SCN) and consists of a network of coupled neurons, which are entrained to the environmental light-dark cycle. The phase coherence of the neurons is plastic and driven by the duration of daylight. With aging, the capacity to behaviorally adapt to seasonal changes in photoperiod reduces. The mechanisms underlying photoperiodic adaptation are largely unknown, but are important to unravel for the development of novel interventions to improve the quality of life of the elderly. We analyzed the phase coherence of single-cell PERIOD2::LUCIFERASE (PER2::LUC) expression rhythms in the SCN of young and old mice entrained to either long or short photoperiod. The phase coherence was used as input to a 2-community noisy Kuramoto model to estimate the coupling strength between and within neuronal subpopulations. The model revealed a correlation between coupling strength and photoperiod-induced changes in the phase relationship among neurons, suggesting a functional link. We found that the SCN of young mice adapts in coupling strength over a large range, with weak coupling in long photoperiod (LP) and strong coupling in short photoperiod (SP). In aged mice, we also found weak coupling in LP, but a reduced capacity to reach strong coupling in SP. The inability to respond with an increase in coupling strength suggests that manipulation of photoperiod is not a suitable strategy to enhance clock function with aging. We conclude that the inability of aged mice to reach strong coupling contributes to deficits in behavioral adaptation to seasonal changes in photoperiod.

Ketamine is known for its antidepressant effects, but the mechanism underlying this effect remains largely unclear. In contrast to most antidepressant drugs, the action of ketamine is rapid, suggesting a different mode of action. A rapid antidepressant effect is also observed following sleep deprivation (SD). In the present study, we aimed to evaluate the effect of a 6-h SD and acute ketamine treatment on vigilance states, locomotor activity, and electroencephalogram (EEG) power density spectra in Brown Norway rats under constant condition over 2 recording days. After SD and after the initial waking period induced by ketamine, both treatments induced a similar increase in non-rapid eye movement (NREM) sleep and EEG slow-wave activity (SWA) in NREM sleep. Rapid eye movement (REM) sleep was reduced immediately after both treatments but was recovered later only after the SD. The effects on the waking EEG differed between the treatments, with a faster theta peak during and after SD, and no change in the waking spectrum after ketamine. In conclusion, SD and ketamine both lead to an acute increment in NREM sleep SWA as well as in a reduction in REM sleep. The results suggest that selective suppression of REM sleep, combined with enhancement of SWA during NREM may be effective in the treatment of depression., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Introduction: Aging impairs the function of the central circadian clock in mammals, the suprachiasmatic nucleus (SCN), leading to a reduction in the output signal. The weaker timing signal from the SCN results in a decline in rhythm strength in many physiological functions, including sleep-wake patterns. Accumulating evidence suggests that the reduced amplitude of the SCN signal is caused by a decreased synchrony among the SCN neurons. The present study was aimed to investigate the hypothesis that the excitation/inhibition (E/I) balance plays a role in synchronization within the network., Methods: Using calcium (Ca 2+ ) imaging, the polarity of Ca 2+ transients in response to GABA stimulation in SCN slices of old mice (20-24 months) and young controls was studied., Results: We found that the amount of GABAergic excitation was increased, and that concordantly the E/I balance was higher in SCN slices of old mice when compared to young controls. Moreover, we showed an effect of aging on the baseline intracellular Ca 2+ concentration, with higher Ca 2+ levels in SCN neurons of old mice, indicating an alteration in Ca 2+ homeostasis in the aged SCN. We conclude that the change in GABAergic function, and possibly the Ca 2+ homeostasis, in SCN neurons may contribute to the altered synchrony within the aged SCN network., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Olde Engberink, de Torres Gutiérrez, Chiosso, Das, Meijer and Michel.)

The noradrenergic Locus Cœruleus is one of the major arousal structures involved in inducing wakefulness. While brain noradrenaline (NA) amounts display 24-h variations, the origin of NA rhythm is currently unknown. In this study, we tested the hypothesis that NA rhythm could result from its rhythmic synthesis. Therefore, we investigated the 24-h expression profile of NA rate-limiting enzyme, tyrosine hydroxylase (th), in the Locus Cœruleus (LC) of the nocturnal rat and the diurnal rodent Arvicanthis, under 12 h:12 h light/dark (LD) and constant darkness (DD) conditions. In both species, th mRNA levels vary significantly over 24-h. In nocturnal rats, th mRNA profiles show a unimodal rhythm, with peak values in late day in LD, and in the middle of the subjective day in DD. In contrast, th mRNA rhythm in Arvicanthis is characterized by a bimodal profile, with higher levels at the beginning of the day and of the night in LD, and in the middle of the subjective day and night in DD. The rhythmic pattern of th expression may be dependent on a LC clock machinery. Therefore, we investigated the expression of three clock genes, namely bmal1, per1, and per2, and found that their mRNAs display significant variations between day and nighttime points in both species, but in opposite directions. These data show that NA rhythm may be related to circadian expression of th gene in both species, but differs between nocturnal and diurnal rodents. Furthermore, the phase opposition of clock gene expression in the rat compared to Arvicanthis suggests that the clock machinery might be one of the mechanisms involved in th rhythmic expression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Our daily 24-h rhythm is synchronized to the external light-dark cycle resulting from the Earth's daily rotation. In the mammalian brain, the suprachiasmatic nucleus (SCN) serves as the master clock and receives light-mediated input via the retinohypothalamic tract. Abrupt changes in the timing of the light-dark cycle (e.g., due to jet lag) cause a phase shift in the circadian rhythms in the SCN. Here, we investigated the effects of a 6-h delay in the light-dark cycle on PERIOD2::LUCIFERASE expression at the single-cell level in mouse SCN organotypic explants. The ensemble pattern in phase shift response obtained from individual neurons in the anterior and central SCN revealed a bimodal distribution; specifically, neurons in the ventrolateral SCN responded with a rapid phase shift, while neurons in the dorsal SCN generally did not respond to the shift in the light-dark cycle. We also stimulated the hypothalamic tract in acute SCN slices to simulate light-mediated input to the SCN; interestingly, we found similarities between the distribution and fraction of rapid shifting neurons (in response to the delay) and neurons that were excited in response to electrical stimulation. These results suggest that a subpopulation of neurons in the ventral SCN that have an excitatory response to light input, shift their clock more readily than dorsal located neurons, and initiate the SCN's entrainment to the new light-dark cycle. Thus, we propose that light-excited neurons in the anterior and central SCN play an important role in the organism's ability to adjust to changes in the external light-dark cycle., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

