Science.gov

Sample records for neurons conveying circadian

  1. Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons

    PubMed Central

    Webb, Alexis B.; Angelo, Nikhil; Huettner, James E.; Herzog, Erik D.

    2009-01-01

    Circadian rhythms are modeled as reliable and self-sustained oscillations generated by single cells. The mammalian suprachiasmatic nucleus (SCN) keeps near 24-h time in vivo and in vitro, but the identity of the individual cellular pacemakers is unknown. We tested the hypothesis that circadian cycling is intrinsic to a unique class of SCN neurons by measuring firing rate or Period2 gene expression in single neurons. We found that fully isolated SCN neurons can sustain circadian cycling for at least 1 week. Plating SCN neurons at <100 cells/mm2 eliminated synaptic inputs and revealed circadian neurons that contained arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP) or neither. Surprisingly, arrhythmic neurons (nearly 80% of recorded neurons) also expressed these neuropeptides. Furthermore, neurons were observed to lose or gain circadian rhythmicity in these dispersed cell cultures, both spontaneously and in response to forskolin stimulation. In SCN explants treated with tetrodotoxin to block spike-dependent signaling, neurons gained or lost circadian cycling over many days. The rate of PERIOD2 protein accumulation on the previous cycle reliably predicted the spontaneous onset of arrhythmicity. We conclude that individual SCN neurons can generate circadian oscillations; however, there is no evidence for a specialized or anatomically localized class of cell-autonomous pacemakers. Instead, these results indicate that AVP, VIP, and other SCN neurons are intrinsic but unstable circadian oscillators that rely on network interactions to stabilize their otherwise noisy cycling. PMID:19805326

  2. Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons.

    PubMed

    Webb, Alexis B; Angelo, Nikhil; Huettner, James E; Herzog, Erik D

    2009-09-22

    Circadian rhythms are modeled as reliable and self-sustained oscillations generated by single cells. The mammalian suprachiasmatic nucleus (SCN) keeps near 24-h time in vivo and in vitro, but the identity of the individual cellular pacemakers is unknown. We tested the hypothesis that circadian cycling is intrinsic to a unique class of SCN neurons by measuring firing rate or Period2 gene expression in single neurons. We found that fully isolated SCN neurons can sustain circadian cycling for at least 1 week. Plating SCN neurons at <100 cells/mm(2) eliminated synaptic inputs and revealed circadian neurons that contained arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP) or neither. Surprisingly, arrhythmic neurons (nearly 80% of recorded neurons) also expressed these neuropeptides. Furthermore, neurons were observed to lose or gain circadian rhythmicity in these dispersed cell cultures, both spontaneously and in response to forskolin stimulation. In SCN explants treated with tetrodotoxin to block spike-dependent signaling, neurons gained or lost circadian cycling over many days. The rate of PERIOD2 protein accumulation on the previous cycle reliably predicted the spontaneous onset of arrhythmicity. We conclude that individual SCN neurons can generate circadian oscillations; however, there is no evidence for a specialized or anatomically localized class of cell-autonomous pacemakers. Instead, these results indicate that AVP, VIP, and other SCN neurons are intrinsic but unstable circadian oscillators that rely on network interactions to stabilize their otherwise noisy cycling. PMID:19805326

  3. CGRP neurons mediate sleep-specific circadian output in Drosophila

    PubMed Central

    Kunst, Michael; Hughes, Michael E.; Raccuglia, Davide; Felix, Mario; Li, Michael; Barnett, Gregory; Duah, Janelle; Nitabach, Michael N.

    2014-01-01

    Summary Background Imbalances in amount and timing of sleep are harmful to physical and mental health. Therefore, the study of the underlying mechanisms is of great biological importance. Proper timing and amount of sleep is regulated by both the circadian clock and homeostatic sleep drive. However, very little is known about the cellular and molecular mechanisms by which the circadian clock regulates sleep. In this study we describe a novel role for DIURETIC HORMONE 31 (DH31), the fly homologue of the vertebrate neuropeptide CALCITONIN GENE RELATED PEPTIDE (CGRP), as a circadian wake-promoting signal that awakens the fly in anticipation of dawn. Results Analysis of loss-of-function and gain-of-function Drosophila mutants demonstrates that DH31 suppresses sleep late at night. DH31 is expressed by a subset of dorsal circadian clock neurons that also express the receptor for the circadian neuropeptide PIGMENT DISPERSING FACTOR (PDF). PDF secreted by the ventral pacemaker subset of circadian clock neurons acts on PDF receptors in the DH31-expressing dorsal clock neurons to increase DH31 secretion before dawn. Activation of PDFR in DH31 positive DN1 specifically affects sleep and has no effect on circadian rhythms, thus constituting a dedicated locus for circadian regulation of sleep. Conclusions We identified a novel signaling molecule (DH31) as part of a neuropeptide relay mechanism for circadian control of sleep. Our results indicate that outputs of the clock controlling sleep and locomotor rhythms are mediated via distinct neuronal/cellular channels. PMID:25455031

