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Background Environmental noise pollution is serious, and there are few studies on the effects of long-term noise exposure during sleep on cognitive function and possible biological clock mechanism. Objective To explore the cognitive impairment induced by noise exposure during sleep in mice and possible biological clock mechanism, and to provide a theoretical basis for the protection against noise exposure. Methods Twenty male C57BL/6J mice were randomly divided into a control group and a noise-exposed group, 10 mice in each group. The noise-exposed group was exposed to sleep-period noise using a noise generator for 12 h (08:00–20:00) per day for a total of 30 d. The calibrated noise intensity was set at 90 dB. No intervention was imposed on the control group. At the end of the noise exposure, cognitive function of mice was examined using the new object recognition experiment and the open field test, and the hippocampal tissue damage of mice were evaluated by Nissl staining, ionized calcium binding adaptor molecule 1 (Iba1) immunofluorescence staining, and real-time fluorescence quantitative PCR for inflammatory factors and biological clock genes. Oxidative stress indicators in the hippocampus of mice were also detected by assay kit. Results After noise exposure during sleep period, the results of new object recognition experiment showed that the discrimination index of mice in the noise-exposed group was 0.06±0.04, which was significantly lower than that of the control group (0.65±0.13) (P<0.05). The results of open field test showed that the central activity distance of the noise-exposed group was (242.20±176.10) mm, which was significantly lower than that of the control group, (1548.00±790.30) mm (P < 0.05), and the central activity time of the noise-exposed group was (0.87±0.64) s, which was significantly lower than that of the control group, (6.00±2.86) s (P < 0.05). The Nissl staining results showed that compared with the control group, neurons in the hippocampus of the noise-exposed mice were shrunken, deeply stained, disorganized, and loosely connected. The immunofluorescence results showed that microglia in the hippocampus of the noise-exposed mice were activated and the expression of Iba1 was significantly increased compared with those of the control group (P<0.05). The real-time PCR results of showed that the mRNA levels of the biological clock genes Clock, Per2, and Rev-erbα were significantly increased compared with those of the control group (P<0.05), and the mRNA level of Per1 was significantly decreased compared with that of the control group (P<0.05); and the mRNA levels of IL-18, IL-6, iNOS, and NLRP3 in the hippocampal tissues of mice were significantly increased compared with those of the control group (P<0.05). The results of oxidative stress evaluation showed that compared with the control group, reduced glutathione content was significantly reduced in the noise-exposed group (P<0.001). Conclusion Noise exposure during sleep period can lead to the destabilization of biological clock genes in hippocampal tissues and trigger hippocampal neuroinflammation, which can lead to the activation of microglia and cause cognitive impairment in mice.
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With the development of society, the incidence of myopia and the population of myopia has increased year by year, which has become a major public health problem. Therefore, the research on the pathogenesis and prevention and control measures of myopia is imminent. In recent years, the role of the biological clock in the development of myopia has gradually attracted scholars interest. Now the author starts from the impact of the biological clock on the axial length, retina and choroid in the development of myopia. In order to provide new ideas for the study of prevention and control measures and the pathogenesis of myopia, a brief review is made from the perspective of contemporary society and disrupted body clock.
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The essence-qi-spirit theory is an important part of traditional Chinese medicine， whose steady state is the material and functional basis for the balance of yin and yang in the body， making the essence， qi and spirit integrated， and body and spirit harmonized. Based on this theory， it is proposed that essence and qi depletion， spirit dissipation and qi dispersion， disharmony between yin and yang is the main pathogenesis of sleep disorders. Therefore， the method of regulating and harmonzing yin and yang by essence gathering， qi nourishing and spirit storing can be used to treat sleep disorder. The biological clock system of the circadian rhythm of sleep is regulated by the molecular oscillation that is generated by the transcription of the biological clock gene， and is a clock gradually formed by orga-nisms constantly adapting to the laws of nature. As the material basis， power， and embodiment of sound and peaceful sleep， essence， qi and spirit can perceive and transmit natural signals， whose functions are similar to what is recognized by modern science that oscillation amplifies the rhythm signal， and synchronously regulates the expression signal of the biological clock gene， thereby forming a biological clock system with “input-oscillation-output” as the feedback cycle. It is believed that the regulation method of yin and yang by essence gathering， qi nourishing and spirit storing may comprehensively regulate the physiological activities through brain/ muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 （BMAL1）/circadian locomotor output cycles kaput （CLOCK）-period protein （PER）/ cryptochrome （CRY） transcriptional feedback loop， thereby adapting to the natural environment changes， playing an active role in the treatment of sleep disorders， and provideing a new idea for traditional Chinese medicine to reshape the molecular regulation system of the endogenous biological clock to prevent and treat sleep disorders.
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Diabetic retinopathy (DR) is one of the most common and serious complication of diabetes mellitus, which is the main cause of vision loss in adults. Biological clock genes produce circadian rhythms and control its operation, while the disorder of the expression causes the occurrence and development of a series of diseases. It has been demonstrated that biological clock genes might take effects in the development and progression of DR. On the one hand, circadian rhythm disorder-related behavior disrupts the circadian oscillation of clock genes, and the change in its expression level is prone to unbalanced regulation of glucose metabolism, ultimately increasing the risk of type 2 diabetes mellitus and DR pathogenesis. On the other hand, DR patients exhibit symptoms of circadian rhythm disorders, and it has been suggested that the clock genes may control the development and progression of DR by affecting a variety of retinal pathophysiological processes. Therefore, maintaining normal circadian rhythm can be used as a disease prevention strategy, and studying the molecular mechanism of clock genes in DR can provide new ideas for more comprehensive elaboration of the pathogenesis of DR and search for new therapeutic targets.
