J Biol Rhythms
· 2025 Aug · PMID 40432273
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High-grade gliomas, like glioblastoma multiforme (GBM), are the most common malignant brain tumors in adults and are treated with the chemotherapy drug temozolomide (TMZ). In humans, a retrospective analysis of patients'...High-grade gliomas, like glioblastoma multiforme (GBM), are the most common malignant brain tumors in adults and are treated with the chemotherapy drug temozolomide (TMZ). In humans, a retrospective analysis of patients' overall survival suggests that morning dosing may confer a benefit over evening dosing. Circadian variation in O6-methylguanine-DNA methyltransferase (MGMT) gene expression and promoter methylation has been implicated in increased tumor cell sensitivity to TMZ in the morning. Although patient compliance with timed oral administration of TMZ was high in a prospective trial, it is not known whether differences in daily sleep patterns of patients impact the biological time of drug administration or overall survival. Using wrist actigraphy collected from 10 high-grade glioma patients, we quantified the moment of oral TMZ delivery in terms of wall clock time and internal biological time during the months after surgical tumor resection. We found that variation of daily rhythms within and between individuals caused dosing times to vary more in their internal biological time than wall clock time so that, for example, some doses taken by patients assigned for the evening (2000 h) were closer to the patient's internal biological morning. We conclude that wrist actigraphy provides a reliable and non-invasive estimate of personal circadian time that could improve efficacy and precision of TMZ delivery. These findings may inform personalized circadian medicine and optimized times for TMZ delivery in the clinic.
Shin M, Carpenter JS, Park SH
… +11 more, Janiszewski C, Tonini E, McKenna S, Hindmarsh G, Iorfino F, Nichles A, Zmicerevska N, Scott EM, Smarr BL, Hickie IB, Crouse JJ
J Biol Rhythms
· 2025 Jun · PMID 40285489
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While circadian disruptions are common in some sub-groups of youth with mood disorders, skin temperature rhythms in these cohorts are understudied. We examined 24-h wrist skin temperature rhythms in youth with emerging m...While circadian disruptions are common in some sub-groups of youth with mood disorders, skin temperature rhythms in these cohorts are understudied. We examined 24-h wrist skin temperature rhythms in youth with emerging mood disorders, exploring associations with clinical stage and proposed illness subtypes. Youth ( = 306, 23.42 ± 4.91 years, 65% females) accessing mental health care and 48 healthy controls (23.44 ± 3.38 years, 60% females) were examined. Skin temperature parameters including rhythm-adjusted mean temperature, inter-daily stability (day-to-day consistency), intra-daily variability (rhythm fragmentation), and peak temperature time were derived from a wearable sensor. Based on our illness trajectory-pathophysiology model, participants were classified by mood disorder subtypes ("hyperarousal-anxious" [ = 209], "neurodevelopmental-psychosis" [ = 40], or "circadian-bipolar spectrum" [ = 43]), as well as by clinical stage (subthreshold disorders classed as 1a or 1b [ = 47, 173, respectively], and full-threshold disorders as 2+ [ = 76]). Compared to controls, youth with mood disorders had delayed, less stable, and more variable skin temperature rhythms, indicated by lower rhythm-adjusted mean skin temperature (29.94 ± 0.10 °C vs 31.04 ± 0.25 °C, < 0.001), delayed peak timing (0533 ± 0014 vs 0332 ± 0036, = 0.002), reduced inter-daily stability ( = 0.009), and increased intra-daily variability ( = 0.020). Peak skin temperature also occurred later relative to sleep midpoint (0.31 ± 0.14 vs -0.48 ± 0.35 radians, = 0.037). The "circadian-bipolar spectrum" subtype exhibited lower relative amplitude (0.07 ± 0.005 vs 0.08 ± 0.002 [hyperarousal-anxious] and 0.09 ± 0.005 [neurodevelopmental-psychosis], = 0.039), with no delay in sleep midpoint. Clinical stages were not associated with differences in skin temperature parameters. These findings highlight the potential of use of 24-h skin temperature rhythms as a non-invasive biomarker of circadian disturbances in youth with emerging mood disorders. The observed disruptions in temperature patterns and rhythmicity support the notion that disrupted circadian rhythms may mediate the onset or illness course of some subgroups of youth with emerging major mood disorders.