In both diurnal and nocturnal mammals, the timing of activity is regulated by the central circadian clock of the suprachiasmatic nucleus (SCN). The SCN is synchronized to the external light cycle via the retinohypothalamic tract (RHT). To investigate potential differences in light processing between nocturnal mice and the diurnal rodent Rhabdomys pumilio, we mimicked retinal input by stimulation of the RHT ex vivo. Using Ca 2+ imaging, we observed excitations as well as inhibitions of SCN neurons in response to electrical RHT stimulation. In mice, the vast majority of responses were excitatory (85%), whereas in Rhabdomys, the proportion of excitatory and inhibitory responses was similar (51% excitatory, 49% inhibitory). Glutamate blockers AP5 and CNQX blocked the excitatory responses to RHT stimulation but did not abolish the inhibitory responses in mice or Rhabdomys, indicating that the inhibitions were monosynaptically transmitted via the RHT. Simultaneous application of glutamate blockers with the GABA A antagonist gabazine blocked all inhibitory responses in mice, but not in Rhabdomys. Collectively, our results indicate that in Rhabdomys, considerably more inhibitory responses to light are present and that these responses are driven directly by the RHT. We propose that this increased proportion of inhibitory input could reflect a difference in the entrainment mechanism employed by diurnal rodents., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Cancer-related fatigue (CRF) is the most devastating long-term side effect of many cancer survivors that confounds the quality of life for months to years after treatment. However, the cause of CRF is poorly understood. As a result, cancer survivors, at best, receive psychological support. Chemotherapy has been shown to increase the risk of CRF. Here, we study therapy-induced fatigue in a non-tumor-bearing mouse model with three different topoisomerase II-poisoning cancer drugs. These drugs either induce DNA damage and/or chromatin damage. Shortly before and several weeks after treatment, running wheel activity and electroencephalographic sleep were recorded. We show that doxorubicin, combining DNA damage with chromatin damage, unlike aclarubicin or etoposide, induces sustained CRF in this model. Surprisingly, this was not related to changes in sleep. In contrast, our data indicate that the therapy-induced CRF is associated with a disrupted circadian clock. The data suggest that CRF is probably a circadian clock disorder that influences the quality of waking and that the development of CRF depends on the type of chemotherapy provided. These findings could have implications for selecting and improving chemotherapy for the treatment of cancer in order to prevent the development of CRF.

In mammals, behavioral activity is regulated both by the circadian system, orchestrated by the suprachiasmatic nucleus (SCN), and by arousal structures, including the serotonergic system. While the SCN is active at the same astronomical time in diurnal and nocturnal species, little data are available concerning the serotonergic (5HT) system in diurnal mammals. In this study, we investigated the functioning of the 5HT system, which is involved both in regulating the sleep/wake cycle and in synchronizing the SCN, in a diurnal rodent, Arvicanthis ansorgei. Using in situ hybridization, we characterized the anatomical extension of the raphe nuclei and we investigated 24 h mRNA levels of the serotonin rate-limiting enzyme, tryptophan hydroxylase 2 (tph2). Under both 12 h:12 h light/dark (LD) and constant darkness (DD) conditions, tph2 mRNA expression varies significantly over 24 h, displaying a bimodal profile with higher values around the (projected) light transitions. Furthermore, we considered several SCN outputs, namely melatonin, corticosterone, and locomotor activity. In both LD and DD, melatonin profiles display peak levels during the biological night. Corticosterone plasma levels show a bimodal rhythmic profile in both conditions, with higher levels preceding the two peaks of Arvicanthis locomotor activity, occurring at dawn and dusk. These data demonstrate that serotonin synthesis in Arvicanthis is rhythmic and reflects its bimodal behavioral phenotype, but differs from what has been previously described in nocturnal species., (© 2022 Federation of American Societies for Experimental Biology.)

