Entrainment Of Circadian Rhythms Research Articles

Incubation Temperature and Lighting: Effect on Embryonic Development, Post-Hatch Growth, and Adaptive Response.

During incubation, the content of the egg is converted into a chick. This process is controlled by incubation conditions, which must meet the requirements of the chick embryo to obtain the best chick quality and maximum hatchability. Incubation temperature and light are the two main factors influencing embryo development and post-hatch performance. Because chicken embryos are poikilothermic, embryo metabolic development relies on the incubation temperature, which influences the use of egg nutrients and embryo development. Incubation temperature ranging between 37 and 38°C (typically 37.5–37.8°C) optimizes hatchability. However, the temperature inside the egg called “embryo temperature” is not equal to the incubator air temperature. Moreover, embryo temperature is not constant, depending on the balance between embryonic heat production and heat transfer between the eggshell and its environment. Recently, many studies have been conducted on eggshell and/or incubation temperature to meet the needs of the embryo and to understand the embryonic requirements. Numerous studies have also demonstrated that cyclic increases in incubation temperature during the critical period of incubation could induce adaptive responses and increase the thermotolerance of chickens without affecting hatchability. Although the commercial incubation procedure does not have a constant lighting component, light during incubation can modify embryo development, physiology, and post-hatch behavior indicated by lowering stress responses and fearful behavior and improving spatial abilities and cognitive functions of chicken. Light-induced changes may be attributed to hemispheric lateralization and the entrainment of circadian rhythms in the embryo before the hatching. There is also evidence that light affects embryonic melatonin rhythms associated with body temperature regulation. The authors’ preliminary findings suggest that combining light and cyclic higher eggshell temperatures during incubation increases pineal aralkylamine N-acetyltransferase, which is a rate-limiting enzyme for melatonin hormone production. Therefore, combining light and thermal manipulation during the incubation could be a new approach to improve the resistance of broilers to heat stress. This review aims to provide an overview of studies investigating temperature and light manipulations to improve embryonic development, post-hatch growth, and adaptive stress response in chickens.

Magnetic Fluctuations Entrain the Circadian Rhythm of Locomotor Activity in Zebrafish: Can Cryptochrome Be Involved?

Simple SummaryMost physiological processes are subject to biological circadian rhythms maintained by a complex cascade of biochemical events. The circadian rhythmicity of behavior allows organisms to use energy and resources optimally under changing environmental conditions. To that end, endogenous circadian rhythms are synchronized with external pacemakers (zeitgebers), especially daily changes in illumination. In the 1960s, it was assumed that, in addition to this primary photic cue, animals can use diurnal geomagnetic variation as a secondary zeitgeber. Earlier research found that slow magnetic fluctuations can affect some behavioral endpoints of circadian rhythms by modulating an organism’s physiological state. However, no direct experiments to test such an entrainment of biological clocks by artificial magnetic fields were performed due to the technical difficulty of eliminating natural geomagnetic variation. For the first time, we carried out such tests in a fully controlled magnetic environment using zebrafish as a research model. The experimental treatments included various light/dark cycles and continuous illumination coupled with pre-recorded natural geomagnetic variations. The obtained results indicate that slow magnetic fluctuations can entrain endogenous rhythmical activity in vertebrates. Probably, cryptochromes play a key role in this process. This research provides promising opportunities for the magnetic control of circadian processes, e.g., correcting circadian dysfunctions.In the 1960s, it was hypothesized that slow magnetic fluctuations could be a secondary zeitgeber for biological circadian rhythms. However, no comprehensive experimental research has been carried out to test the entrainment of free-running circadian rhythms by this zeitgeber. We studied the circadian patterns of the locomotor activity of zebrafish (Danio rerio) under different combinations of light regimes and slow magnetic fluctuations, based on a record of natural geomagnetic variation. A rapid synchronization of activity rhythms to an unusual 24:12 light/dark cycle was found under magnetic fluctuations with a period of 36 h. Under constant illumination, significant locomotor activity rhythms with 26.17 h and 33.07 h periods were registered in zebrafish exposed to magnetic fluctuations of 26.8 h and 33.76 h, respectively. The results reveal the potential of magnetic fluctuations for entrainment of circadian rhythms in zebrafish and genuine prospects to manipulate circadian oscillators via magnetic fields. The putative mechanisms responsible for the entrainment are discussed, including the possible role of cryptochromes.