Circadian clocks regulate many aspects of human physiology, including cardiovascular function and drug metabolism. Administering drugs at optimal times of the day may enhance effectiveness and reduce side effects. Certai...Circadian clocks regulate many aspects of human physiology, including cardiovascular function and drug metabolism. Administering drugs at optimal times of the day may enhance effectiveness and reduce side effects. Certain cardiac antiarrhythmic drugs have been withdrawn from the market due to unexpected proarrhythmic effects such as fatal Torsade de Pointes (TdP) ventricular tachycardia. The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a recent global initiative to create guidelines for the assessment of drug-induced arrhythmias that recommends a central role for computational modeling of ion channels and evaluation of compounds for TdP risk. We simulated circadian regulation of cardiac excitability and explored how dosing time of day affects TdP risk for 11 drugs previously classified into risk categories by CiPA. The model predicts that a high-risk drug taken at the most optimal time of day may actually be safer than a low-risk drug taken at the least optimal time of day. Based on these proof-of-concept results, we advocate for the incorporation of circadian clock modeling into the CiPA paradigm for assessing drug-induced TdP risk. Since cardiotoxicity is the leading cause of drug discontinuation, modeling cardiac-related chronopharmacology has significant potential to improve therapeutic outcomes.
Duyvesteyn E, Vizcarra VS, Waight E
… +2 more, Balbuena E, Hablitz LM
J Biol Rhythms
· 2025 Jun · PMID 40145493
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While there is extensive literature on both the neuronal circuitry of rhythms and the intracellular molecular clock, there is a large component of signaling that has been understudied: interstitial fluid (ISF)-fluid that...While there is extensive literature on both the neuronal circuitry of rhythms and the intracellular molecular clock, there is a large component of signaling that has been understudied: interstitial fluid (ISF)-fluid that surrounds the cells in the extracellular space of tissue. In this review, we highlight evidence in the circadian literature supporting ISF signaling as key to circadian synchronization and entrainment and propose new mechanisms of how fluid movement between the brain and periphery may act as zeitgebers by examining the main ISF pathways of the body, focusing on circadian regulation of the glymphatic and lymphatic systems. We identify key pieces of circadian research that point to ISF as an important timing medium, expand on the basics of cerebrospinal fluid (CSF) and ISF production, and outline the basic structure and function of the glymphatic and lymphatic systems.
J Biol Rhythms
· 2025 Jun · PMID 40145492
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Recent studies have shown that cyclic aversive stimuli (time-specific footshocks) act as a nonphotic zeitgeber, shifting circadian behaviors to the daytime in nocturnal rodents through entrainment. It has remained untest...Recent studies have shown that cyclic aversive stimuli (time-specific footshocks) act as a nonphotic zeitgeber, shifting circadian behaviors to the daytime in nocturnal rodents through entrainment. It has remained untested whether diurnal species exhibit similar plasticity in behavioral timing. This study investigated whether antelope ground squirrels (, AGS), naturally diurnal rodents, shift activity timing in response to cyclic aversive stimuli delivered at specific phases of the light-dark (LD) cycle. We conducted two experiments with 20 AGS housed in custom cages featuring a safe nesting area and a separate foraging area rendered potentially aversive by unsignaled time-specific footshocks. In Experiment 1, animals were subjected to a 12:12 LD cycle. One group was exposed to a foraging area that produced footshocks during the light phase, and a control group with footshocks during the dark phase. In Experiment 2, under a 16:8 LD cycle, animals were divided into three groups, with footshock exposure either during the first or second half of the light phase or during the dark phase. Following treatments, animals were released into constant darkness (DD) to assess free-running rhythms. Contrary to findings in nocturnal rodents, AGS did not exhibit consistent complementary shifts to nocturnal activity as an avoidance of footshocks received during daytime. Most animals maintained diurnal activity, showing minor, and inconsistent phase adjustments. In Experiment 2, animals exposed to footshocks during part of the light phase also failed to reliably shift activity to the "safe" portion of the light phase. These findings show AGS do not substantially shift activity patterns in response to cyclic aversive stimuli and that a 24-h cyclic fear stimulus fails to override the LD cycle as a zeitgeber. This suggests a lack of plasticity in circadian behavior and highlights the importance of species-specific differences in response to potential nonphotic zeitgebers.
Circadian medicine aims to leverage the body's internal clock to develop safer and more effective therapeutics. Traditionally, biological time has been estimated using dim light melatonin onset (DLMO), a method that requ...Circadian medicine aims to leverage the body's internal clock to develop safer and more effective therapeutics. Traditionally, biological time has been estimated using dim light melatonin onset (DLMO), a method that requires collecting saliva samples over a long period under controlled conditions, to ensure the observation of DLMO, making it time-consuming and labor-intensive. While some studies have mitigated this by reducing the length of the sampling window, they significantly failed to identify the DLMO for shift workers. In this study, we present a framework that reduces the DLMO experiment time for shift workers to just 5 h. This approach combines sleep-wake pattern data from wearable devices with a mathematical model to predict DLMO prospectively. Based on this prediction, we define a targeted 5-h sampling window, from 3 h before to 2 h after the estimated DLMO. Testing this framework with 19 shift workers, we successfully identified the DLMO for all participants, whereas traditional methods failed for more than 40% of participants. This approach significantly reduces the experiment time required for measuring the DLMO of shift workers from 24 h to 5 h, simplifying the circadian phase measurements for shift workers.