SignificanceThe function of our biological clock is dependent on environmental light. Rodent studies have shown that there are multiple colors that affect the clock, but indirect measures in humans suggest blue light is key. We performed functional MRI studies in human subjects with unprecedented spatial resolution to investigate color sensitivity of our clock. Here, we show that narrowband blue, green, and orange light were all effective in changing neuronal activity of the clock. While the clock of nocturnal rodents is excited by light, the human clock responds with a decrease in neuronal activity as indicated by a negative BOLD response. The sensitivity of the clock to multiple colors should be integrated in light therapy aimed to strengthen our 24-h rhythms.

Aging is a multifactorial process likely stemming from damage accumulation and/or a decline in maintenance and repair mechanisms in the organisms that eventually determine their lifespan. In our review, we focus on the morphological and functional alterations that the aging brain undergoes affecting sleep and the circadian clock in both human and rodent models. Although both species share mammalian features, differences have been identified on several experimental levels, which we outline in this review. Additionally, we delineate some challenges on the preferred analysis and we suggest that a uniform route is followed so that findings can be smoothly compared. We conclude by discussing potential interventions and highlight the influence of physical exercise as a beneficial lifestyle intervention, and its effect on healthy aging and longevity. We emphasize that even moderate age-matched exercise is able to ameliorate several aging characteristics as far as sleep and circadian rhythms are concerned, independent of the species studied., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Ambient light detection is important for the synchronization of the circadian clock to the external solar cycle. Light signals are sent to the suprachiasmatic nuclei (SCN), the site of the major circadian pacemaker. It has been assumed that cone photoreceptors contribute minimally to synchronization. Here, however, we find that cone photoreceptors are sufficient for mediating entrainment and transmitting photic information to the SCN, as evaluated in mice that have only cones as functional photoreceptors. Using in vivo electrophysiological recordings in the SCN of freely moving cone-only mice, we observed light responses in SCN neuronal activity in response to 60-s pulses of both ultraviolet (UV) (λ max 365 nm) and green (λ max 505 nm) light. Higher irradiances of UV light led to irradiance-dependent enhancements in SCN neuronal activity, whereas higher irradiances of green light led to a reduction in the sustained response with only the transient response remaining. Responses in SCN neuronal activity decayed with a half-max time of ∼9 min for UV light and less than a minute for green light, indicating differential input between short-wavelength-sensitive and mid-wavelength-sensitive cones for the SCN responsiveness. Furthermore, we show that UV light is more effective for photoentrainment than green light. Based on the lack of a full sustained response in cone-only mice, we confirmed that rapidly alternating light levels, rather than slowly alternating light, caused substantial phase shifts. Together, our data provide strong evidence that cone types contribute to photoentrainment and differentially affect the electrical activity levels of the SCN., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

The circadian timing system optimizes health by temporally coordinating behavior and physiology. During mammalian gestation, fetal circadian rhythms are synchronized by the daily fluctuations in maternal body temperature, hormones and nutrients. Circadian disruption during pregnancy is associated with negative effects on developmental outcomes in the offspring, highlighting the importance of regular and robust 24-h rhythms over gestation. In the case of preterm birth (before 37 weeks of gestation), maternal cues no longer synchronize the neonate's circadian system, which may adversely affect the neonate. There is increasing evidence that introducing robust light-dark cycles in the Neonatal Intensive Care Unit has beneficial effects on clinical outcomes in preterm infants, such as weight gain and hospitalization time, compared to infants exposed to constant light or constant near-darkness. However, the biological basis for these effects and the relationship with the functional and anatomical development of the circadian system is not fully understood. In this review, we provide a concise overview of the effects of light-dark cycles on clinical outcomes of preterm neonates in the NICU and its alignment with the development of the circadian system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hazelhoff, Dudink, Meijer and Kervezee.)

In this study, we investigated the effect of social environment on circadian patterns in activity by group housing either six male or six female mice together in a cage, under regular light-dark cycles. Based on the interactions among the animals, the social dominance rank of individual mice was quantitatively established by calculating Elo ratings. Our results indicated that, during our experiment, the social dominance hierarchy was rapidly established, stable yet complex, often showing more than one dominant mouse and several subordinate mice. Moreover, we found that especially dominant male mice, but not female mice, displayed a significantly higher fraction of their activity during daytime. This resulted in reduced rhythm amplitude in dominant males. After division into separate cages, male mice showed an enhancement of their 24 h rhythm, due to lower daytime activity. Recordings of several physiological parameters showed no evidence for reduced health as a potential consequence of reduced rhythm amplitude. For female mice, transfer to individual housing did not affect their daily activity pattern. We conclude that 24 h rhythms under light-dark cycles are influenced by the social environment in males but not in females, and lead to a decrement in behavioural rhythm amplitude that is larger in dominant mice., (© 2021 The Authors.)

