Journal of Biological Rhythms最新文献

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.

Maternal care is essential for offspring survival. Circadian regulation of maternal behavior and feeding behavior was determined in mice after parturition. The maternal crouching behavior (covering over pups) occurred intensively in the late half of the dark phase (nighttime), referred to as the "crouching-dominant time." Interestingly, a rapid decrease in body temperature preceded the onset of crouching-dominant time. Feeding behavior during lactation increased in line with the increased energy demand. However, during the night, feeding behavior intensively occurred in the first half of the nighttime, as seen during the non-lactation period, and intermittent feeding behavior was added during the daytime. The clock genes expression of the suprachiasmatic nucleus (SCN) showed robust oscillation even during lactation. In contrast, marked changes in expression profiles of peroxisome proliferator-activated receptor α (PPARα)-regulated metabolic genes in the liver during lactation (postpartum 7 to 12 days) were dissociated from the peripheral clock control, compared to those in virgin mice. During lactation, a critical time for the survival of the species, the maternal circadian clock may regulate multiple important behaviors so that they can occur in the appropriate time frame while adapting to energy requirements.

Time-restricted feeding (TRF) can improve metabolic outcomes. Rodents experiencing TRF exhibit an increase in spontaneous locomotor activity before mealtime and show a phase shift in the rhythm of clock gene expression in peripheral organs, particularly in the liver. Because activation of the transient receptor potential vanilloid-1 (TRPV1) channel produces similar beneficial effects on metabolism as TRF, we hypothesized that this channel mediates the metabolic changes induced by TRF. To assess the role of TRPV1 in metabolism and circadian responses, we utilized the agonist resiniferatoxin (RTX), which at a dosage of 20 µg/kg desensitizes TRPV1. After treatment with RTX or its vehicle, adult male rats were exposed to 21 days of TRF during the light phase. RTX-treated rats show some effects of TRF similar to vehicle-treated controls, with increased locomotor activity and body temperature at the beginning of the light phase, decreased body weight gain and food intake relative to ad-libitum-fed controls. However, RTX-treated rats did not show a decrease in VO₂ consumption or an improvement in glucose tolerance induced by TRF. In addition, RTX treatment eliminated the temporal changes in the expression of clock genes Per1 and Rev-Erba in the liver as well as leptin blood levels. In addition, RTX abolished the temporal alterations of the Trb3 gene in the liver, which encodes a protein that negatively modulates insulin signaling without affecting the expression of insulin, Pparα, Pck1, G6pc, or other clock genes in the liver. In conclusion, TRPV1 may participate in the TRF-induced alterations in metabolism, most likely through its regulation of the temporal changes in Per1, Rev-Erba, and Trb3 expressions in the liver, along with leptin secretion.

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.

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 (n = 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" [n = 209], "neurodevelopmental-psychosis" [n = 40], or "circadian-bipolar spectrum" [n = 43]), as well as by clinical stage (subthreshold disorders classed as 1a or 1b [n = 47, 173, respectively], and full-threshold disorders as 2+ [n = 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, p < 0.001), delayed peak timing (0533 ± 0014 vs 0332 ± 0036, p = 0.002), reduced inter-daily stability (p = 0.009), and increased intra-daily variability (p = 0.020). Peak skin temperature also occurred later relative to sleep midpoint (0.31 ± 0.14 vs -0.48 ± 0.35 radians, p = 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], p = 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.

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 (Ammospermophilus leucurus, 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 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 in silico 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.