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Principles of the molecular circadian machinery in mouse and Drosophila. The core circadian positive and negative feedback loops in Drosophila (a) and mouse (b). a In Drosophila, clock genes involve per(iod) and tim(eless), whose protein products inhibit the action of their activators CLOCK (CLK) and CYCLE (CYC). CLOCK/CYCLE heterodimers activate transcription circadian target genes including per, tim, vri (vrille), and pdp (pigment dispersing factor). In addition to this negative feedback, there is a positive feedback of PDP and negative feedback of VRI on cycle transcription. PER and TIM proteins are phosphorylated by DBT (doubletime) and CRY (cryptochrome), respectively. CRY can be activated by light and, thus, acts as photoreceptor of the circadian clock. b In mammals, the positive arm of the feedback involves the BMAL1 (brain and muscle ARNT-like 1) and CLOCK (circadian locomotor output cycles kaput) heterodimers, which activate the transcription of Per(1–3), Cry(1/2), Ror(a/b; retinoid orphan receptor), and Rev-erb(a/b; reverse erythroblastoma). In the negative feedback, PER proteins are phosphorylated by casein kinase 1 (CK1δ/ε). PER and CRY proteins inhibit their own transcription by inhibiting the activity of BMAL1/CLOCK heterodimers. REV-ERB inhibits Bmal1 transcription and ROR mediates opposite actions on Bmal1 gene expression. Light resetting is mediated via photic induction of Per expression in the SCN. The potential role of the putative clock component TIM in the mammalian circadian machinery remains unclear
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Life on earth is shaped by the 24-h rotation of our planet around its axes. To adapt behavior and physiology to the concurring profound but highly predictable changes, endogenous circadian clocks have evolved that drive 24-h rhythms in invertebrate and vertebrate species. At the molecular level, circadian clocks comprised a set of clock genes organ...
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In many animals the circadian rhythm of locomotor activity is controlled by an endogenous circadian clock. Using custom made housing and video tracking software in order to obtain high spatial and temporal resolution, we studied the statistical properties of the locomotor activity of wild type and two clock mutants of Drosophila melanogaster. We sh...
Light is one of the most important factors regulating rhythmical behavior of Drosophila melanogaster. It is received by different photoreceptors and entrains the circadian clock, which controls sleep. The retina is known to be essential for light perception, as it is composed of specialized light-sensitive cells which transmit signal to deeper part...
Citations
... The circadian system regulates the temporality of physiological and behavioral functions enabling organisms to anticipate and adapt to the changing conditions of the environment (Pilorz et al., 2018). The alternation of the light-dark cycle is the main time cue that synchronizes the mammalian circadian system to the external 24 h day (Vetter, 2020). ...
Introduction
Access to electric light has exposed living organisms to varying intensities of light throughout the 24 h day. Dim light at night (DLAN) is an inappropriate signal for the biological clock, which is responsible for the circadian organization of physiology. During the gestational period, physiological adaptations occur to ensure a successful pregnancy and optimal fetal development. Environmental maternal conditions, such as disruptions of maternal circadian rhythms, could negatively affect offspring health. We have previously demonstrated that exposure of female Wistar rats to DLAN results in circadian, metabolic, and behavioral alterations. A relevant behavior during adolescence is social play, primarily regulated by the nucleus accumbens (NAc) which is crucial for the proper performance of important behaviors in adulthood. Throughout development, microglia are responsible for the remodeling of diverse brain regions via synaptic pruning. During adolescence, this process occurs within the NAc, where immune-mediated remodeling directly impacts social play behavior.
Methods
This study investigated the effects of maternal exposure to DLAN or a light-dark cycle (LD) before (5 weeks) and during the gestational period (21–23 days) on the metabolism and behavior of offspring in adolescence and adulthood. Body mass was measured every 5 days from postnatal day 1 (PN1) to PN25 and every 10 days from PN40 to PN90; food consumption was monitored weekly from PN40 to PN90. Social play behavior was evaluated at PN40. The quantification and morphology of microglia in the NAc were measured on PN30. An open field test was conducted at PN60, and anhedonia test was assessed at PN90.
Results and discussion
Male and female offspring from mothers exposed to DLAN showed increased body mass gain at PN25. DLAN male offspring had lower food consumption, while DLAN females exhibited increased food consumption. In social play behavior, no differences were found between DLAN and LD female offspring. In contrast, DLAN male offspring exhibited a significant decrease in social play behavior compared to LD animals, which was associated with higher numbers of microglia in the NAc that had more ramified morphology. Importantly, at PN90, DLAN offspring presented increased anxiety-like behaviors. These results demonstrate that DLAN exposure induces intergenerational behavioral alterations that persist until adulthood.