In mammals, the part of the nervous system responsible for most circadian behavior can be localized to a bilaterally paired structure in the hypothalamus known as the suprachiasmatic nucleus (SCN). Understanding the mammalian circadian system will require a detailed multilevel analysis of neural SCN circuits ex vivo and in vivo. Many of the techniques and approaches that are used for the analysis of the circuitry driving circadian oscillations in the SCN are similar to those employed in other brain regions. There is, however, one fundamental difference that needs to be taken into consideration, that is, the physiological, cell, and molecular properties of SCN neurons vary with the time of day. In this chapter, we will consider the preparations and electrophysiological techniques that we have used to analyze the SCN circuit focusing on the acute brain slice and intact, freely moving animal.

Artificial light exposure is associated with dyslipidemia in humans, which is a major risk factor for the development of atherosclerotic cardiovascular disease. However, it remains unclear whether artificial light at night can exacerbate atherosclerosis. In this study, we exposed female APOE*3-Leiden.CETP mice, a well-established model for human-like lipid metabolism and atherosclerosis, to either a regular light-dark cycle or to constant bright light for 14 weeks. Mice exposed to constant light demonstrated a minor reduction in food intake, without any effect on body weight, body composition, or the weight of metabolic organs. Constant light increased the plasma levels of proatherogenic non-high-density lipoprotein (HDL) cholesterol but did not increase the size or severity of atherosclerotic lesions in the aortic root. Mice exposed to constant light did show lower immune cell counts, which could explain the absence of an effect of atherosclerosis despite increased non-HDL cholesterol levels. Behavioral analysis demonstrated variability in the response of mice to the light intervention. Constant light completely blunted behavioral rhythms in some mice, while others extended their behavioral period. However, rhythm strength was not an important determinant of atherosclerosis. Altogether, these results demonstrate that constant bright light does not affect atherosclerosis in APOE*3-Leiden.CETP mice. Whether artificial light exposure contributes to cardiovascular disease risk in humans remains to be investigated.

The central circadian pacemaker in mammals, the suprachiasmatic nucleus (SCN), is important for daily as well as seasonal rhythms. The SCN encodes seasonal changes in day length by adjusting phase distribution among oscillating neurons thereby shaping the output signal used for adaptation of physiology and behavior. It is well-established that brief light exposure at the beginning and end of the day, also referred to as "skeleton" light pulses, are sufficient to evoke the seasonal behavioral phenotype. However, the effect of skeleton light exposure on SCN network reorganization remains unknown. Therefore, we exposed mice to brief morning and evening light pulses that mark the time of dawn and dusk in a short winter- or a long summer day. Single-cell PER2::LUC recordings, electrophysiological recordings of SCN activity, and measurements of GABA response polarity revealed that skeleton light-regimes affected the SCN network to the same degree as full photoperiod. These results indicate the powerful, yet potentially harmful effects of even relatively short light exposures during the evening or night for nocturnal animals., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Given the current shortage of respirator masks and the resulting lack of personal protective equipment for use by clinical staff, we examined bottom-up solutions that would allow hospitals to fabricate respirator masks that: (i) meet requirements in terms of filtering capacities, (ii) are easy to produce rapidly and locally, and (iii) can be constructed using materials commonly available in hospitals worldwide. We found that Halyard H300 material used for wrapping of surgical instruments and routinely available in hospitals, met these criteria. Specifically, three layers of material achieved a filter efficiency of 94%, 99%, and 100% for 0.3 μm, 0.5 μm, and 3.0 μm particles, respectively; importantly, these values are close to the efficiency provided by FFP2 and N95 masks. After re-sterilization up to 5 times, the filter's efficiency remains sufficiently high for use as an FFP1 respirator mask. Finally, using only one layer of the material satisfies the criteria for use as a 'surgical mask'. This material can therefore be used to help protect hospital staff and other healthcare professionals who require access to high quality masks but lack commercially available solutions., Competing Interests: The authors have declared that no competing interests exist.

Aging impairs circadian clock function, leading to disrupted sleep-wake patterns and a reduced capability to adapt to changes in environmental light conditions. This makes shift work or the changing of time zones challenging for the elderly and, importantly, is associated with the development of age-related diseases. However, it is unclear what levels of the clock machinery are affected by aging, which is relevant for the development of targeted interventions. We found that naturally aged mice of >24 months had a reduced rhythm amplitude in behavior compared with young controls (3-6 months). Moreover, the old animals had a strongly reduced ability to adapt to short photoperiods. Recording PER2::LUC protein expression in the suprachiasmatic nucleus revealed no impairment of the rhythms in PER2 protein under the 3 different photoperiods tested (LD: 8:16, 12:12, and 16:8). Thus, we observed a discrepancy between the behavioral phenotype and the molecular clock, and we conclude that the aging-related deficits emerge downstream of the core molecular clock. Since it is known that aging affects several intracellular and membrane components of the central clock cells, it is likely that an impairment of the interaction between the molecular clock and these components is contributing to the deficits in photoperiod adaptation.