Daylength Shapes Entrainment Patterns to Artificial Photoperiods in a Subterranean Rodent.

Photoperiodism plays an important role in the synchronization of seasonal phenomena in various organisms. In mammals, photoperiod encoding is mediated by differential entrainment of the circadian system. The limits of daily light entrainment and photoperiodic time measurement can be verified in organisms that inhabit extreme photic environments, such as the subterranean. In this experimental study, we evaluated entrainment of circadian wheel-running rhythms in South American subterranean rodents, the Anillaco tuco-tucos (Ctenomys aff. knighti), exposed to different artificial photoperiods, from extremely long to extremely short photophases (LD 21:3, LD 18:6, LD 15:9, LD 9:15, LD 6:18 and LD 3:21). Artificial photoperiods synchronized their activity/rest rhythms and clear differences occurred in (a) phase angles of entrainment relative to the LD cycle and (b) duration of the daily activity phase α. These photoperiod-dependent patterns of entrainment were similar to those reported for epigeous species. Release into constant darkness conditions revealed aftereffects of entrainment to different photoperiods, observed in α but not in the free-running period τ. We also verified if animals coming from summer and winter natural photoperiods entrained equally to the artificial photoperiods by evaluating their phase angle of entrainment, α and τ aftereffects. To this end, experimental animals were divided into "Matching" and "Mismatching" groups, based on whether the experimental photoperiod (short-day [L < 12 h] or long-day [L > 12 h]) matched or not the natural photoperiod to which they had been previously exposed. No significant differences were found in the phase angle of entrainment, α and τ aftereffects in each artificial photoperiod. Our results indicate that the circadian clocks of tuco-tucos are capable of photoperiodic time measurement despite their natural subterranean habits and that the final entrainment patterns achieved by the circadian clock do not depend on the photoperiodic history.

A Perspective Emphasizing Circadian Rhythm Entrainment to Ensure Sustainable Crop Production in Controlled Environment Agriculture: Dynamic Use of LED Cues

World-wide, sustainable crop production is increasingly dependent on the protection of crops from adverse local climate conditions by using controlled environment agriculture (CEA) facilities. Today's greenhouses and plant factories are becoming very technologically advanced. Important breakthroughs in our understanding of the deployment of affordable artificial lighting systems that can supplement and even replace solar radiation is the subject of this perspective article. The key to improving sustainable CEA is to synchronize those environmental cues that best entrain the natural circadian rhythm of the crop. Patterns of circadian rhythms reflect the balance of daily metabolic cycles and phenological stages of development that integrate and anticipate environmental changes for all complex organisms. Within the last decade, our understanding of the use of light-emitting diodes (LEDs) as spectrally tunable tools for stimulating plant responses has expanded rapidly. This perspective proposes that extending the photoperiod in CEA is an economically sustainable goal to for year-round productivity of tomato, using dynamic LED shifts that entrain the circadian rhythm. When the photoperiod is extended too far, tomato experiences injury. To avoid yield reduction, we look to nature for clues, and how circadian rhythms evolved in general to long-photoperiods during the summer in high-latitudes. It follows that circadian rhythm traits are good targets for breeders to select new tomato cultivars suitable for CEA. Circadian rhythm entrainment, using dynamic LED cues, can be tailored to any latitude-of-origin crop, and thus expands the strategies ensuring sustainable food security including healthy diets locally in any region of the world.

Synergies of Multiple Zeitgebers Tune Entrainment.

Circadian rhythms are biological rhythms with a period close to 24h. They become entrained to the Earth's solar day via different periodic cues, so-called zeitgebers. The entrainment of circadian rhythms to a single zeitgeber was investigated in many mathematical clock models of different levels of complexity, ranging from the Poincaré oscillator and the Goodwin model to biologically more detailed models of multiple transcriptional translational feedback loops. However, circadian rhythms are exposed to multiple coexisting zeitgebers in nature. Therefore, we study synergistic effects of two coexisting zeitgebers on different components of the circadian clock. We investigate the induction of period genes by light together with modulations of nuclear receptor activities by drugs and metabolism. Our results show that the entrainment of a circadian rhythm to two coexisting zeitgebers depends strongly on the phase difference between the two zeitgebers. Synergistic interactions of zeitgebers can strengthen diurnal rhythms to reduce detrimental effects of shift-work and jet lag. Medical treatment strategies which aim for stable circadian rhythms should consider interactions of multiple zeitgebers.