... Circadian rhythms are 24 h physiological oscillations that underpin a temporal architecture of sleep/wake behavior [42]. The circadian system comprises a network of endogenously oscillating 24 h rhythms, known as circadian rhythms, that operate across multiple physiological and behavioral domains [43]. This system consists of multiple autonomous, self-sustaining oscillators throughout the brain and periphery. ...
Background/Objectives: Recent research has explored the presence of subthreshold autistic traits (ATs) in individuals with borderline personality disorder (BPD), suggesting that these traits may contribute to the severity of BPD symptoms and increase the risk of other mental health issues, including suicidal behaviors. This study aims to investigate the relationship between ATs and affective symptoms, such as mood instability and suicidality, in people diagnosed with BPD. Methods: A total of 48 subjects with BPD were assessed with self-report questionnaires including the Adult Autism Subthreshold Spectrum (AdAS Spectrum), the mood spectrum self-report version (MOODS-SR) and the ruminative response scale (RRS). Results: Subjects with significant ATs scored higher than BPD subjects in all domains and in the total score of AdAS Spectrum, RRS, and MOODS-SR, as well as in the items investigating suicidality. RRS total score, its depression domain, and the MOODS-SR rhythmicity domain, as well as suicidality, were predictors of the presence of ATs. Conclusions: Our data confirm the relationship between the presence of clinically significant ATs and affective symptoms, ruminative thinking, and suicidality in patients with BPD.
... The circadian rhythm, also referred to as the circadian clock system, modulates daily behavioral and physiological rhythms essential for adaptation to environmental and internal disturbances (Pilorz et al., 2018;Sun et al., 2023). Variations in environmental cues (zeitgebers), i. e., water temperature, dissolved oxygen, and physical disturbance, can interfere with the circadian clock system, causing alterations in the circadian rhythm of fish (López-Olmeda et al., 2006;Mortola, 2007;Costa et al., 2016). ...
... In mammals, circadian rhythms are generated by a central clock (pacemaker) located in the suprachiasmatic nuclei (SCN) of the hypothalamus and modified by peripheral clocks found in various cells of the body. Both the central clock and peripheral clocks significantly influence the regulation of homeostasis and the functioning of numerous biological processes [1][2][3][4]. ...
The circadian clock controls various physiological processes, including synaptic function and neuronal activity, affecting the functioning of the entire organism. Light is an important external factor regulating the day–night cycle. This study examined the effects of the circadian clock and light on synaptic plasticity, and explored how locomotor activity contributes to these processes. We analyzed synaptic protein expression and excitatory synapse density in the somatosensory cortex of mice from four groups exposed to different lighting conditions (LD 12:12, DD, LD 16:8, and LL). Locomotor activity was assessed through individual wheel-running monitoring. To explore daily and circadian changes in synaptic proteins, we performed double-immunofluorescence labeling and laser scanning confocal microscopy imaging, targeting three pairs of presynaptic and postsynaptic proteins (Synaptophysin 1/PSD95, Piccolo/Homer 1, Neurexins/PICK1). Excitatory synapse density was evaluated by co-labeling presynaptic and postsynaptic markers. Our results demonstrated that all the analyzed synaptic proteins exhibited circadian regulation modulated by light. Under constant light conditions, only Piccolo and Homer 1 showed rhythmicity. Locomotor activity was also associated with the circadian clock’s effects on synaptic proteins, showing a stronger connection to changes in postsynaptic protein levels. Excitatory synapse density peaked during the day/subjective day and exhibited an inverse relationship with locomotor activity. Continued light exposure disrupted cyclic changes in synapse density but kept it consistently elevated. These findings underscore the crucial roles of light and locomotor activity in regulating synaptic plasticity.
... Clock/Clock mutant mice have differences in pregnancy, severe birth defects, morphological deformity, and reduction of estradiol and progesterone serum levels (Miller and Takahashi 2013;Pilorz et al., 2018). Clock mutant mice do not have significant amounts of prolactin and secrete less milk than wild-type mice (Miller and Takahashi 2013). ...
... Circadian clocks are intrinsic oscillators in cells and organisms, coordinating multiple biological processes within an approximate 24-hour cycle. The circadian timekeeping system comprises a network of clock genes (CGs) interlocked in a complex of autoregulatory transcriptional-translational feedback loops that generate and synchronize circadian rhythms, primarily influenced by light-dark cycles [1]. This self-sustained internal system orchestrates fundamental physiological processes, including the sleep-wake cycle, energy metabolism, immune function, cognitive and physical performance, as well as cell proliferation and tumorigenesis [2,3]. ...