The suprachiasmatic nucleus (SCN), which serves as the central pacemaker in mammals, regulates the 24-h rhythm in behavioral activity. However, it is currently unclear whether and how bouts of activity and rest are regulated within the 24-h cycle (i.e., over ultradian time scales). Therefore, we used passive infrared sensors to measure temporal behavior in mice housed under either a light-dark (LD) cycle or continuous darkness (DD). We found that a probabilistic Markov model captures the ultradian changes in the behavioral state over a 24-h cycle. In this model, the animal's behavioral state in the next time interval is determined solely by the animal's current behavioral state and by the "toss" of a proverbial "biased coin." We found that the bias of this "coin" is regulated by light input and by the phase of the clock. Moreover, the bias of this "coin" for an animal is related to the average length of rest and activity bouts in that animal. In LD conditions, the average length of rest bouts was greater during the day compared to during the night, whereas the average length of activity bouts was greater during the night compared to during the day. Importantly, we also found that day-night changes in the rest bout lengths were significantly greater than day-night changes in the activity bout lengths. Finally, in DD conditions, the activity and rest bouts also differed between subjective night and subjective day, albeit to a lesser extent compared to LD conditions. The ultradian regulation represented by the model does not result in ultradian rhythms, although some weak ultradian rhythms are present in the data. The persistent differences in bout length over the circadian cycle following loss of the external LD cycle indicate that the central pacemaker plays a role in regulating rest and activity bouts on an ultradian time scale., (Copyright © 2020 Ananthasubramaniam and Meijer.)

In mammals, the central pacemaker that coordinates 24-hr rhythms is located in the suprachiasmatic nucleus (SCN). Individual neurons of the SCN have a molecular basis for rhythm generation and hence, they function as cell autonomous oscillators. Communication and synchronization among these neurons are crucial for obtaining a coherent rhythm at the population level, that can serve as a pace making signal for brain and body. Hence, the ability of single SCN neurons to produce circadian rhythms is equally important as the ability of these neurons to synchronize one another, to obtain a bona fide pacemaker at the SCN tissue level. In this chapter we will discuss the mechanisms underlying synchronization, and plasticity herein, which allows adaptation to changes in day length. Furthermore, we will discuss deterioration in synchronization among SCN neurons in aging, and gain in synchronization by voluntary physical activity or exercise., (© 2019 The Authors European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Disruption of circadian rhythm by means of shift work has been associated with cardiovascular disease in humans. However, causality and underlying mechanisms have not yet been established. In this study, we exposed hyperlipidemic APOE*3-Leiden.CETP mice to either regular light-dark cycles, weekly 6 hours phase advances or delays, or weekly alternating light-dark cycles (12 hours shifts), as a well-established model for shift work. We found that mice exposed to 15 weeks of alternating light-dark cycles displayed a striking increase in atherosclerosis, with an approximately twofold increase in lesion size and severity, while mice exposed to phase advances and delays showed a milder circadian disruption and no significant effect on atherosclerosis development. We observed a higher lesion macrophage content in mice exposed to alternating light-dark cycles without obvious changes in plasma lipids, suggesting involvement of the immune system. Moreover, while no changes in the number or activation status of circulating monocytes and other immune cells were observed, we identified increased markers for inflammation, oxidative stress, and chemoattraction in the vessel wall. Altogether, this is the first study to show that circadian disruption by shifting light-dark cycles directly aggravates atherosclerosis development., (© 2019 The Authors. Journal of Pineal Research published by John Wiley & Sons Ltd.)

Objective: To review and discuss the putative role of light, sleep, and the biological clock in cluster headache., Discussion: Cluster headache attacks are believed to be modulated in the hypothalamus; moreover, the severe pain and typical autonomic cranial features associated with cluster headache are caused by abnormal activity of the trigeminal-autonomic reflex. The temporal pattern of cluster headache attacks suggests involvement of the biological clock, and the seasonal pattern is influenced by the number of daylight hours. Although sleep is often reported as a trigger for cluster headache attacks, to date no clear correlation has been established between these attacks and sleep stage., Conclusions: We hypothesize that light, sleep, and the biological clock can change the brain's state, thereby lowering the threshold for activating the trigeminal-autonomic reflex, resulting in a cluster headache attack. Understanding the mechanisms that contribute to the daily and seasonal fluctuations in cluster headache attacks may provide new therapeutic targets.

The importance of circadian biology has rarely been considered in pre-clinical studies, and even more when translating to the bedside. Circadian biology is becoming a critical factor for improving drug efficacy and diminishing drug toxicity. Indeed, there is emerging evidence showing that some drugs are more effective at nighttime than daytime, whereas for others it is the opposite. This suggests that the biology of the target cell will determine how an organ will respond to a drug at a specific time of the day, thus modulating pharmacodynamics. Thus, it is now time that circadian factors become an integral part of translational research., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Neural systems are organized in a modular way, serving multiple functionalities. This multiplicity requires that both positive (e.g. excitatory, phase-coherent) and negative (e.g. inhibitory, phase-opposing) interactions take place across brain modules. Unfortunately, most methods to detect modules from time series either neglect or convert to positive, any measured negative correlation. This may leave a significant part of the sign-dependent functional structure undetected. Here we present a novel method, based on random matrix theory, for the identification of sign-dependent modules in the brain. Our method filters out both local (unit-specific) noise and global (system-wide) dependencies that typically obfuscate the presence of such structure. The method is guaranteed to identify an optimally contrasted functional 'signature', i.e. a partition into modules that are positively correlated internally and negatively correlated across. The method is purely data-driven, does not use any arbitrary threshold or network projection, and outputs only statistically significant structure. In measurements of neuronal gene expression in the biological clock of mice, the method systematically uncovers two otherwise undetectable, negatively correlated modules whose relative size and mutual interaction strength are found to depend on photoperiod., Competing Interests: The authors have declared that no competing interests exist.