  4. Circadian gating of neuronal functionality: a basis for iterative metaplasticity.

    PubMed

    Iyer, Rajashekar; Wang, Tongfei A; Gillette, Martha U

    2014-01-01

    Brain plasticity, the ability of the nervous system to encode experience, is a modulatory process leading to long-lasting structural and functional changes. Salient experiences induce plastic changes in neurons of the hippocampus, the basis of memory formation and recall. In the suprachiasmatic nucleus (SCN), the central circadian (~24-h) clock, experience with light at night induces changes in neuronal state, leading to circadian plasticity. The SCN's endogenous ~24-h time-generator comprises a dynamic series of functional states, which gate plastic responses. This restricts light-induced alteration in SCN state-dynamics and outputs to the nighttime. Endogenously generated circadian oscillators coordinate the cyclic states of excitability and intracellular signaling molecules that prime SCN receptivity to plasticity signals, generating nightly windows of susceptibility. We propose that this constitutes a paradigm of ~24-h iterative metaplasticity, the repeated, patterned occurrence of susceptibility to induction of neuronal plasticity. We detail effectors permissive for the cyclic susceptibility to plasticity. We consider similarities of intracellular and membrane mechanisms underlying plasticity in SCN circadian plasticity and in hippocampal long-term potentiation (LTP). The emerging prominence of the hippocampal circadian clock points to iterative metaplasticity in that tissue as well. Exploring these links holds great promise for understanding circadian shaping of synaptic plasticity, learning, and memory. PMID:25285070

  5. Heterogeneity induces rhythms of weakly coupled circadian neurons.

    PubMed

    Gu, Changgui; Liang, Xiaoming; Yang, Huijie; Rohling, Jos H T

    2016-01-01

    The main clock located in the suprachiasmatic nucleus (SCN) regulates circadian rhythms in mammals. The SCN is composed of approximately twenty thousand heterogeneous self-oscillating neurons, that have intrinsic periods varying from 22 h to 28 h. They are coupled through neurotransmitters and neuropeptides to form a network and output a uniform periodic rhythm. Previous studies found that the heterogeneity of the neurons leads to attenuation of the circadian rhythm with strong cellular coupling. In the present study, we investigate the heterogeneity of the neurons and of the network in the condition of constant darkness. Interestingly, we found that the heterogeneity of weakly coupled neurons enables them to oscillate and strengthen the circadian rhythm. In addition, we found that the period of the SCN network increases with the increase of the degree of heterogeneity. As the network heterogeneity does not change the dynamics of the rhythm, our study shows that the heterogeneity of the neurons is vitally important for rhythm generation in weakly coupled systems, such as the SCN, and it provides a new method to strengthen the circadian rhythm, as well as an alternative explanation for differences in free running periods between species in the absence of the daily cycle. PMID:26898574

  6. Heterogeneity induces rhythms of weakly coupled circadian neurons

    PubMed Central

    Gu, Changgui; Liang, Xiaoming; Yang, Huijie; Rohling, Jos H. T.

    2016-01-01

    The main clock located in the suprachiasmatic nucleus (SCN) regulates circadian rhythms in mammals. The SCN is composed of approximately twenty thousand heterogeneous self-oscillating neurons, that have intrinsic periods varying from 22 h to 28 h. They are coupled through neurotransmitters and neuropeptides to form a network and output a uniform periodic rhythm. Previous studies found that the heterogeneity of the neurons leads to attenuation of the circadian rhythm with strong cellular coupling. In the present study, we investigate the heterogeneity of the neurons and of the network in the condition of constant darkness. Interestingly, we found that the heterogeneity of weakly coupled neurons enables them to oscillate and strengthen the circadian rhythm. In addition, we found that the period of the SCN network increases with the increase of the degree of heterogeneity. As the network heterogeneity does not change the dynamics of the rhythm, our study shows that the heterogeneity of the neurons is vitally important for rhythm generation in weakly coupled systems, such as the SCN, and it provides a new method to strengthen the circadian rhythm, as well as an alternative explanation for differences in free running periods between species in the absence of the daily cycle. PMID:26898574