This review delved into the intricate relationship between circadian clocks and physiological processes, emphasizing their critical role in maintaining homeostasis. Orchestrated by interlocked clock genes, the circadian timekeeping system regulates fundamental processes like the sleep-wake cycle, energy metabolism, immune function, and cell proliferation. The central oscillator in the hypothalamic suprachiasmatic nucleus synchronizes with light-dark cycles, while peripheral tissue clocks are influenced by cues such as feeding times. Circadian disruption, linked to modern lifestyle factors like night shift work, correlates with adverse health outcomes, including metabolic syndrome, cardiovascular diseases, infections, and cancer. We explored the molecular mechanisms of circadian clock genes and their impact on metabolic disorders and cancer pathogenesis. Specific associations between circadian disruption and endocrine tumors, spanning breast, ovarian, testicular, prostate, thyroid, pituitary, and adrenal gland cancers, are highlighted. Shift work is associated with increased breast cancer risk, with PER genes influencing tumor progression and drug resistance. CLOCK gene expression correlates with cisplatin resistance in ovarian cancer, while factors like aging and intermittent fasting affect prostate cancer. Our review underscored the intricate interplay between circadian rhythms and cancer, involving the regulation of the cell cycle, DNA repair, metabolism, immune function, and the tumor microenvironment. We advocated for integrating biological timing into clinical considerations for personalized healthcare, proposing that understanding these connections could lead to novel therapeutic approaches. Evidence supports circadian rhythm-focused therapies, particularly chronotherapy, for treating endocrine tumors. Our review called for further research to uncover detailed connections between circadian clocks and cancer, providing essential insights for targeted treatments. We emphasized the importance of public health interventions to mitigate lifestyle-related circadian disruptions and underscored the critical role of circadian rhythms in disease mechanisms and therapeutic interventions.
... Several factors can serve as circadian biomarkers, including body temperature and various hormones. Nearly all hormones in the human body are released in a 24-h cycle that aligns with the circadian rhythm [13]. However, what distinguishes melatonin as the most advantageous hormone to be used as a circadian biomarker is its resilience to external influences [14]. ...
... However, what distinguishes melatonin as the most advantageous hormone to be used as a circadian biomarker is its resilience to external influences [14]. While markers such as body temperature, heart rate, cortisol, and thyrotropin hormones can serve as circadian markers, they are susceptible to external factors such as stress and sleep [13]. In contrast, melatonin is not influenced by these factors, making it a more reliable circadian biomarker [15]. ...
Over the past 300 years, scientific observations have revealed the significant influence of circadian rhythms on various human functions, including sleep, digestion, and immune system regulation. Access to natural daylight is crucial for maintaining these rhythms, but modern lifestyles often limit its availability. Despite its importance, there is a lack of a comprehensive design framework to assist designers. This study proposes an architectural design framework based on the review of literature, lighting-related codes and standards, and available design and analysis tools that guides the creation of lighting systems supporting healthy circadian rhythms. The framework outlines key decision-making stages, incorporates relevant knowledge, and promotes the integration of dynamic lighting techniques into building design. The proposed framework was presented to a group of design professionals as a focus group and their feedback on the relevance and usability of the tool was obtained through a survey (n = 10). By empowering designers with practical tools and processes, this research bridges the gap between scientific understanding and design implementation, ensuring informed decisions that positively impact human health. This research contributes to the ongoing pursuit of creating lighting environments that support healthy circadian rhythms and promote human well-being.
... Circadian clocks are inbuilt timekeeping systems that regulate multiple facets of cellular homeostasis with the suprachiasmatic nucleus (SCN) serving as the central circadian pacemaker (Cox and Takahashi 2019;Isojima et al. 2003). This central clock synchronizes with the peripheral clocks to regulate a multitude of physiological processes (Pilorz et al. 2018). Circadian perturbations originating due to shift work (Antunes et al. 2010), exposure to artificial light at night (ALAN) or consumption of high calorie diet are known to cause a higher susceptibility towards lifestyle disorders (Zubidat and Haim 2017). ...
Chronic consumption of a high-calorie diet coupled with an altered sleep-wake cycle causes disruption of circadian clock that can impact the gut microbiome leading to metabolic syndrome and associated diseases. Herein, we investigate the effects of a high fat high fructose diet (H) alone or in combination with photoperiodic shifts induced chronodisruption (CD) on gut microbiota of C57BL/6J male mice. Further, the merits of daily evening intraperitoneal administration of melatonin in restoring gut microbiota are studied herein. Experimental groups viz. H, CD and HCD mice recorded higher levels of serum pro-inflammatory cytokines (TNF-α and IL-6) and lower levels of the anti-inflammatory cytokine, IL-10. These findings correlate with a concomitant increase in the transcripts of TLR4, TNF-α, and IL-6 in small intestine of the said groups. A decrement in mRNA levels of Ocln, ZO-1 and Vdr in these groups implied towards an altered gut permeability. These results were in agreement with the observed decrement in percentage abundance of total gut microflora and Firmicutes: Bacteroidetes (F/B) ratio. Melatonin administration accounted for lower-level inflammation (serum and gut) along with an improvement in gut permeability markers. The total abundance of gut microflora and F/B ratio showed an improvement in all the melatonin-treated groups and the same is the highlight of this study. Taken together, our study is the first to report perturbations in gut microbiota resulting due to a combination of photoperiodic shifts induced CD and a high fat high calorie diet-induced lifestyle disorder. Further, melatonin-mediated rejuvenation of gut microbiome provides prima facie evidence of its role in improving gut dysbiosis that needs a detailed scrutiny.