In Alzheimer's disease (AD), disturbances in the circadian rhythm and sleep-wake cycle are frequently observed. Both are controlled by the master clock: the suprachiasmatic nucleus (SCN), which was reported in postmortem studies of AD subjects to be compromised. However, the influence of age and gender on the biophysical integrity and subtle microstructural changes of SCN and mechanistic connections between SCN dysfunction and AD progression in vivo remain to be explored. In the present study, we utilized state-of-the-art in vivo magnetic resonance relaxation measurements in combination with immunohistochemistry to follow microstructural changes in SCN of the Tg2576 mouse model of AD. Longitudinal monitoring of in vivo T2 relaxation with age shows significant shortening of T2 values in the SCN of transgenic mice and more substantially in female transgenic than aged-matched controls. Multiexponential T2 analysis detected a unique long T2 component in SCN of transgenic mice which was absent in wild-type mice. Immunohistochemical examination revealed significantly elevated numbers of activated astrocytes and an increase in the astrocyte to neuron ratio in SCN of transgenic compared to wild-type mice. This increase was more substantial in female than in male transgenic mice. In addition, low GABA production in SCN of transgenic mice was detected. Our results offer a brief appraisal of SCN dysfunction in AD and demonstrate that inflammatory responses may be an underlying perpetrator for the changes in circadian rhythmicity and sleep disturbance in AD and could also be at the root of marked sex disparities observed in AD subjects.

Background: Caffeine is one of the most widely consumed psychostimulants, and it impacts sleep and circadian physiology., Aim: Caffeine is generally used chronically on a daily basis. Therefore, in the current study, we investigated the chronic effect of caffeine on sleep in mice., Methods: We recorded the electroencephalogram and electromyogram on a control day, on the first day of caffeine consumption (acute), and following two weeks of continuous caffeine consumption (chronic). In the latter condition, a period of six-hour sleep deprivation was conducted during the light period. Control mice, which received normal drinking water, were also recorded and sleep deprived., Results: We found that caffeine induced differential effects following acute and chronic consumption. Over 24 h, waking increased following acute caffeine whereas no changes were found in the chronic condition. The daily amplitude of sleep-wake states increased in both acute and chronic conditions, with the highest amplitude in the chronic condition, showing an increase in sleep during the light and an increase in waking during the dark. Furthermore, electroencephalogram slow-wave-activity in non-rapid eye-movement sleep was increased, compared with both control conditions, during the first half of the light period in the chronic condition. It was particularly challenging to keep the animals awake during the sleep deprivation period under chronic caffeine., Conclusions: Together the data suggest an increased sleep pressure under chronic caffeine. In contrast to the traditional conception on the impact on sleep, chronic caffeine intake seems to increase the daily sleep-wake cycle amplitude and increase sleep pressure in mice.

Background: Many physiological processes in our body are controlled by the biological clock and show circadian rhythmicity. It is generally accepted that a robust rhythm is a prerequisite for optimal functioning and that a lack of rhythmicity can contribute to the pathogenesis of various diseases. Here, we tested in a heterogeneous laboratory zebrafish population whether and how variation in the rhythmicity of the biological clock is associated with the coping styles of individual animals, as assessed in a behavioural assay to reliably measure this along a continuum between proactive and reactive extremes., Results: Using RNA sequencing on brain samples, we demonstrated a prominent difference in the expression level of genes involved in the biological clock between proactive and reactive individuals. Subsequently, we tested whether this correlation between gene expression and coping style was due to a consistent change in the level of clock gene expression or to a phase shift or to altered amplitude of the circadian rhythm of gene expression. Our data show a remarkable individual variation in amplitude of the clock gene expression rhythms, which was also reflected in the fluctuating concentrations of melatonin and cortisol, and locomotor activity. This variation in rhythmicity showed a strong correlation with the coping style of the individual, ranging from robust rhythms with large amplitudes in proactive fish to a complete absence of rhythmicity in reactive fish. The rhythmicity of the proactive fish decreased when challenged with constant light conditions whereas the rhythmicity of reactive individuals was not altered., Conclusion: These results shed new light on the role of the biological clock by demonstrating that large variation in circadian rhythmicity of individuals may occur within populations. The observed correlation between coping style and circadian rhythmicity suggests that the level of rhythmicity forms an integral part of proactive or reactive coping styles.