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Circadian rhythm is a phenomenon of diurnal changes in life activities formed by a transcription-translation feedback loop of biological clock genes affected by external environmental conditions. The circadian rhythm system controls almost all physiological processes in the organism, and these processes will change as the external environment changes. Previous studies have shown that the hypothalamic-pituitary-thyroid axis in mammals is regulated by the central diurnal pacemaker of the suprachiasmatic nucleus of the hypothalamus, so part of the thyroid function is controlled by the biological clock, and the secretion of thyroid hormones in blood can present a circadian rhythm. However, the molecular mechanism of the biological clock's regulatory effect on thyroid is still unclear. Whether circadian rhythm interference is related to the disorder of thyroid function or the occurrence of thyroid diseases is worthy of attention. This paper focused on the research progress of biological clock, circadian rhythm, and thyroid function, specifically the characteristics of circadian rhythm of thyroid physiological function and the effects of sleep deprivation, light at night, and night shift work on thyroid function, elaborated the relationships of circadian rhythm disorder with thyroid function and thyroid diseases represented by thyroid malignant tumors. The review summarized that circadian rhythm disorder may disrupt the rhythmic secretion of thyroid hormones, but no clear conclusion is reached yet on any effect on thyroid diseases, especially thyroid malignant tumors, so it is necessary to further strengthen the relevant epidemiological and molecular mechanism research.
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Objective:To investigate the effect of BMAL1 gene on the proliferation, migration and invasion ability of radiation-resistant nasopharyngeal carcinoma cell line (5-8FR) and the molecular mechanism. Methods:A multi-target click model was constructed for radiation-resistant nasopharyngeal carcinoma cell line 5-8FR by low-dose fractionated irradiation, and the results of clone formation assay were used to fit the multi-target click model and calculate the sensitization ratio of radiotherapy. The expression levels of PI3K/Akt/MMP-2/9 signaling pathway-related proteins in 5-8FR and control 5-8F cell lines were detected by Western blot. The overexpression and knockdown vectors of BMAL1 gene were constructed and transfected with 5-8F and 5-8F cell lines, respectively. The BMAL1 gene overexpression (pcDNA-BMAL1) and its control (pcDNA) and interference (BMAL1-shRNA) and control (con-shRNA) cell lines were stably transfected with nasopharyngeal carcinoma cell line 5-8F and radiation-resistant cell line 5-8FR, respectively. Western blot was performed to verify the infection efficiency and detect the changes of PI3K/Akt/MMP-2/9 signaling pathway-related proteins after overexpression or interference of BMAL1 gene in both groups of cells. CCK-8 assay, cell scratch test and Transwell chamber test were conducted to investigate the proliferation, migration and invasion capabilities of 5-8FR cell line after overexpression or interference of BMAL1 gene. Results:BMAL1 gene expression was down-regulated, and those of PI3K/Akt pathway proteins and downstream related molecules of MMP-2 and MMP-9 were up-regulated, and TIMP-2 and TIMP-1 expression was down-regulated in nasopharyngeal carcinoma radiation-resistant cell lines. Overexpression of BMAL1 gene inhibited the expression of PI3K/Akt pathway proteins and downstream related molecules of MMP-2 and MMP-9, promoted the expression of TIMP-2 and TIMP-1, and inhibited the proliferation, migration and invasion capabilities of radiation-resistant nasopharyngeal carcinoma cells, while interference with BMAL1 gene yielded the opposite results. Conclusions:BMAL1 gene can reverse the expression of PI3K/Akt/MMP-2/9 signaling pathway-related proteins in radiation-resistant nasopharyngeal carcinoma cell lines and inhibit the proliferation, migration and invasion capabilities of radiation-resistant nasopharyngeal carcinoma cell lines.
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@#The circadian rhythm is a set of autonomous endogenous oscillators resulting nearly 24h cycles. The biological clock, including central and peripheral biological clock, is a clock system that regulates the circadian rhythm of the body. The biological clock gene and its encoded protein constituent the transcription-translation oscillation loop, which could regulate the circadian rhythm of biochemical, physiological, and behavioral processes through neural and humoral pathways. The mammalian eyeball contains a complete biological clock system, thus controlling the circadian rhythm of important physiological functions and various parameters of the eyeball. Abnormal circadian clock genes caused by various reasons will affect the circadian rhythm and may lead to the occurrence and development of the ocular diseases. Therefore, the pathogenesis and clinical manifestations of ocular diseases are characterized by diurnal variation. The change of circadian clock gene expression is not only involved in the pathophysiological process of ocular diseases, but also may be an important target for the prevention and treatment of diseases. This article introduces the circadian rhythm characteristics of corneal disease, glaucoma and myopia and the related biological clock regulation mechanism. Further research on the circadian clock provides a new strategy for the prevention and treatment of ocular diseases.