Mice hypomorphic for Pitx3 show robust entrainment of circadian behavioral and metabolic rhythms to scheduled feeding.

Pitx3ak mice lack a functioning retina and develop fewer than 10% of dopamine neurons in the substantia nigra. Del Río-Martín etal. (2019) reported that entrainment of circadian rhythms to daily light-dark (LD) cycles is absent in these mice, and that rhythms of locomotor activity, energy expenditure, and other metabolic variables are disrupted with food available ad libitum and fail to entrain to a daily feeding. The authors propose that retinal innervation of the suprachiasmatic nucleus is required for development of cyclic metabolic homeostasis, but methodological issues limit interpretation of the results. Using standardized feeding schedules and procedures for distinguishing free-running from entrained circadian rhythms, we confirm that behavioral and metabolic rhythms in Pitx3ak mice do not entrain to LD cycles, but we find no impairment in circadian organization of metabolism with food available ad libitum and no impairment in entrainment of metabolic or behavioral rhythms by daily feeding schedules. This Matters Arising paper is in response to Del Río-Martín etal. (2019), published in Cell Reports. See also the response by Fernandez-Perez etal. (2022), published in this issue.

Photoreceptors for Entrainment of Circadian Rhythms

In mammals, the intrinsic circadian clock regulates various physiological rhythms, including sleep-wake cycles. These circadian rhythms can be entrained to daily 24-hour light-dark cycles by virtue of photoreception within the retina. The photo-entrainment of circadian rhythms is predominantly mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). In this article, we review the mechanisms of action of ipRGC photoreception, the retinal circuit involving ipRGCs, and the heterogeneity of ipRGCs in mice.

TU12. COPY NUMBER VARIATION (CNV) IN AUTISM SPECTRUM DISORDERS (ASD) AND CO-OCCURRING EPILEPSY

Recent research has shown expression of clock genes in peripheral tissue explants, targeting multiple pathways leading to the entrainment of circadian rhythms. Temporal variations are not solely regulated by photoperiod, but factors such as maternal feed availability can entrain fetal circadian clock. Currently, a paucity of information exists for clock gene expression and short-term temporal transcript abundance in the bovine placenta, which is essential for proper offspring development. Therefore, the objective of this study was to determine the effect of early to mid-gestational nutrient restriction on clock genes, angiogenic factors, and nutrient sensing genes mRNA transcript abundance in placental explants during a 24 h period. Placentomes from adequately fed and nutrient restricted heifers were collected via Cesarean section at day 180 of gestation; separated into caruncular and cotyledonary tissue and placed in culture media for a 24 h period. The mRNA transcript abundance of clock genes (ARNTL, CRY1, and PER2), angiogenic factors (HIF1A and VEGFA), and nutrient sensing genes (NAMPT and NR3C1) was determined every 4 h. Clock genes were expressed in caruncular and cotyledonary explant tissue. The caruncular explant transcript abundance of the clock genes was not influenced by time (P > 0.05); while ARNTL abundance decreased over time in the cotyledon explant (P < 0.05). A main effect of time was observed for HIF1A, VEGFA, and NR3C1 in the caruncular tissue (P < 0.05). Although, angiogenic factors and nutrient sensing genes in cotyledonary tissue displayed evident temporal variation in transcript abundance (P < 0.05). Nutrient restriction did not alter (P > 0.15) mRNA transcript abundance of clock genes, angiogenic factors, or nutrient sensing genes in either caruncular or cotyledonary tissue. Interestingly, these data may indicate limited transmission and synchronization of maternal and fetal temporal variations in transcript abundance. These findings demonstrate that multiple timepoint collections are needed in future studies due to the innate existence of temporal oscillations observed in the bovine placenta.

Social synchronization of circadian rhythms with a focus on honeybees.