  7. Noise Induces Oscillation and Synchronization of the Circadian Neurons.

    PubMed

    Gu, Changgui; Xu, Jinshan; Rohling, Jos; Yang, Huijie; Liu, Zonghua

    2015-01-01

    The principle clock of mammals, named suprachiasmatic nucleus (SCN), coordinates the circadian rhythms of behavioral and physiological activity to the external 24 h light-dark cycle. In the absence of the daily cycle, the SCN acts as an endogenous clock that regulates the ~24 h rhythm of activity. Experimental and theoretical studies usually take the light-dark cycle as a main external influence, and often ignore light pollution as an external influence. However, in modern society, the light pollution such as induced by electrical lighting influences the circadian clock. In the present study, we examined the effect of external noise (light pollution) on the collective behavior of coupled circadian oscillators under constant darkness using a Goodwin model. We found that the external noise plays distinct roles in the network behavior of neurons for weak or strong coupling between the neurons. In the case of strong coupling, the noise reduces the synchronization and the period of the SCN network. Interestingly, in the case of weak coupling, the noise induces a circadian rhythm in the SCN network which is absent in noise-free condition. In addition, the noise increases the synchronization and decreases the period of the SCN network. Our findings may shed new light on the impact of the external noise on the collective behavior of SCN neurons. PMID:26691765

  8. Circadian neuron feedback controls the Drosophila sleep--activity profile.

    PubMed

    Guo, Fang; Yu, Junwei; Jung, Hyung Jae; Abruzzi, Katharine C; Luo, Weifei; Griffith, Leslie C; Rosbash, Michael

    2016-08-18

    Little is known about the ability of Drosophila circadian neurons to promote sleep. Here we show, using optogenetic manipulation and video recording, that a subset of dorsal clock neurons (DN1s) are potent sleep-promoting cells that release glutamate to directly inhibit key pacemaker neurons. The pacemakers promote morning arousal by activating these DN1s, implying that a late-day feedback circuit drives midday siesta and night-time sleep. To investigate more plastic aspects of the sleep program, we used a calcium assay to monitor and compare the real-time activity of DN1 neurons in freely behaving males and females. Our results revealed that DN1 neurons were more active in males than in females, consistent with the finding that male flies sleep more during the day. DN1 activity is also enhanced by elevated temperature, consistent with the ability of higher temperatures to increase sleep. These new approaches indicate that DN1s have a major effect on the fly sleep-wake profile and integrate environmental information with the circadian molecular program. PMID:27479324

  9. Influences of the circadian clock on neuronal susceptibility to excitotoxicity

    PubMed Central

    Karmarkar, Sumedha W.; Tischkau, Shelley A.

    2013-01-01

    Stroke is the third leading cause of death and the primary cause of morbidity in the United States, thus posing an enormous burden on the healthcare system. The factors that determine the risk of an individual toward precipitation of an ischemic event possess a strong circadian component as does the ischemic event itself. This predictability provided a window of opportunity toward the development of chronopharmaceuticals which provided much better clinical outcomes. Experiments from our lab showed for the first time that neuronal susceptibility to ischemic events follows a circadian pattern; hippocampal neurons being most susceptible to an ischemic insult occurring during peak activity in a rodent model of global cerebral ischemia. We also demonstrated that the SCN2.2 cells (like their in vivo counterpart) are resistant to excitotoxicity by glutamate and that this was dependent on activation of ERK signaling. We are currently working on elucidating the complete neuroprotective pathway that provides a barricade against glutamate toxicity in the SCN2.2 cells. Our future experiments will be engaged in hijacking the neuroprotective mechanism in the SCN2.2 cells and applying it to glutamate-susceptible entities in an effort to prevent their death in the presence of excitotoxicity. Despite the advancement in chronopharmaceuticals, optimal clinical outcome with minimal adverse events are difficult to come by at an affordable price. Superior treatment options require a better understanding of molecular mechanisms that define the disease, including the role of the circadian clock. PMID:24204346

  10. Circadian Factor BMAL1 in Histaminergic Neurons Regulates Sleep Architecture

    PubMed Central

    Yu, Xiao; Zecharia, Anna; Zhang, Zhe; Yang, Qianzi; Yustos, Raquel; Jager, Polona; Vyssotski, Alexei L.; Maywood, Elizabeth S.; Chesham, Johanna E.; Ma, Ying; Brickley, Stephen G.; Hastings, Michael H.; Franks, Nicholas P.; Wisden, William