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A cana-de-açúcar e a cana energia são plantas intercruzáveis que compõe o complexo Saccharum. Estas plantas são fonte de biomassa para produção de açúcar, biocombustíveis, eletricidade, entre outros, e utilizam a energia assimilada pela fotossíntese de forma contrastante, ainda que ambas resultem em alta produtividade. O relógio biológico é um mecanismo molecular que gera informações sobre a hora do dia em conjunto com estímulos ambientais, adaptando respostas fisiológicas em prol de otimizar o desenvolvimento dos organismos em um ambiente cíclico, processo que regula cerca de 64% dos genes de cana-deaçúcar no campo. Em organismos sésseis como as plantas, o recorrente processo de produção de energia apenas durante o período luminoso, gera ritmos de metabólitos que influenciam na atividade de enzimas quinases que assim funcionam como sensores do estado energético, em vias conservadas nos eucariotos. Porém, pouco se sabe a respeito de como estes sinais são percebidos a nível transcricional, principalmente em plantas cultiváveis. Para elucidar como estas vias atuam em conjunto em plantas do complexo Saccharum, medimos o nível de transcrição de componentes do relógio biológico, de subunidades que compõe o complexo TOR, e da subunidade catalítica de SnRK1, KIN10. Medimos o desempenho do relógio biológico das variedades através da quantificação de amido em quatro pontos temporais, para obter uma dinâmica de produção e consumo, processo que é regulado pelo relógio biológico e tem genes com perfil de expressão rítmicos em cana de-açúcar. Curiosamente, uma das quatro variedades onde identificamos provável perfil rítmico de consumo de amido é a S.officinarum SP80-3280, cana-de-açúcar utilizada anteriormente para estudos de relógio biológico. Os nove acessos foram divididos em dois grupos com base em sua partição de carbono contrastante. HF (high fiber) com mais fibras e perfilho e grupo HS (high sucrose), com maior armazenamento de açúcares e amido que HF, em todos os horários de coleta, e com baixa produção de fibras. Estes grupos não diferem em expressão dos componentes de relógio biológico, no entanto, HS tem maior transcrição de uma subunidade do complexo TOR, em apenas um dos horários analisados (ZT12). Em conjunto, a expressão dos componentes do relógio biológico divide os acessos entre os que possuem altos níveis de transcrição de ScLHY, no ZT03, e os que possuem maior transcrição dos genes PRR59, 73 e 95, no ZT12, grupos com contrastante partição de carbono. A transcrição dos sensores energéticos se correlaciona no começo da noite em acessos de HS e Krakatau e, no começo da manhã, em acessos de HF e IN84-105, sem agrupar as variedades por espécie ou destino de carbono. Este trabalho sugere que há diferentes níveis de correlação entre a transcrição dos genes mensurados e as contrastantes partições de carbono das plantas do complexo Saccharu
Sugarcane and Energycane are intercrossable plants that make up the Saccharum complex. These plants are a source of biomass, sugar, biofuels, electricity among others, and even though they use the energy assimilated by photosynthesis in a contrasting way, both results in high productivity. The biological clock is a molecular mechanism that generates information about the time of day in conjunction with environmental stimuli, adapting physiological responses to optimize the development of organisms in a cyclic environment, a process that regulates about 64% of sugarcane genes in field-grown plants. In organisms such as plants, the recurrent process of energy production that happens only during the luminous period generates rhythmicity that may influence the activity of kinase enzymes, thus giving an energy sensor property for then. However, little is known about how these signs are perceived at the transcriptional level, especially in crops and monocots. To elucidate how these pathways act together in plants of the Saccharum complex, we measured the transcription level of the daytime loop of the biological clock, subunits that make up the TOR complex, and the catalytic subunit of SnRK1, KIN10. We measured starch content in four time points, to obtain a dynamic of production and consumption, a process that is regulated by the biological clock and has genes with a rhythmic expression profile in sugarcane. Interestingly, one of the four varieties where we could identify a probable rhythmic profile of starch consumption is a sugarcane SP80-3280 (S. officinarum), that have been used for biological clock studies. The nine genotypes were divided into two groups based on their contrasting carbon partition. HF (high fiber) with more fiber and tiller and group HS (high sucrose), with higher sugar and starch storage than HF, but with lower fiber production. These groups do not differ in expression of biological clock components; however, HS has a higher transcription of a subunit of the TOR complex, in only one of the analyzed times (ZT12). Together, the expression of components of the biological clock divides the genotypes between those with higher levels of ScLHY in ZT03 and those with more transcripts of PRR59, 73 and 95 genes in ZT12, groups that also have contrasting carbon partition. The transcription of TOR complex correlates in the early evening in HS and KRAKATAU, but in the morning, in HF and IN84-105, with no clear correlation with the C destination preferences. This work suggests that there are different levels of correlation between the transcription of biological clock and energy sensors component genes and the contrasting carbon partitions of plants from the Saccharum complex
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Plants/adverse effects , Biological Clocks , Saccharum/adverse effects , Energy Metabolism , Phosphotransferases , Sucrose , Biomass , Growth and Development , Efficiency/classification , Sugars/classificationABSTRACT
Vitamin A (VA) is a fat-soluble vitamin with all-trans-retinoic biological activities. In addition to maintaining the normal functions of the eye, skin, immune, and reproductive systems, VA is also widely distributed in brain tissues, and important to the generation and differentiation of neural progenitor cells in the developing nervous system. Pregnant women are susceptible to vitamin A deficiency (VAD). Retinoic acid, the active form of VA, is very important to the brain development of offspring. This article reviews the literatures of maternal VAD during pregnancy, summarizing the risk factors of maternal VAD during pregnancy, and the research findings of the effects of maternal VAD during pregnancy on offspring neurodevelopment based on both human studies and animal experiments, and the possible underlying mechanisms by which maternal VAD affects the development of embryonic layers, brain structures, hippocampal synaptic transmission, and the biological clock in offspring.
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Circadian rhythm is an internal regulatory mechanism that allows organisms to adapt to circadian changes in the external environment, and can regulate the body's steady state by affecting the metabolic pathways of multiple organs. When exogenous factors such as eating time, worktime changes, and sleep disturbances cause the body's circadian rhythm to be disrupted, the risk of developing metabolic syndrome is significantly increased. This article explores the relationship between circadian rhythm and body metabolism and summarizes the molecular mechanisms by which circadian rhythm regulates the digestive system, liver and bile acid production, and kidney function. We review research progress on intervention in the circadian rhythm by traditional Chinese medicine and provide a reasonable and valuable basis for follow-up studies on the role of traditional Chinese medicine in research on the molecular mechanisms of regulation of circadian rhythm.
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The circadian rhythm maintains various physiological functions of our body, and regulates the body to cope with the external environment. The disorder in the circadian rhythm could produce harmful effects and increase the risk of diseases. A grow ing research has shown that many small molecule regulators could target the circadian rhythm system, and many new techniques and strategies, including the high-throughput screening technique, have been used in the discovery and investigation of new small mole cule regulators of the circadian rhythm system. In this review, we introduce basic components and molecular mechanisms of the circa dian rhythm system, summarize research progresses in the small molecule regulators, explain the relationship between various chronic diseases and circadian clocks, and discuss potential applications of the small molecule modulators in the treatment of circadian rhythm-related diseases.