... [1] The most recognized of these rhythms is the circadian rhythm, which operates on a roughly 24-hour cycle, governing processes such as sleepwake cycles and hormone secretion. [2] Seasonal rhythms, however, align our physiology with annual changes, affecting mood, metabolism, and immune function. [3] Among these rhythms, the lunar cycle (LC), especially its impact on human health and behavior, has recently garnered significant attention. ...
BACKGROUND
Children with Down syndrome (DS) offer a compelling context within the fieldof human biology for examining potential lunar influences. While the exact mechanisms governing lunar effects are still under investigation, a growing body of scientific inquiry suggests possible connections between lunar phases and physiological, physical, and cognitive parameters. This investigation holds promise for uncovering the intricate interplay between lunar cycles (LCs) and the unique biology of children with DS. This study investigated the potential influence of the LC on physiological, physical, and cognitive parameters in children with DS, focusing on sleep patterns, physical performance, and cognitive abilities.
MATERIALS AND METHODS
Seventeen children with DS participated in this study. Sleep data, physical performance metrics, and cognitive test results were collected throughout the LC, including the new moon (NM), first quarter, full moon (FM), and third quarter. Statistical analyses were conducted to assess the differences in these parameters across lunar phases.
RESULTS
Significant differences were observed in sleep patterns, with reduced total sleep time ( P < 0.01) and sleep efficiency ( P < 0.001) during the FM phase. Heart rates (HRs) before ( P < 0.001) and after ( P < 0.01) exercise also displayed pronounced changes during LC. Additionally, the reaction time (RT) exhibited a significant difference ( P < 0.01) across the lunar phases. However, physical performance metrics, including squat jump (SJ), sprint, and 6-minute walk distance (6MWD), did not show significant variations.
CONCLUSION
This study suggests that LC may have a moderating effect on sleep patterns, HR, and cognitive performance in children with DS. These findings have practical implications for caregivers and educators and highlight the importance of considering lunar-associated variations in planning schedules and interventions for children with DS.
... In turn, a variety of peripheral signals feedback to adjust and stabilize SCN rhythmicity (3,4). However, our understanding of the cellular and molecular mechanisms and rules that mediate this coupling is still fragmentary (5). ...
... Circadian clocks impose daily periodicities to behavior, physiology, and metabolism (5,48,49). This control is mediated by the activity of a central clock and of peripheral clocks, which are housed in a variety of relevant organs. ...
... Similarly, even though ALK acts through Ras/ERK and PI3K signaling pathways in the PG (18), we showed that PI3K signaling is not involved in the circadian gating of emergence, suggesting that, similar to TORSO, ALK and PVR contribute to the rhythm of emergence via the Ras/ ERK pathway. Interestingly, the involvement of multiple signals in the transmission of the time information is consistent with the general principle of coherent coupling between multiple oscillators, which helps to stabilize and strengthen period, phase distribution, and amplitude in the SCN, and between central and peripheral body clocks (5,66). ...
Circadian clocks impose daily periodicities to behavior, physiology, and metabolism. This control is mediated by a central clock and by peripheral clocks, which are synchronized to provide the organism with a unified time through mechanisms that are not fully understood. Here, we characterized in Drosophila the cellular and molecular mechanisms involved in coupling the central clock and the peripheral clock located in the prothoracic gland (PG), which together control the circadian rhythm of emergence of adult flies. The time signal from central clock neurons is transmitted via small neuropeptide F (sNPF) to neurons that produce the neuropeptide Prothoracicotropic Hormone (PTTH), which is then translated into daily oscillations of Ca ²⁺ concentration and PTTH levels. PTTH signaling is required at the end of metamorphosis and transmits time information to the PG through changes in the expression of the PTTH receptor tyrosine kinase (RTK), TORSO, and of ERK phosphorylation, a key component of PTTH transduction. In addition to PTTH, we demonstrate that signaling mediated by other RTKs contributes to the rhythmicity of emergence. Interestingly, the ligand to one of these receptors (Pvf2) plays an autocrine role in the PG, which may explain why both central brain and PG clocks are required for the circadian gating of emergence. Our findings show that the coupling between the central and the PG clock is unexpectedly complex and involves several RTKs that act in concert and could serve as a paradigm to understand how circadian clocks are coordinated.