Introduction: Most organisms display circadian rhythms in physiology and behaviour. In mammals, these rhythms are orchestrated by the suprachiasmatic nucleus (SCN). Recently, several metabolites have emerged as important regulators of circadian timekeeping. Metabolomics approaches have aided in identifying some key metabolites in circadian processes in peripheral tissue, but methods to routinely measure metabolites in small brain areas are currently lacking., Objective: The aim of the study was to establish a reliable method for metabolite quantifications in the central circadian clock and relate them to different states of neuronal excitability., Methods: We developed a method to collect and process small brain tissue samples (0.2 mm 3 ), suitable for liquid chromatography-mass spectrometry. Metabolites were analysed in the SCN and one of its main hypothalamic targets, the paraventricular nucleus (PVN). Tissue samples were taken at peak (midday) and trough (midnight) of the endogenous rhythm in SCN electrical activity. Additionally, neuronal activity was altered pharmacologically., Results: We found a minor effect of day/night fluctuations in electrical activity or silencing activity during the day. In contrast, increasing electrical activity during the night significantly upregulated many metabolites in SCN and PVN., Conclusion: Our method has shown to produce reliable and physiologically relevant metabolite data from small brain samples. Inducing electrical activity at night mimics the effect of a light pulses in the SCN, producing phase shifts of the circadian rhythm. The upregulation of metabolites could have a functional role in this process, since they are not solely products of physiological states, they are significant parts of cellular signalling pathways.

Physical activity is beneficial for health. It has been shown to improve brain functioning and cognition, reduce severity of mood disorders, as well as facilitate healthy sleep and healthy aging. Sleep has been studied in healthy aged mice and absolute slow-wave-activity levels (SWA, electroencephalogram power between 0.75 and 4.0 Hz) in non-rapid-eye-movement sleep (NREM) were elevated, suggesting changes in brain connectivity. To investigate whether physical activity can diminish this aging-induced effect, mice of three age groups were provided with a running wheel (RW) for 1-3 months (6-months-old, n = 9; 18-months-old, n = 9; 24-months-old, n = 8) and were compared with control sedentary mice ( n = 11, n = 8 and n = 9 respectively). Two weeks before the sleep-wake recordings the running wheels were removed. The electroencephalogram (EEG) and electromyogram were continuously recorded during undisturbed 24 h baseline (BL) and a sleep-deprivation was conducted during the first 6 h of the second day. Increased waking and decreased NREM sleep was found in the young RW mice, compared to young controls. These effects were not evident in the 18 and 24 months old mice. Unlike sleep architecture, we found that SWA was altered throughout the whole age spectrum. Notably, SWA was increased with aging and attenuated with exercise, exhibiting the lowest levels in the young RW mice. To utilize the cross-age revealing features of SWA, we applied machine learning techniques and found that characteristic information regarding age and exercise was enclosed in SWA. In addition, with cluster analysis, we could classify and accurately distinguish the different groups based solely on their SWA. Therefore, our study comprises a three-fold contribution: (a) effects of exercise on sleep are sustained following 2 weeks after removal of the wheel, (b) we show that EEG SWA can be used as a physiological marker of brain age in the mouse,, ((c) long-term voluntary regular age-matched exercise leads to a younger phenotype.)

People suffering of attention-deficit/hyperactivity disorder (ADHD) and treated with the psychostimulant methylphenidate (MPH) show sleep-wake cycle and daily rhythm alterations despite the beneficial effects of MPH on behavioral symptoms (i.e., hyperactivity, attention). In nocturnal rodents (i.e., mice), chronic exposure to MPH alters the neural activity of the circadian clock in the suprachiasmatic nucleus (SCN), behavioral rhythms, and the sleep-wake cycle. Here, we studied the effects of MPH on daily rhythms of behavior and body temperature of the diurnal rodent Arvicanthis ansorgei. Under a light-dark cycle, chronic exposure to MPH in drinking water delayed the onset of both activity and body temperature rhythms. Interestingly, delays were larger when MPH access was restricted to the first 6 h of the light phase (i.e., activity phase) of the 24-h cycle. Since MPH effects are dependent on animal's fluid intake, in a last experiment, we controlled the time and dose of MPH delivery in Arvicanthis using an intraperitoneal perfusion method. Similarly to the experiment with MPH in drinking water, Arvicanthis showed a delay in the onset of general activity and body temperature when MPH infusions, but not vehicle, were during the first 6 h of the light phase. This study indicates that MPH alters daily rhythms in a time-dependent manner and proposes the use of a diurnal rodent for the study of the effects of MPH on the circadian clock. Knowing the circadian modulation on the effects of MPH in behavior could give new insights in the treatment of ADHD.

Schizophrenia patients have difficulties identifying odors, possibly a marker of cognitive and social impairment. This study investigated olfactory identification (OI) differences between patients and controls, related to cognitive and social functioning in childhood and adolescence, to present state cognition and to present state social cognition. 132 schizophrenia patients and 128 healthy controls were assessed on OI performance with the Sniffin' Sticks task. Multiple regression analyses were conducted investigating OI in association with cognitive and social functioning measures in childhood/adolescence and in association with IQ, memory, processing speed, attention, executive functioning, face recognition, emotion recognition and theory of mind. Patients had reduced OI performance compared to controls. Also, patients scored worse on childhood/adolescence cognitive and social functioning, on present state cognitive functioning and present state social cognition compared to controls. OI in patients and controls was significantly related to cognitive and social functioning in childhood/adolescence, to present state cognition and to present state social cognition, with worse functioning being associated with worse OI. In this study, findings of worse OI in patients relative to controls were replicated. We also showed associations between OI and cognitive and social functioning which are not specific to schizophrenia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