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OBJECTIVE：To study the improvement effects of isopimpinelline on p-chlorophenylalanine（PCPA）-induced pineal injury model rats and its effect on expression of biological clock gene. METHODS ：Totally 60 rats were divided into blank control group（2％ polysorbate solution），model control group （2％ polysorbate solution），positive control group （melatonin，10 mg/kg） and isopimpinelline high-dose ，medium-dose and low-dose groups （3，1.5，0.75 mg/kg）. Except for blank control group ，rats in other groups were given PCPA intraperitoneally （450 mg/kg）to establish pineal injury model. After modeling finished ，they were given relevant medicine intragastrically ，once a day ，for consecutive 7 d. On the 6th day of administration ，the sleep latency and sleep duration of rats in each group were investigated by pentobarbital sodium coordination sleep test ；after last administration ， ELISA assay was used to determine the serum level of melatonin in rats. Fluorescence microscope and electron microscope were used to observe the pathological tissue and cell ultrastructure changes of the pineal gland. RT-qPCR was used to detect the mRNA expressions of biological clock gene Clock，Bmal1，Per1，Per2，Per3，Cry1，Cry2 in pineal gland of rats. RESULTS ：Compared with blank control group ，model control group had significantly longer sleep latency （P＜0.05）；serum melatonin ，mRNA expressions of Bmal1 and Per1 in pineal gland were significantly decreased （P＜0.05 or P＜0.01）while mRNA expression of Per3 was increased significantly （P＜0.05）. The pineal gland cell arrangement disorder ，nuclear pyknosis ，vacuolar degeneration increased and cell number decreased significantly ；mitochondria swollen ，cristae broken and pyknosis were observed. Compared with model control group ，the sleep latency of isopimpinelline high-dose group was shortened significantly （P＜0.05），sleep duration time was prolonged significantly （P＜0.05）；the levels of melatonin in serum ，mRNA expressions of Clock，Bmal1， Per1，Cry1 and Cry2 in pineal gland of rats were increased significantly （P＜0.05 or P＜0.01）. In isopimpinelline medium-dose group，the sleep latency was shortened significantly （P＜0.05）；the levels of melatonin in serum and mRNA expressions of Clock， Bmal1，Per1，Cry1，Cry2 in pineal gland were increased significantly （P＜0.05 or P＜0.01），while mRNA expression of Per3 was decreased significantly （P＜0.05）. In isopimpinelline low-dose group ，the levels of mRNA expressions of Clock，Bmal1，Per2 and Cry2 were increased significantly （P＜0.05），while mRNA expression of Per3 was decreased significantly （P＜0.05）. Cell arrangement disorder was improved and nuclear pyknosis vacuole degeneration was decreased to some extent in isopimpinelline groups；mitochondria swelled ，cristae fractured ，and pyknosis decreased to some extent. CONCLUSIONS ：Isopimpinelline can improve PCPA-induced pineal gland injury in rats ；it can up-regulate the expressions of positive regulators Clock，Bmal1 and negative regulators Per1，Per2，Cry1，Cry2，while down-regulate the expression of negative regulator Per3.
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Many physiological activities including endocrine, metabolism and immunity are regulated by circadian rhythm. Abnormal circadian rhythms are associated with a variety of diseases, including tumer, obesity, diabetes and mood disorders, as well as neurodegenerative diseases. Parkinson's disease is the second most common neurodegenerative disease, second only to Alzheimer's disease. The cardinal features of Parkinson's disease include rest tremor, bradykinesia, rigidity, and gait impairment, which are also accompanied by many non-motor symptoms. Circadian dysfunction is one of the most common non-motor symptoms of Parkinson's disease, which may occur before the onset of motor symptoms or last throughout the course of the disease, causing significant negative effects on the quality of life of patients and caregivers. In this article we review the clinical manifestations, biological markers and current treatment strategies of circadian dysfunction in Parkinson's disease.
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Los estudios sobre los efectos del envejecimiento en la fisiología y el metabolismo cada vez son más, uno de sus objetivos es contribuir a instrumentar programas para mejorar la calidad de vida y prevenir discapacidades en la vejez. Es de gran importancia mencionar que durante el envejecimiento se presenta una desaceleración natural del metabolismo, se produce una serie de cambios en la regulación de la energía, lo que contribuye a la pérdida de peso y grasa; estos cambios en la regulación de la ingesta calórica contribuyen en un aumento de la susceptibilidad al desequilibrio energético tanto positivo como negativo, lo cual va asociado a un deterioro en la salud. Sin embargo, el llegar a la vejez, no es una sentencia de muerte para el metabolismo, por el contrario, éste puede ser controlado mediante el mantenimiento de un estilo de vida activo, aunado a esto investigaciones han demostrado que el metabolismo puede ser regulado mediante el papel que desempeña un sistema de reloj sincronizado (ritmos biológicos), el cual a su vez es modulado por varias proteínas reguladoras; esta relación garantiza que las células funcionen correctamente y por tanto el mantenerse saludables. El objetivo de esta revisión es aportar información actualizada sobre la regulación metabolismo-energía y su relación con la gran variedad de componentes involucrados en el gasto energético que acompañan al envejecimiento; analizar la regulación de este sistema para mejorar la calidad de vida y mantener la salud en la vejez.
Aging and metabolism: changes and regulation. Studies about the effects of aging in the physiology and metabolism are increasingly, one of its objectives is to help implement programs to improve the quality of life and prevent disability in elderly. It is relevant to mention that, during aging, there is a natural metabolic deceleration, a series of changes in the regulation of energy are produced, which contributes to loss of weight and fat; the changes in the regulation of caloric intake contribute to increase the susceptibility to energy imbalance both positive and negative, which is associated with a deterioration in health. However, to grow old, is not a death sentence for metabolism, on the other hand, it can be controlled by maintaining an active lifestyle, coupled with this, research has shown that the metabolism can be regulated by a synchronized clock (circadian rhythms), which is mediated by regulatory proteins, this relationship ensures the proper functioning of the cells and therefore good health. The aim of this review is to provide updated information on the energy- metabolism-regulation and its relationship with the great variety of components involved in energy expenditure that accompany aging, to analyze the regulation of this system to improve the quality of life and maintenance of health in old age.