Many animals benefit from synchronizing their daily activities with conspecifics. In this hybrid paper, we first review recent literature supporting and extending earlier evidence for a lack of clear relationship between the level of sociality and social entrainment of circadian rhythms. Social entrainment is specifically potent in social animals that live in constant environments in which some or all individuals do not experience the ambient day-night cycles. We next focus on highly social honeybees in which there is good evidence that social cues entrain the circadian clocks of nest bees and can override the influence of conflicting light-dark cycles. The current understanding of social synchronization in honeybees is consistent with self-organization models in which surrogates of forager activity, such as substrate-borne vibrations and colony volatiles, entrain the circadian clocks of bees dwelling in the dark cavity of the nest. Finally, we present original findings showing that social synchronization is effective even in an array of individually caged callow bees placed on the same substrate and is improved for bees in connected cages. These findings reveal remarkable sensitivity to social time-giving cues and show that bees with attenuated rhythms (weak oscillators) can nevertheless be socially synchronized to a common phase of activity.This article is part of the theme issue ‘Synchrony and rhythm interaction: from the brain to behavioural ecology’.

Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients.

To determine whether there was evidence of circadian or sleep-regulatory dysfunction in sighted individuals with non-24-hour sleep-wake rhythm disorder. Three sighted individuals with signs and/or symptoms of non-24-hour sleep-wake rhythm disorder were studied. Thirty-five- to 332-day laboratory and home-based assessments of sleep-wake and circadian timing, endogenous circadian period, photic input to the circadian pacemaker, and/or circadian and sleep-wake-dependent regulation of sleep were conducted. No evidence of circadian dysfunction was found in these individuals. Instead, sleep-wake timing appeared to dissociate from the circadian timing system, and/or self-selected sleep-wake and associated light/dark timing shifted the circadian pacemaker later, rather than the circadian pacemaker determining sleep-wake timing. These findings suggest that the etiology of this disorder may be light- and/or behaviorally induced in some sighted people, which has implications for the successful treatment of this disorder. Emens JS, St Hilaire MA, Klerman EB, etal. Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients. J Clin Sleep Med. 2022;18(2):453-459.

Long-Term Narrowband Lighting Influences Activity but Not Intrinsically Photosensitive Retinal Ganglion Cell-Driven Pupil Responses.

Purpose: Light affects a variety of non-image forming processes, such as circadian rhythm entrainment and the pupillary light reflex, which are mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). The purpose of this study was to assess the effects of long- and short-wavelength ambient lighting on activity patterns and pupil responses in rhesus monkeys.Methods: Infant rhesus monkeys were reared under either broadband “white” light (n = 14), long-wavelength “red” light (n = 20; 630 nm), or short-wavelength “blue” light (n = 21; 465 nm) on a 12-h light/dark cycle starting at 24.1 ± 2.6 days of age. Activity was measured for the first 4 months of the experimental period using a Fitbit activity tracking device and quantified as average step counts during the daytime (lights-on) and nighttime (lights-off) periods. Pupil responses to 1 s red (651 nm) and blue (456 nm) stimuli were measured after approximately 8 months. Pupil metrics included maximum constriction and the 6 s post-illumination pupil response (PIPR).Results: Activity during the lights-on period increased with age during the first 10 weeks (p < 0.001 for all) and was not significantly different for monkeys reared in white, red, or blue light (p = 0.07). Activity during the 12-h lights-off period was significantly greater for monkeys reared in blue light compared to those in white light (p = 0.02), but not compared to those in red light (p = 0.08). However, blue light reared monkeys exhibited significantly lower activity compared to both white and red light reared monkeys during the first hour of the lights-off period (p = 0.01 for both) and greater activity during the final hour of the lights-off period (p < 0.001 for both). Maximum pupil constriction and the 6 s PIPR to 1 s red and blue stimuli were not significantly different between groups (p > 0.05 for all).Conclusion: Findings suggest that long-term exposure to 12-h narrowband blue light results in greater disruption in nighttime behavioral patterns compared to narrowband red light. Normal pupil responses measured later in the rearing period suggest that ipRGCs adapt after long-term exposure to narrowband lighting.

The effect of season of birth on brain epigenome-wide DNA methylation of older adults.