Activity rhythms of laboratory rodents are usually measured by running wheels, and although wheel running activity-or-rest data enable straightforward rhythmic analyses, it provides limited behavioral information. In sub...Activity rhythms of laboratory rodents are usually measured by running wheels, and although wheel running activity-or-rest data enable straightforward rhythmic analyses, it provides limited behavioral information. In subterranean rodents (tuco-tucos), we used bio-loggers (accelerometers) to measure activity rhythms in both lab and field conditions, detecting diverse movements that compose activity. However, understanding these different accelerometer-detected activity components requires more complex analytical tools. Here we used supervised hidden Markov models (HMMs) as a machine learning analysis, to identify behavioral patterns in accelerometer data of tuco-tucos from field enclosures and characterize their behavioral rhythms in this condition. Activity of tuco-tucos was previously video-recorded in the laboratory with simultaneous accelerometer measurements. Video-obtained behavioral data were used in HMM models to refine (train) the classification of accelerometer recordings into different behavioral states. The classification obtained by HMM matched in 93% the one obtained by the video-observed method. Trained models were then used to automatically extract behavior information from accelerometers attached to 20 unobserved tuco-tucos first maintained in field enclosures and then transferred to the laboratory. Activity bouts associated with digging and locomotion were responsible for the diurnal rhythm in field enclosures and the nocturnal rhythm in the laboratory. Bouts of activity spread throughout day and night (cathemeral) were present in both conditions and were associated with feeding, coprophagy, and grooming. Finally, while rest occurs throughout day and night in the laboratory setting, tuco-tucos restrict rest episodes to nighttime under field enclosures, possibly as a behavioral adjustment to challenging environments. HMM models provide more behavioral information from accelerometry data, expanding the scope of activity pattern studies in small mammals under natural conditions.
Binge and chronic alcohol intake impair skeletal muscle and liver circadian clocks. Scheduled exercise is suggested to protect against circadian misalignment, like that induced by alcohol. It was tested whether scheduled...Binge and chronic alcohol intake impair skeletal muscle and liver circadian clocks. Scheduled exercise is suggested to protect against circadian misalignment, like that induced by alcohol. It was tested whether scheduled, voluntary daily wheel running would protect the gastrocnemius and liver clocks against alcohol-induced perturbations. Female C57BL6/Hsd mice were assigned to 1 of 4 groups: control-sedentary (CON SED, = 26), control-exercise (CON EX, = 28), alcohol-sedentary (ETOH SED, = 27), or alcohol-exercise (ETOH EX, = 25). Exercise mice were granted access to running wheels for 2 h/day (ZT13-15) while ETOH mice consumed alcohol-containing liquid diet for 6 weeks. Tissues were collected every 4 h starting at ZT12 from 4-5 mice/group and were used for RNA/cDNA/RT-PCR (gastrocnemius and liver) and Western blotting (gastrocnemius). A second cohort of mice were weaned off alcohol, given regular chow, and continued daily exercise (2 h/day) for ~2 weeks. Then, all mice (EX and SED) were given 24-h wheel access for 1 week to assess cyclic running behaviors during abstinence. While alcohol differentially disrupted muscle and liver clocks in sedentary mice, differences between exercised groups were minimized. BMAL1 protein expression increased in the nuclear-enriched fraction in the gastrocnemius of both exercise groups compared to both sedentary groups. In the second cohort, wheel running was increased in ETOH EX compared to ETOH SED in the dark cycle. In the light cycle, ETOH mice ran less than CON mice, and EX mice ran less than SED mice despite all mice receiving chow diet and no EtOH. Overall, scheduled wheel running partially offset the alcohol-induced perturbations in the muscle and liver clock while ETOH and EX both influenced the timing of subsequent activity after the dietary intervention ended.