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Aged , Aged, 80 and over , Humans , Aging/metabolism , Energy Intake/physiology , Energy Metabolism/physiology , Circadian Rhythm/physiology , Feeding Behavior/physiology , Nutritional StatusABSTRACT
Objective To investigate the influence of illumination changes on the drosophila circadian rhythm and 24 h sleep time.Methods We collect the unmated fruit flies (a total of 128,single-sex) under CO2 anesthesia within 8 hours of eclosion.And put them into the group of normal light group,day and night reversed group,24 h light group and 24 h dark group with the simple random sampling method,male and female with 4 single-sex groups(n=32).Change the illumination conditions of the living environment of the fruit flies and use Drosophila Activity Monitoring System (DAMS) and Data Acquisition System (DAS),to observe and compare the changes of drosophila circadian rhythm and 24 h sleep time between the different illumination conditions.Results Compared with the normal light group,drosophila circadian rhythm of the day and night reversed group was significantly reversed,the number of fruit flies' activities of 24 h light group was increased,and circadian rhythm was decline,drosophila circadian rhythm of the 24 h dark group is still there,but frequent activity appears during the day,and the 19 : 00 activity peak disappears.Conclusion The drosophila circadian rhythm and 24 h sleep time changes with illumination conditions change.
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Life on our planet is ruled by a temporary structure that governs our activities, our days and our calendars. In order to cope with a daily changing environment, organisms have developed adaptive strategies by exhibiting daily behavioral and physiological changes. Biological rhythms are properties conserved in all the levels of organization, from unicellular to prokaryotes to upper plants and mammals. A biological rhythm is defined as the recurrence of a biological phenomenon in regular intervals of time. Biological rhythms in behaviour and physiology are controled by an internal clock which synchronizes its oscillations to external time cues that have the capacity to adjust the clock's mechanism and keep it coupled to external fluctuations. The suprachiasmatic nucleus (SCN) of the hypothalamus in mammals is the master circadian clock which is mainly entrained by the light-dark cycle. The SCN transmits time signals to the brain and then to the whole body and by means of its time signals the SCN keeps a temporal order in diverse oscillations of the body and adjusted to the light-dark cycle. The correct temporal order enables an individual to adequate functioning in harmony with the external cycles. Biological rhythms have a hereditary character, thus its expression is genetically determined. All animals, plants, and probably all organism show some type of physiological rhythmic variation (metabolic rate, production of heat, flowering, etc.) that allow for the adaptation to a rhythmic environment. Biological rhythms enable individuals to anticipate and to be prepared to the demands of the prominent cyclic environmental changes, which are necessary for survival. Also, biological rhythms promote showing maximum levels of a physiological variable at the right moment when the environment requires a maximal response. In humans, an example of circadian rhythms is the sleep-wake cycle; simultaneously, a series of physiological changes are exhibited, also with circadian characteristics (close to 24 hours). Circadian oscillations are observed in the liberation of luteinizant hormone, in plasma cortisol, leptin, insulin, glucose and growth hormone just to mentions some examples. The SCN controls circadian rhythmicity via projections to the autonomic system and by controlling the hypothalamus-adenohipofisis-adrenal axis. In this way, the SCN transmits phase and period to the peripheral oscillators to maintain an internal synchrony. Modern life favors situations that oppose the time signals in the environment and promote conflicting signals to the SCN and its effectors. The consequence is that circadian oscillators uncouple from the master clock and from the external cycles leading to oscillations out of synchrony with the environment, which is known as internal desynchronization. The consequence is that physiological variables reach their peak expression at wrong moments according to environmental demands leading then to deficient responses and to disease in the long run. Also, levels of attention, learning and memory reach peak expression at wrong moments of the day leading individuals to exhibit a deficient performance at school or work. The disturbed sleep patterns promote fatigue and irritability, which difficult social interaction. Internal desynchronization results from transmeridional traveling for which people pass multiple hourly regions. This results in an abrupt change in the time schedule and a syndrome known as <
La vida se rige por una estructura temporal que gobierna nuestras horas, nuestros días y nuestros calendarios. Como parte de la adaptación a los ciclos de tiempo que impone el planeta, todo organismo presenta ritmos en su actividad y fisiología. Los ritmos biológicos son una propiedad conservada en todos los niveles de organización, desde organismos unicelulares procariontes hasta plantas superiores y mamíferos. De ellos, los más sólidos son aquellos asociados a los ciclos externos por la alternancia del día y la noche y por la alternancia de las estaciones del año. Los ritmos biológicos fisiológicos y conductuales son procesos dependientes de un reloj interno capaz de ajustar sus oscilaciones a claves de tiempo externas que lo mantienen sincronizado a estas fluctuaciones externas. El núcleo supraquiasmático del hipotálamo (NSQ) es en los mamíferos el principal reloj circadiano y se sincroniza principalmente por el ciclo luz-oscuridad. El NSQ transmite señales de tiempo al cerebro y de ahí al resto del organismo, y por medio de estas señales de tiempo mantiene un orden temporal en diversas funciones del cuerpo y las mantiene ajustadas al ciclo luz-oscuridad. El correcto orden temporal interno permite un adecuado funcionamiento del individuo en armonía con el medio externo y le permite exhibir respuestas adecuadas a un ambiente cambiante y predecible. El estilo de vida del hombre moderno propicia situaciones que llevan a alteraciones de nuestros ritmos biológicos que causan una desadaptación temporal, que a su vez redunda en daños a la salud, ya que afecta tanto la fisiología como la forma en que organizamos nuestra conducta. Un ejemplo de ello son los viajes a través de múltiples regiones horarias. Estos cambios de horario bruscos provocan un síndrome conocido como jet-lag, que consiste en un conflicto transitorio entre el tiempo <
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resumen está disponible en el texto completo