Perinatal light exposure predisposes towards health and behaviour in adulthood. Season of birth is associated with psychiatric, allergic, cardiovascular and metabolic problems. It has been proposed that early-life environmental light disrupts the development of biological rhythms which, in turn, influence later-life health. However, the mechanisms linking perinatal seasonal light to later-life biological rhythm and health in humans are unknown. In this study, we investigated the association between season of birth and epigenome-wide DNA methylation of two postmortem human brain regions (16 hypothalamus, 14 temporal cortex). We did not find statistically significant differences at the whole epigenome level, either because we lacked statistical power or that no association exists. However, when we examined 24 CpG sites that had the highest significance or differential methylation, we identified regions which may be associated with circadian rhythm entrainment, cholinergic neurotransmission and neural development. Amongst methylation of the core clock genes, we identified that hypothalamus Neuronal PAS Domain Protein 2 (NPAS2) gene has hypermethylated regions in long photoperiod-born individuals. In addition, we found nominal associations between season of birth and genes linked to chronotype and narcolepsy. Season of birth-related brain DNA methylation profile was different than a previously reported blood methylation profile, suggesting a tissue-specific mechanism of perinatal light programming. Overall, we are the first to analyse the relationship between season of birth and human brain DNA methylation. Further studies with larger sample sizes are required to confirm an imprinting effect of perinatal light on the circadian clock.

Optimization of light exposure and sleep schedule for circadian rhythm entrainment.

The circadian rhythm, called Process C, regulates a wide range of biological processes in humans including sleep, metabolism, body temperature, and hormone secretion. Light is the dominant synchronizer of the circadian rhythm—it has been used to regulate the circadian phase to cope with jet-lag, shift work, and sleep disorder. The homeostatic oscillation of the sleep drive is called Process S. Process C and Process S together determine the sleep-wake cycle in what is known as the two-process model. This paper addresses the regulation of both Process C and Process S by scheduling light exposure and sleep based on numerical simulations of circadian rhythm and sleep mathematical models. This is a significant step beyond the existing literature that only considers the entrainment of Process C. Regulation of the two-process model poses several unique features and challenges: 1. Process S is non-smooth, i.e., the homeostatic dynamics are different in the sleep and wake regimes; 2. Light only indirectly affects Process S through Process C; 3. Light does not affect Process C during sleep. We consider two scenarios: optimizing light intensity as the control input with spontaneous (i.e., unscheduled) sleep/wake times and jointly optimizing the light intensity and the sleep/wake times, which allows limited delayed sleep and early waking as part of the decision variables. We solve the time-optimal entrainment problem for the two-process model for both scenarios using an extension of the gradient descent algorithm to non-smooth systems. To illustrate the efficacy of our time-optimal entrainment strategies, we consider two common use cases: transmeridian travelers and shift workers. For transmeridian travelers, joint optimization of the two-process model avoids the unrealistic long wake duration when only Process C is considered. The entrainment time also decreases when both the light input and the sleep schedule are optimized compared to when only the light input is optimized. For shift workers, we show that the entrainment time is significantly shortened by optimizing the night shift working light.

The Role of Colony Temperature in the Entrainment of Circadian Rhythms of Honey Bee Foragers.

Honey bees utilize their circadian rhythms to accurately predict the time of day. This ability allows foragers to remember the specific timing of food availability and its location for several days. Previous studies have provided strong evidence toward light/dark cycles being the primary Zeitgeber for honey bees. Work in our laboratory described large individual variation in the endogenous period length of honey bee foragers from the same colony and differences in the endogenous rhythms under different constant temperatures. In this study, we further this work by examining the temperature inside the honey bee colony. By placing temperature and light data loggers at different locations inside the colony we measured temperature at various locations within the colony. We observed significant oscillations of the temperature inside the hive, that show seasonal patterns. We then simulated the observed temperature oscillations in the laboratory and found that using the temperature cycle as a Zeitgeber, foragers present large individual differences in the phase of locomotor rhythms for temperature. Moreover, foragers successfully synchronize their locomotor rhythms to these simulated temperature cycles. Advancing the cycle by six hours, resulting in changes in the phase of activity in some foragers in the assay. The results are shown in this study highlight the importance of temperature as a potential Zeitgeber in the field. Future studies will examine the possible functional and evolutionary role of the observed phase differences of circadian rhythms.

Comparative Neurology of Circadian Photoreception: The Retinohypothalamic Tract (RHT) in Sighted and Naturally Blind Mammals.