One of the principal neurotransmitters of the central nervous system is GABA. In the adult brain, GABA is predominantly inhibitory, but there is growing evidence indicating that GABA can shift to excitatory action depending on environmental conditions. In the mammalian central circadian clock of the suprachiasmatic nucleus (SCN) GABAergic activity shifts from inhibition to excitation when animals are exposed to long day photoperiod. The polarity of the GABAergic response (inhibitory versus excitatory) depends on the GABA equilibrium potential determined by the intracellular Cl - concentration ([Cl - ] i ). Chloride homeostasis can be regulated by Cl - cotransporters like NKCC1 and KCC2 in the membrane, but the mechanisms for maintaining [Cl - ] i are still under debate. This study investigates the role of KCC2 on GABA-induced Ca 2+ transients in SCN neurons from mice exposed to different photoperiods. We show for the first time that blocking KCC2 with the newly developed blocker ML077 can cause a shift in the polarity of the GABAergic response. This will increase the amount of excitatory responses in SCN neurons and thus cause a shift in excitatory/inhibitory ratio. These results indicate that KCC2 is an essential component in regulating [Cl - ] i and the equilibrium potential of Cl - and thereby determining the sign of the GABAergic response. Moreover, our data suggest a role for the Cl - cotransporters in the switch from inhibition to excitation observed under long day photoperiod., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Obesity prevalence and sleep habit changes are commonplace nowadays, due to modern lifestyle. A bidirectional relationship likely exists between sleep quality and metabolic disruptions, which could impact quality of life. In our study, we investigated the effects of a chronic high-caloric diet on sleep architecture and sleep regulation in mice. We studied the effect of 3 months high-caloric diet (HCD, 45% fat) on sleep and the sleep electroencephalogram (EEG) in C57BL/6J mice during 24-hr baseline (BL) recordings, and after 6-hr sleep deprivation (SD). We examined the effect of HCD on sleep homeostasis, by performing parameter estimation analysis and simulations of the sleep homeostatic Process S, a measure of sleep pressure, which is reflected in the non-rapid-eye-movement (NREM) sleep slow-wave-activity (SWA, EEG power density between 0.5 and 4.0 Hz). Compared to controls (n = 11, 30.7 ± 0.8 g), mice fed with HCD (n = 9, 47.6 ± 0.8 g) showed an increased likelihood of consecutive NREM-REM sleep cycles, increased REM sleep and decreased NREM sleep EEG SWA. After SD, these effects were more pronounced. The simulation resulted in a close fit between the time course of SWA and Process S in both groups. HCD fed mice had a slower time constant (T i  = 15.98 hr) for the increase in homeostatic sleep pressure compared with controls (5.95 hr) indicating a reduced effect of waking on the increase in sleep pressure. Our results suggest that chronic HCD consumption impacts sleep regulation., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The lateral hypothalamus (LH) is a relatively large hypothalamic structure containing several neurochemically different, but spatially intermingled, neuronal populations. While the role of these neurons in the homeostatic regulation of diverse physiological and behavioral functions such as sleep/wake cycle has been studied extensively, the impact of sleep history on the electrophysiology of the LH and whether this effect is homogenous across LH is unknown. By combining multiunit activity (MUA) recordings in different regions of LH with electroencephalogram recordings in freely moving rats, we unravelled a heterogeneity of neural-activity patterns within different subregions of LH. This heterogeneity was evident in both the circadian and the vigilance state-dependent modulation of MUA. Interestingly, and consistent with this heterogeneity under baseline conditions, the magnitude of MUA suppression following 6 hr of sleep deprivation (SD) was also different within different locations of LH. Unlike the cortex and in contrast to the predictions of the synaptic homeostatic hypothesis, no correlation was found between the magnitude of activity increase during SD and the percentage of suppression of MUA during recovery sleep. These data provide in vivo evidence of a functional heterogeneity in the circadian and homeostatic modulation of neuronal activity in LH.

Organisms can be synchronized not only to the natural 24-h light-dark cycle but also to artificial non-24-h cycles. Interestingly, when the period of the cycle is far from 24 h, organisms may show complicated behavioral patterns. For example, exposed to a 22-h light-dark cycle, in behavioral activity of rats, a phenomenon called "dissociation" emerges, i.e., one periodic component shows a 22-h period and the other shows a period close to the endogenous period of the animal (around 24 h). It has been found that these two components are regulated by two subgroups of the suprachiasmatic nucleus (SCN), respectively, with the ventrolateral part regulating the 22-h component and the dorsomedial part regulating the other component. In the present study, based on a mathematical model, we will examine how the ratio of amplitudes between these two subgroups affects the entrainment of the SCN to the external 22-h light-dark cycle. Our results show that the dissociation happens when the ratio is smaller than 1 and the maximal entrainment (synchronization) ability of the SCN to the external cycle is obtained when the ratio is larger than 1. Our finding sheds light on the dissociation between the subgroups and suggests that the heterogeneity in the amplitudes alter the entrainment ability of the SCN.