Knutson KL, Reid KJ, Wong M
… +7 more, Alexandria SJ, Thomas SJ, Lewis CE, Schreiner PJ, Sidney S, Kershaw K, Carnethon MR
J Biol Rhythms
· 2025 Apr · PMID 39921210
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Chronotype indicates a person's "circadian preference," that is, the time of day when they prefer to perform certain activities (e.g. a "morning" vs "evening" person). Sleep timing is related to chronotype but is also co...Chronotype indicates a person's "circadian preference," that is, the time of day when they prefer to perform certain activities (e.g. a "morning" vs "evening" person). Sleep timing is related to chronotype but is also constrained by social requirements. When sleep timing does not align with chronotype, circadian disruption can occur, and circadian disruption impairs cardiometabolic health. There are well-known racial disparities in cardiometabolic health whereby Black adults are at higher risk. It is not well-known, however, whether sleep timing within each chronotype varies between Black and White adults, which was the focus of these analyses. These data are from a cross-sectional sleep study conducted in 2020 to 2023 as an ancillary to the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study, in the United States. The Morningness-Eveningness Questionnaire (MEQ) captured chronotype in 2,373 participants aged 52-70 years. Chronotype was based on both overall MEQ score and question 19 categories. A subset of participants wore a wrist actigraphy monitor for ~7 days to assess sleep timing ( = 720). Our sample included 27% Black women, 17% Black men, 33% White women, and 24% White men. Mean MEQ score and chronotype distribution did not differ among race-gender groups. Among morning types, Black women and men had a later sleep start and midpoint than White women (23-34 minutes later for Black women, 32-53 minutes for Black men). Among intermediate types, Black women had significantly later sleep start (55 minutes later) and midpoint (44 minutes later), and Black men had a later sleep start (50 minutes later) than White women adjusting for age and study site. In summary, regardless of chronotype, Black adults had later sleep timing than White adults.
J Biol Rhythms
· 2025 Apr · PMID 39878301
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The nature of biological research is changing, driven by the emergence of big data, and new computational models to parse out the information therein. Traditional methods remain the core of biological research but are in...The nature of biological research is changing, driven by the emergence of big data, and new computational models to parse out the information therein. Traditional methods remain the core of biological research but are increasingly either augmented or sometimes replaced by emerging data science tools. This presents a profound opportunity for those circadian researchers interested in incorporating big data and related analyses into their plans. Here, we discuss the emergence of novel sources of big data that could be used to gain real-world insights into circadian biology. We further discuss technical considerations for the biologist interested in including data science approaches in their research. We conversely discuss the biological considerations for data scientists so that they can more easily identify the nuggets of biological rhythms insight that might too easily be lost through application of standard data science approaches done without an appreciation of the way biological rhythms shape the variance of complex data objects. Our hope is that this review will make bridging disciplines in both directions (biology to computational and vice versa) easier. There has never been such rapid growth of cheap, accessible, real-world research opportunities in biology as now; collaborations between biological experts and skilled data scientists have the potential to mine out new insights with transformative impact.
Duston A, Holtman S, Bowen AE
… +5 more, Cree MG, Nadeau K, Wright KP, Simon SL, Diniz Behn CG
J Biol Rhythms
· 2025 Feb · PMID 39876068
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Circadian rhythms, intrinsic 24-h cycles that drive rhythmic changes in behavior and physiology, are important for normal physiology and health. Previous work in adults has identified sex differences in circadian rhythms...Circadian rhythms, intrinsic 24-h cycles that drive rhythmic changes in behavior and physiology, are important for normal physiology and health. Previous work in adults has identified sex differences in circadian rhythms of melatonin, temperature, and the intrinsic period of the human circadian timing system. However, less is known about sex differences in circadian rhythms at other developmental stages. To address this gap, we considered a secondary analysis of sleep and circadian data from two studies involving adolescent participants during the academic year: ( = 32, 15 females). We collected 1 week of in-home actigraphy data to calculate sleep-wake parameters and in-laboratory salivary melatonin data collection in dim-light conditions was used to compute dim-light melatonin onset (DLMO) and offset (DLMOff) using a threshold of 4 pg/mL. We found that DLMO was an average of 96 min earlier, the time between DLMO and bedtime was an average of 56 min greater, and the biological night (time between DLMO and DLMOff) was 60 min longer in females compared to males, even though bedtimes and waketimes were not statistically different between the groups. In addition, after accounting for differences in bedtime, sex was still a significant predictor of DLMO. Conversely, no evidence was found indicating a difference in DLMOff or the phase angle between DLMOff and waketime by sex. These findings suggest that sex differences in circadian rhythms are present in adolescents and may have implications for circadian health during this important developmental period.