The mammalian eye contains two systems for light perception: an image detecting system constituted primarily of the classical photoreceptors, rods and cones, and a non-image forming system (NIF) constituted of a small group of intrinsically photosensitive retinal ganglion cells driven by melanopsin (mRGCs). The mRGCs receive input from the outer retina and NIF mediates light entrainment of circadian rhythms, masking behavior, light induced inhibition of nocturnal melatonin secretion, pupillary reflex (PLR), and affect the sleep/wake cycle. This review focuses on the mammalian NIF and its anatomy in the eye as well as its neuronal projection to the brain. This pathway is known as the retinohypothalamic tract (RHT). The development and functions of the NIF as well as the knowledge gained from studying gene modified mice is highlighted. Furthermore, the similarities of the NIF between sighted (nocturnal and diurnal rodent species, monkeys, humans) and naturally blind mammals (blind mole rats Spalax ehrenbergi and the Iberian mole, Talpa occidentalis) are discussed in relation to a changing world where increasing exposure to artificial light at night (ALAN) is becoming a challenge for humans and animals in the modern society.

The Transcription Factor Ventral Anterior Homeobox 1 Modulates Circadian Time-Keeping and Fertility Through Direct Regulation of Vasoactive Intestinal Polypeptide Expression in the Suprachiasmatic Nucleus

Light provides the primary timing signal that enables fine-tuned behavioral and hormonal entrainment of circadian rhythms to the environment. Light is transmitted from the eye to the brain through the retinohypothalamic tract, where one target is the hypothalamic suprachiasmatic nucleus (SCN), which generates self-sustained circadian rhythms. The vasoactive intestinal polypeptide (VIP) expressing neurons of the SCN relay light information to peripheral cells and tissues through control of hormonal and nervous signals, allowing synchronization of molecular clocks located in individual cells throughout the body. Non-natural light cycles, ie shiftwork, and weakened SCN function through genetic manipulation, disrupt the body’s circadian rhythms, causing deregulated hormone release, metabolic disorders, and negative effects on reproductive systems such as irregular menstrual cycles and decreased sperm count. To further our understanding of how the SCN translates light information into neuroendocrine control of fertility, we conditionally deleted the SCN enriched transcription factor Ventral anterior homeobox 1 (Vax1) in post-developmental VIP neurons, generating Vax1-flox/flox:Vip-Cre+ (cKO) mice. To determine if the SCN timekeeping function was impacted in cKO mice, we single housed males and females with running wheels to examine activity during both 12-hour light/dark cycles and in constant darkness. Wheel-running behavior in constant darkness revealed a shortening of the endogenous free-running period (Tau) of the SCN. Aside from Tau, wheel running behaviors were comparable to controls. Weakened SCN output can negatively impact fertility. While on 12-hour light/dark cycles, we found a modest, but significant change in follicle stimulating hormone and estrogen in cKO females and a reduced sensitivity of GnRH neurons to kisspeptin in males. The changes in hormone release were associated with a slightly lengthened estrous cycle in cKO females and reduced sperm quality in cKO males. To identify the molecular origin of the shortened SCN period, we used immunohistochemistry and RNAscope to examine expression of Vip. We found that diestrus cKO females had a significant reduction in Vip expression at ZT16 and preliminary data suggest a reduction in the circadian clock gene Bmal1. Together, these studies identify a novel role of VAX1 in VIP neurons where VAX1 is required for VIP expression and circadian timekeeping. Loss of VAX1 in VIP neurons weakens SCN output, deregulating reproductive hormone release and modestly reducing reproductive function in both males and females.

Retraction Statement: Morphological and functional diversity of intrinsically photosensitive retinal ganglion cells.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are a special type of ganglion cell that express the photopigment melanopsin and autonomously respond to light in the mammalian retina. Nearly two decades since their discovery, ipRGCs have been broadly investigated for their basic morphologic features, cell classification, physiologic properties, and functional significance. It is well established that ipRGCs are predominantly responsible for non-image-forming vision, such as circadian rhythm entrainment, pupillary contraction, mood, and sleep regulation. However, there are mounting morphological, physiological, and behavioral pieces of evidence supporting the idea that ipRGCs may contribute to image-forming vision such as color, contrast, and perception. These new compelling pieces of evidence extend our previous thought and provide extensive and profound insights into the melanopsin-mediated light response affecting visual functions. This article summarizes what we currently know about ipRGCs' subtypes, signal transduction, axonal projections, synaptic inputs, and functions with the emphasis on non-image-forming vision and image-forming vision.