SUMMARY One of the most important functions in which the circadian system participates is to assess that the behavioural and physiological variables adjust appropriately to daily events in the environment, a process referred to as entrainment. Since in the nature the food disposition and predators' activity also are cyclical, the temporary relation between the circadian rhythm and periodic environmental signals maximizes the survival of each species in its temporary niche. Thus, through this mechanism, the organisms adapt to their environment through circadian system which entrain the organism activities to different external signals. In nature environments the predominance of photic entrainment like primary zeitgeber of the biological clock (suprachiasmatic nucleus) is a clear adaptation to the earthly life; nevertheless other biological advantages can be conferred to an individual if the circadian system also is sensible to other environmental signals that they provide from the external time. In such way, the light is not the only synchronizer affecting the biological clock. Other stimuli like the temperature and locomotor activity induced by novel stimuli and certain drugs are also able to entrain the biological clock. These signals have been described like non-photic stimuli. The general effects of the non-photic signals are able to generate phase response and entrain a free running rhythm, only during the subjective day, time in which the biological clock is sensible to these signals which are able to generate phase advances. These phase response are of great magnitude, even of greater magnitude than the induced ones by a light signal. The non-photic signals are also able to induce residual effects (after-effects) on entrainment process, thereby generating changes in the endogenous period, therefore affecting the phase angle in a cycle L:O and promoting the development of locomotor activity rhythm splitting. Furthermore, the light entrainment has been characterized in a wide variety of diurnal and nocturnal species. While, the non-photic entrainment only appears in nocturnal rodents. Being the hamster's biological clock one of that responds to the greater number of biological non-photic signals such as the acute exposition to sexual odors, social interactions, as well as by simple injection of saline solution, all of these non-photic signals are able to induce phase advances of the locomotor activity rhythm in free running when they are applied onto the subjective day. The entrainment to a non-photic stimulus is also observed in humans. Among the non-photic stimuli we can have the pharmacological treatments, social stimuli, stress, food restriction and communication between mother and product in the foetal and neonatal life. These later stimuli are of a particular importance to optimize the circadian function and sensitize the newborn to external environment. Thus the non-photic stimuli could be categorized like behavioural or pharmacological stimuli. These manipulations involve an increase in the locomotor activity, excitation or states able to phase resetting the circadian clock and peripheral oscillators in different species. The non-photic stimuli can affect to the biological clock through an afferent projection from the SCN that translate the non-photic information and is able to induce phase responses. Additionally, non-photic stimuli could also affect the biological clock through the action of a peripheral oscillator, which is sensitive to this type of signals. These peripheral oscillators translate the non-photic information and it communicates with the SCN, through synaptic and no-synaptic mechanisms. With regard to the physiological mechanisms involved on this process, there has been suggested to participate four neurotransmitter systems in the circadian system: a) the serotonergic system originating from the raphe nucleus, b) the NPY system from the leaflet intergeniculate (IGL), c) the GABAergic system, which it is present in most of the neurons of the SCN and IGL (the afferent projections of the raphe and the IGL nucleus make synapse with GABAergic neurons in the SCN) and 4) finally a neural system involving dopamine and melatonin signals, which have been importantly implicated in the brain in the foetal and neonatal live. In comparison to the cascade of intracellular signals caused by glutamatergic stimulation associated to photic entrainment, which excites to the SCN cells, the transmitters implicated in the nonphotic entrainment typically inhibit the SCN neurons. For example the melatonin's main action on the SCN neurons is inhibiting adenylyl cyclase and the translation of related signals driven by the AMPc, such inhibition of activity of the protein kinase depended of AMPc (PKA), which give rise to a decreased phospho- rylation of the transcription factor CREB. In this way, the phase responses induced by non-photic stimuli are not associate with the phosphorylation of the transcription factor (CREB) associated to responsive DNA-elements to binding AMPciclic or with the transcription of early expression genes in the SCN, events of metabothrophic signalling pathway of the photic entrainment. The phase responses generated by the non-photic signals occur during the subjective day, time in which the spontaneous expression of clock genes is high in diurnal and nocturnal animals. A reason why the phase resetting of biological clock to non-photic signals can be generated by a fast suppression in the expression levels of the genes clock. The decrease of Per1 and Per2 messenger RNA's expression levels in the SCN generated by non-photic stimuli occurs during a half of the subjective day, not during the subjective night, which suggests that these genes may participate in the phase resetting of biological clock during the subjective day. The interactions between phase response induced by the light and those induced by non-photic stimuli have been described previously. When a photic stimulus is applied after a non-photic signal during subjective day, with the purpose of studying the interaction between photic stimuli and non-photic stimuli, the photic stimulus blocks or attenuates the phase advances generated in response to different non-photic stimuli applied, such as the forced locomotor activity, sleep privation, NPY administration, or serotonergic agonists (8-OH-DPAT) administration. If the genes clock responds to the non-photic stimuli, then the lack of some of them will have to generate alterations in the response to non-photic signals. In the Clock mutant mice, the biological clock responses to the non-photic signals applied during the subjective day generate phase responses in opposed direction from those generated by intact subjects. This latter suggests that different genes clock participate in the generation of the phase response to a non-photic stimulus. The non-photic entrainment of the circadian system has a biological and/or social importance in several contexts. In the early products life, the communication of circadian information from the mother is important in regulating the biological clock of the foetus or newborn before they are sensitive to light. Under circumstances where the social and work routines are altered, by changes of constant "work turn" (shift work), the biological clock receives photic and non-photic signals which generate a dysfunction and poor work efficiency. The absence of non-photic signals followed by a social abstinence can induce alterations in the mental health (depression). The sleep disorder, experimented blind subject can arise from a lost of the social entrainment, therefore a decrease in the efficiency of the clock mechanism. Thus latter alterations of the clock, it could be possible to develop new forms of pharmacological and behavioural treatments.