The role of the hierarchical organization of the suprachiasmatic nucleus (SCN) in its functioning, jet lag, and the light treatment of jet lag remains poorly understood. Using the core-shell model, we mimic collective be...The role of the hierarchical organization of the suprachiasmatic nucleus (SCN) in its functioning, jet lag, and the light treatment of jet lag remains poorly understood. Using the core-shell model, we mimic collective behavior of the core and shell populations of the SCN oscillators in transient states after rapid traveling east and west. The existence of a special region of slow dynamical states of the SCN oscillators can explain phenomena such as the east-west asymmetry of jet lag, instances when entrainment to an advance is via delay shifts, and the dynamics of jet lag recovery time. If jet lag brings the SCN state into this region, it will take a long time to leave it and restore synchronization among oscillators. We show that the population of oscillators in the core responds quickly to a rapid phase shift of the light-dark cycle, in contrast to the shell, which responds slowly. A slow recovery of the synchronization among the shell oscillators in transient states may strongly affect reentrainment in peripheral tissues and behavioral rhythms. We discuss the relationship between molecular, electrical, and behavioral rhythms. We also describe how light pulses affect the SCN and analyze the efficiency of the light treatment in facilitating the adaptation of the SCN to a new time zone. Light pulses of a moderate duration and intensity reduce the recovery time after traveling east, but not west. However, long duration and high intensity of light pulses are more detrimental than beneficial for speeding up reentrainment. The results of the core-shell model are compared with experimental data and other biologically motivated models of the SCN.
Zhang Q, Litwin C, Dietert K
… +4 more, Tsialtas I, Chen WH, Li Z, Koronowski KB
J Biol Rhythms
· 2025 Apr · PMID 39773136
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Circadian disruption is pervasive in modern society and associated with increased risk of disease. Chronic jet lag paradigms are popular experimental tools aiming to emulate human circadian disruption experienced during...Circadian disruption is pervasive in modern society and associated with increased risk of disease. Chronic jet lag paradigms are popular experimental tools aiming to emulate human circadian disruption experienced during rotating and night shift work. Chronic jet lag induces metabolic phenotypes tied to liver and systemic functions, yet lack of a clear definition for how rhythmic physiology is impaired under these conditions hinders the ability to identify the underlying molecular mechanisms. Here, we compared 2 common chronic jet lag paradigms and found that neither induced arrythmicity of the liver and each had distinct effects on rhythmicity. Instead, more frequent 8-h forward shifts of the light schedule induced more severe misalignment and non-fasted hyperglycemia. Every other day shifts eventually uncoupled behavioral and hepatic rhythms from the light cycle, reminiscent of free-running conditions. These results point to misalignment, not arrhythmicity, as the initial disturbance tied to metabolic dysfunction in environmental circadian disruption and highlight considerations for the interpretation and design of chronic jet lag studies.
Hartstein LE, Wright KP, Diniz Behn C
… +2 more, Stowe SR, LeBourgeois MK
J Biol Rhythms
· 2025 Apr · PMID 39773135
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Although the sensitivity of the circadian system to the characteristics of light (e.g., biological timing, intensity, duration, spectrum) has been well studied in adults, data in early childhood remain limited. Utilizing...Although the sensitivity of the circadian system to the characteristics of light (e.g., biological timing, intensity, duration, spectrum) has been well studied in adults, data in early childhood remain limited. Utilizing a crossover, within-subjects design, we examined differences in the circadian response to evening light exposure at two different correlated color temperatures (CCT) in preschool-aged children. Healthy, good sleeping children ( = 10, 3.0-5.9 years) completed two 10-day protocols. In each protocol, after maintaining a stable sleep schedule for 7 days, a 3-day in-home dim-light circadian assessment was performed. On the first and third evenings of the in-home protocol, dim-light melatonin onset (DLMO) was assessed. On the second evening, children received a 1-h light exposure of 20 lux from either 2700 K (low CCT) or 5000 K (high CCT) (~9 and ~16 melanopic equivalent daylight illuminance (mEDI lux), respectively) centered around their habitual bedtime. Children received the remaining light condition during their second protocol, with the order counterbalanced across participants. Salivary melatonin was collected to compute melatonin suppression and circadian phase shift resulting from each experimental light condition. Melatonin suppression across the 1-h light stimulus was significantly greater during exposure to the high CCT light ( = 56.3%, = 19.25%) than during the low CCT light ( = 23.90%, = 41.06%). Both light conditions resulted in marked delays of circadian timing, but only a small difference ( = -0.25) was observed in the delay between the 5000 K ( = 35.3 min, = 34.3 min) and 2700 K ( = 26.7 min, = 15.9 min) conditions. Together, these findings add to a growing literature demonstrating high responsivity of the circadian clock to evening light exposure in early childhood and provide preliminary evidence of melatonin suppression sensitivity to differences in light spectrum in preschool-aged children.