Identification of key modules and hub genes in glioblastoma multiforme based on co-expression network analysis.

Glioblastoma multiforme (GBM) is the most malignant primary tumour in the central nervous system, but the molecular mechanisms underlying its pathogenesis remain unclear. In this study, data set GSE50161 was used to construct a co‐expression network for weighted gene co‐expression network analysis. Two modules (dubbed brown and turquoise) were found to have the strongest correlation with GBM. Functional enrichment analysis indicated that the brown module was involved in the cell cycle, DNA replication, and pyrimidine metabolism. The turquoise module was primarily related to circadian rhythm entrainment, glutamatergic synapses, and axonal guidance. Hub genes were screened by survival analysis using The Cancer Genome Atlas and Human Protein Atlas databases and further tested using the GSE4290 and Gene Expression Profiling Interactive Analysis databases. The eight hub genes (NUSAP1, SHCBP1, KNL1, SULT4A1, SLC12A5, NUF2, NAPB, and GARNL3) were verified at both the transcriptional and translational levels, and these gene expression levels were significant based on the World Health Organization classification system. These hub genes may be potential biomarkers and therapeutic targets for the accurate diagnosis and management of GBM.

A Morning Bright Light Therapy Intervention to Improve Circadian Health in Adolescent Cancer Survivors: Methods and Preliminary Feasibility.

Circadian rhythm disturbances are common among children with cancer, and are associated with poor health outcomes. Social zeitgeber theory suggests that intervening in the cascade of events that disrupt circadian rhythms may improve health outcomes. Light, most potently sunlight, is a "zeitgeber," or environmental cue instrumental in maintaining entrainment of circadian rhythms. Bright white light (BWL) therapy, a proxy for sunlight, has been used successfully to prevent deterioration of circadian rhythms in adult cancer patients, and to reentrain these rhythms in adolescents with circadian rhythm disorders. This study aimed to develop and assess preliminary feasibility of a BWL therapy intervention for supporting circadian health of adolescent cancer survivors. We hypothesized that adolescents could independently manage BWL in their home, coordinated by nurses using a mail-, phone- and internet-based format, with minimal side effects. Adolescents were instructed to use BWL for 30 minutes daily on awakening, for 28 days. Actigraphs, measuring the circadian activity rhythms of sleep and wake, were worn for 7 days at baseline and Week 4. Adverse events were screened serially. Analyses were descriptive and nonparametric. Eight adolescents participated. On average, BWL was used on 61% of days, for 15 minutes per day. Adverse events were generally mild, although one participant discontinued BWL due to persistent BWL-related nausea. This nurse-guided remote BWL therapy intervention in adolescent cancer survivors demonstrated preliminary feasibility. Future studies with larger samples are required to verify the feasibility of this study, and to determine its safety and effectiveness in supporting circadian activity rhythms.

Entrainment of circadian rhythms of locomotor activity by ambient temperature cycles in the dromedary camel

In the dromedary camel, a well-adapted desert mammal, daily ambient temperature (Ta)-cycles have been shown to synchronize the central circadian clock. Such entrainment has been demonstrated by examining two circadian outputs, body temperature and melatonin rhythms. Locomotor activity (LA), another circadian output not yet investigated in the camel, may provide further information on such specific entrainment. To verify if daily LA is an endogenous rhythm and whether the desert Ta-cycle can entrain it, six dromedaries were first kept under total darkness and constant-Ta. Results showed that the LA rhythm free runs with a period of 24.8–24.9 h. After having verified that the light–dark cycle synchronizes LA, camels were subjected to a Ta-cycle with warmer temperatures during subjective days and cooler temperatures during subjective nights. Results showed that the free-running LA rhythm was entrained by the Ta-cycle with a period of exactly 24.0 h, while a 12 h Ta-cycle phase advance induced an inversion of the LA rhythm and advanced the acrophase by 9 h. Similarly, activity onset and offset were significantly advanced. All together, these results demonstrate that the Ta-cycle is a strong zeitgeber, able to entrain the camel LA rhythm, hence corroborating previous results concerning the Ta non-photic synchronization of the circadian master clock.