ABSTRACT
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Abstract: Organisms adapt their temporary niche with two complementary mechanisms. The first mechanism is referred to as entrainment of the endogenous biological clock, which circumscribes temporarily the activity of the subject into day or night. The second mechanism is defined as masking, and this refers to an alternative route which does not involve the activity of the pacemaker. It involves, instead, a sharp response of the animal during light-time, inhibiting or enhancing the expression of locomotor activities in nocturnal or diurnal species, respectively. Masking describes the direct and immediate effects on the expression of any biological rhythm induced by the season-dependent signals present in the environment. Moreover, this masking mechanism appears to complement the biological clock entrainment, which is used by organismsto adapt to their specific nocturnal or diurnal niche. Several constraints arise when trying to study the biological clock entrainment or the light-associated oscillators system. Theseare due to the fact that the zeitgeber influences the biological clock and affects the output response of the circadian clock. According to the aforementioned description, it appears the masking effects occur as a natural event and result from an inevitable consequence to the season-dependent life of living organisms. Circadian rhythms do not only reflect the physiological output responses of the biological clocks as their activities also result from a mixture of responses arising either from the masking effects and/or from the entrainment mechanisms driving the timing of the biological clock within the animal. Although conspicuous differences do exist between maskingand entrained- rhythms, both rhythms follow a similar timecourse. Nevertheless, the transition between light and darkness (environmental change) under the masking rhythm results in abrupt changes in the animal behavior activity (i.e, from a resting to an ambulatory activity or viceversa). In contrast, when the environment acts as a zeitgeber under the biological clock entrainment, the behavioural transition of the animal appears to be less abrupt and, therefore, the environment factors affecting the biological rhythms never match. Based on different chronobiological studies in animals, several authors have described different forms of masking mechanisms used by the brain, and classified according to the light-induced decrease or increase locomotor activity responses: a) Positive Masking refers to the increase or decrease of locomotor activity response in a diurnal or nocturnal animal, respectively, as a result of the increase in lighting; b) Negative Masking refers to the decrease of locomotor activity responses as a result of decrease in lighting in a diurnal animal, or an increase in lighting in a nocturnal animal; c) Paradoxical Positive Masking refers either to the increase locomotor activity responses of a nocturnal animal exposed to increase lighting or an increase in locomotor activity responses in a diurnal animal after lighting decreases; d) Paradoxical Negative Masking refers to the decrease of locomotor activity responses in a nocturnal animal when lighting is decreased, or to the decrease of locomotor activity responses in a diurnal animal when lighting is increased. In addition to the aforementioned classification of different masking mechanisms on the behavioral locomotor activity responses in both diurnal and nocturnal animals, other authors classify different forms of masking, based on the neural mechanisms that generate the masking effects. Authors defined the occurence of different forms of masking effects when enviromental factors (i.e, light, darkness) produce direct or indirect effects on the cyrcadian rhythm in an animal. Thus, a) Type I masking occurs when the environment produces a direct effect on the circadian rhythm output; b) Type II masking occurs when behavioral changes in the animal affect other physiological brainrhythms, for instance, an increase or decrease of behavioral locomotor activity may affect the temperature rhythm of an organism, enhancing the expression of an altered activity on the biological clock; c) Type III masking occurs when physiological or biochemical changes alter the neural output of the biological clock that conveys the time-related information of the biological rhythm; for instance, physiological or pathological conditions have been shown to affect the functional activity of specific neural pathways and their membrane receptors involved in the regulation of the body temperature. Such situations appear to modify the phase of the body temperature rhythm with the phase of the biological clock, which both rhythms appear to match under basal conditions. The sensibility limits necessary to generate the inhibition of the synthesis and release of melatonine, in rats and hamster, suggest the involvement of the rods, the predominant photoreceptor in the rodent retina. Nevertheless, studies the mutant mice rd/rd (the mutation rd generates the total loss of photoreceptors type rods and a considerable loss of photoreceptors type cones) presented an inhibition in the synthesis and release of the melatonine and locomotor activity induced by the light. This suggests that the photoreceptors type cones and rods are not necessary to mediate the effects of the light on the locomotor activity and that the light masking depends on another type of contained photoreceptor in the retina. Some studies report the loss of the rhythmycity in drinking, locomotion or sleep-wakefulness, not only when the animals are kept in light constant, also when the animals are kept under lightdarkness cycles (L:D). Other studies that involve to mutant mice of the two genescryptocromos, which they are arrhythmic in constant conditions; they show a SCN functional diminished, light pulses applied in the subjective night do not generate alterations in the inhibition of the locomotor activity induced by the light. This suggests the loss of the masking responses induced by light. Certainly, these results point to a loss or attenuation of the masking by the SCN lesion. On the other hand, other works showing a persistence of the masking pd drinking and locomotor activity in L:D conditions after the SCN lesions. The lesions of other structures of the rodent visual system alter the light masking. It is more a significant increase of the masking in subjects with IGL lesion is observed. Subsequently, it was reported that the masking induced by the light was more significant in mice that were submitted to an NGLd lesions, which suggests that the increase in the masking to the light observed after the IGL lesions are probably due to an incidental damage of the NGLd. It also has been reported that the light masking increase after the visual cortex lesions in hamster and mice. The mutant mice clock shows brilliant light pulses: between 100 to 1600 lux they induce a complete suppression of the locomotor activity (negative masking). On the other hand, dim light pulses induce an increment of the basal levels of the locomotor activity (positive masking) in a similar way to that of the normal subjects. The participation of other genes clock in the regulation of the light-masking has not been specific. The masking is not a limited phenomenon to conditions of laboratory. There are few examples of the direct effects of light on the temporary organization of the behavior in wildlife. An impressive case is the owl primate (Aotus lemurinus griseimembra), which shows a pattern of locomotor activity that depends on the lunar cycle. This primate is nocturnal, but its activity increases (positive masking) when the luminescence is found between 0.1 and 0.5 lux, the luminescence generated precisely by the brightness of the moon. Intensities of light lower to this diminish the locomotor activity (negative masking) of the subject. The masking mechanism is an important process in the adaptation of an organism to its environment as it confers this the capacity to respond quickly to a sudden change in environmental conditions. Since the functional point of view the masking contributes to an increment in the amplitude of a entrainment rhythm, promotes direct responses to geophysical variables that the organism selects that they optimize its evolution and its adaptation to its temporary niche, all this contributes to an increase in the probability of survival of the subject to its environment.
ABSTRACT
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Abstract The periodic fluctuations in diverse physiological parameters are a general property of all organisms. Furthermore, when these fluctuations occur to intervals regulates these are considered as «biological rhythms¼. The biological rhythms are generated by an endogenous mechanism of the organism. The biological rhythms appear in wide interval in frequencies of oscillation, which go from a cycle by millisecond to a cycle per year. Additionally, the geophysical environment is characterized by the existence of cycles deriving from movements of the earth and the moon with regard to sun. These environmental or geophysical cycles are the days, tides, lunar phases and seasons of the year. When the frequency of a biological rhythm approaches that of an environmental cycle, the prefix "circa" is used to refer to it. Likewise, 24-hour biological rhythms are designated as circadian rhythms. The circadian rhythms represent one of the most ubiquitous adaptive characteristics of the organism. In mammals, they represent an important process through which events of the internal milieu are organized in an appropriate temporary sequence, thus enhancing a maximum adaptation to external milieu. This characteristic allows organisms to predict and to be prepared for changes in the geophysical environment associated with the day and the night. To carry out this adaptive role, the circadian rhythms require the biological system having the capacity to measure the biological time. Thus, the circadian rhythm should be generated endogenously, adjusting the geographical time. Moreover, under usual environmental conditions, the period of the oscillator is adjusted to the period of the environmental cycle. The endogenous origin of the biological rhythms is based on the fact that, in temporary environmental signs isolation conditions, the biological rhythm persists with a light but significant variation in the value of the period of oscillation. The afore mentioned considerations suggest that the rhythm observed does not depend on cyclic geophysical phenomena. Thus, the rhythm maintained under constant conditions reflects an internal organism's process. This essential ability of the organism to maintain circadian rhythms, even in the absence of periodic environmental cues, is known as rhythm in spontaneous oscillation or free-running. Nevertheless, the organism is never isolated from temporary signals and it keeps a narrow temporary relation with the environmental cues by which the phase and the period of the overt rhythm can be adjusted to the phase and period of the environmental cyclic changes. This process is called «entrainment¼. It is considered that the three fundamental properties of circadian rhythms are the persisting free-running rhythm, the temperature compensation and the entrainment. Literally, the word entrainment means «to get aboard a train¼ (from the French word entramen «to carry along¼). In this context, the entrainment of a biological clock is generated through a controllers stimuli train with a specific period, which induces a biological clock with a different endogenous period from 24 hours to be adjusted for the period of the periodic environmental cycle. The entrainment of the biological clock provides to internal milieu of a reckoned of the external time. This process can occur for a modulation of the period and/or of the phase of the biological rhythm, that is, the endogenous period of the biological rhythm is adjusted to the period of the zeitgeber with a relation phase stable (or phase angle) between the zeitgeber and the oscillation entrained. Studies where subjects were submitted to a rigorous temporary isolation indicated that only certain environmental variables are capable of acting as temporary signals for the circadian system. In 1951, Aschoff coined the word «Zeitgeber¼ from the German «given of time¼, which describes an environmental cycle capable of affecting the period and the phase of a biological clock. In nature, multiple environmental cues oscillate under a daily cycle, including light, darkness, temperature, humidity, availability of food and social signals. Some of these factors may act as zeitgebers of the biological clock, but the most consistent and predictable environmental signal is the 24-hour cycle of light-darkness (L:O) (photic entrainment). Nevertheless, organisms can be entrained for other stimuli (non-photic entrainment) such as temperature, electromagnetic fields, environmental pressure, sound, availability of food and social signals. Researchers have developed two theoretical models to explain the mechanism(s) by which the circadian clock is entrained to an environmental cycle: the discreet model (non-parametric or phasic) and the continuous model (parametric or tonic). The model of continuous entrainment is based on the observation that the period in free running (POE) to depend of the intensity light and suggests that the light has a continuous action on the biological clock to entrain it to a cycle light-darkness (L:O). The mechanism suggested for this is the acceleration and deceleration of the POE (angular velocity), due to daily changes in the intensity of the light, these permit to circadian pacemaker is continuously adjusted along the environmental cycle. The discreet model has been the most utilized model to explain the entrainment to environmental cycles. The basic premise of this model is that the circadian pacemaker entrained this in equilibrium with the cycle light: darkness (L:D), which consists of brief pulses of light (zeitgeber). When a brief pulse of light falls in a specific phase of the biological clock, this produces an phase response equal to the difference between the POE and the period of the cycle entrained. The day-night cycles generated by the rotation of the earth around its axis influence the life of the organism to a large extension. Many organisms coordinate their activities to these cycles. Some of them are diurnal, while other ones nocturnal. Moreover other animals escape from the daily periodic environment and they organize their life in constant environments as in the depth of the ocean or in natural caverns. It is not clear how and because biological clocks with a period of approximately 24 hours evolved in cyclic environments of exactly 24 hours. A possible explanation is that the cycles L:D provide an optimum stability for their expression. There has been as were that the cycle L:D is the first environmental signal behind the emergency and maintenance of the circadian clocks. A large number of cell functions are affected by the light, and is being speculated that the original organisms could have restricted some of their outstanding metabolic processes at night, thus avoiding the adverse effects of the light. In fact, some organisms adjust several of their sensitive cell processes to the light. For example, there is an augmented replication of the DNA, at night to avoid the exposition to deleterious ultraviolet radiation. Thus it is possible to propose a hypothesis of how the circadian clocks could evolve at phylogenetically level: the ancient organisms generated a temporary program, where sensitive processes to the light were temporarily restricted to avoid the damage induced by the sunlight; these temporary programs turned out to be advantageous and thus they were selected through evolution of species.
ABSTRACT
Cyclic strabismus is a rare entity, which is characterized by alternating periods of strabismus and orthophoria.The mechanism is not clear but seems to be related to the biological clock. Cyclic esotropia is the most common type. On "strabismic"days,a large-angle esotropia will appear, and the binocular vision is impaired. On "straight"days, orthophoria or microstrabismus will appear and no abnor-mal binocular vision is observed. As a treatment, surgery based on the full amount of heterotropia on the strabismic day,has been successful, but treatment by chemodenervation ith botulinum toxin has not been reported yet. Authors experienced the cyclic esotropia following head trauma by a traffic accident in a 3-year-old boy and tried the injection of botulinum toxin on both medial rectus muscles as a treatment. In one-year follow-up observation, the cyclic pattern and esodeviation has disappeared.