    2014-01-01

    Summary Circadian clocks allow anticipation of daily environmental changes [1]. The suprachiasmatic nucleus (SCN) houses the master clock, but clocks are also widely expressed elsewhere in the body [1]. Although some peripheral clocks have established roles [1], it is unclear what local brain clocks do [2, 3]. We tested the contribution of one putative local clock in mouse histaminergic neurons in the tuberomamillary nucleus to the regulation of the sleep-wake cycle. Histaminergic neurons are silent during sleep, and start firing after wake onset [4–6]; the released histamine, made by the enzyme histidine decarboxylase (HDC), enhances wakefulness [7–11]. We found that hdc gene expression varies with time of day. Selectively deleting the Bmal1 (also known as Arntl or Mop3 [12]) clock gene from histaminergic cells removes this variation, producing higher HDC expression and brain histamine levels during the day. The consequences include more fragmented sleep, prolonged wake at night, shallower sleep depth (lower nonrapid eye movement [NREM] δ power), increased NREM-to-REM transitions, hindered recovery sleep after sleep deprivation, and impaired memory. Removing BMAL1 from histaminergic neurons does not, however, affect circadian rhythms. We propose that for mammals with polyphasic/nonwake consolidating sleep, the local BMAL1-dependent clock directs appropriately timed declines and increases in histamine biosynthesis to produce an appropriate balance of wake and sleep within the overall daily cycle of rest and activity specified by the SCN. PMID:25454592

  11. Circadian factor BMAL1 in histaminergic neurons regulates sleep architecture.

    PubMed

    Yu, Xiao; Zecharia, Anna; Zhang, Zhe; Yang, Qianzi; Yustos, Raquel; Jager, Polona; Vyssotski, Alexei L; Maywood, Elizabeth S; Chesham, Johanna E; Ma, Ying; Brickley, Stephen G; Hastings, Michael H; Franks, Nicholas P; Wisden, William

    2014-12-01

    Circadian clocks allow anticipation of daily environmental changes. The suprachiasmatic nucleus (SCN) houses the master clock, but clocks are also widely expressed elsewhere in the body. Although some peripheral clocks have established roles, it is unclear what local brain clocks do. We tested the contribution of one putative local clock in mouse histaminergic neurons in the tuberomamillary nucleus to the regulation of the sleep-wake cycle. Histaminergic neurons are silent during sleep, and start firing after wake onset; the released histamine, made by the enzyme histidine decarboxylase (HDC), enhances wakefulness. We found that hdc gene expression varies with time of day. Selectively deleting the Bmal1 (also known as Arntl or Mop3) clock gene from histaminergic cells removes this variation, producing higher HDC expression and brain histamine levels during the day. The consequences include more fragmented sleep, prolonged wake at night, shallower sleep depth (lower nonrapid eye movement [NREM] δ power), increased NREM-to-REM transitions, hindered recovery sleep after sleep deprivation, and impaired memory. Removing BMAL1 from histaminergic neurons does not, however, affect circadian rhythms. We propose that for mammals with polyphasic/nonwake consolidating sleep, the local BMAL1-dependent clock directs appropriately timed declines and increases in histamine biosynthesis to produce an appropriate balance of wake and sleep within the overall daily cycle of rest and activity specified by the SCN. PMID:25454592

  12. Reliability of neuronal information conveyed by unreliable neuristor-based leaky integrate-and-fire neurons: a model study

    PubMed Central

    Lim, Hyungkwang; Kornijcuk, Vladimir; Seok, Jun Yeong; Kim, Seong Keun; Kim, Inho; Hwang, Cheol Seong; Jeong, Doo Seok

    2015-01-01

    We conducted simulations on the neuronal behavior of neuristor-based leaky integrate-and-fire (NLIF) neurons. The phase-plane analysis on the NLIF neuron highlights its spiking dynamics – determined by two nullclines conditional on the variables on the plane. Particular emphasis was placed on the operational noise arising from the variability of the threshold switching behavior in the neuron on each switching event. As a consequence, we found that the NLIF neuron exhibits a Poisson-like noise in spiking, delimiting the reliability of the information conveyed by individual NLIF neurons. To highlight neuronal information coding at a higher level, a population of noisy NLIF neurons was analyzed in regard to probability of successful information decoding given the Poisson-like noise of each neuron. The result demonstrates highly probable success in decoding in spite of large variability – due to the variability of the threshold switching behavior – of individual neurons. PMID:25966658

  13. Central Control of Circadian Phase in Arousal-Promoting Neurons

    PubMed Central

    Mahoney, Carrie E.; McKinley Brewer, Judy; Bittman, Eric L.

    2013-01-01

    Cells of the dorsomedial/lateral hypothalamus (DMH/LH) that produce hypocretin (HCRT) promote arousal in part by activation of cells of the locus coeruleus (LC) which express tyrosine hydroxylase (TH). The suprachiasmatic nucleus (SCN) drives endogenous daily rhythms, including those of sleep and wakefulness. These circadian oscillations are generated by a transcriptional-translational feedback loop in which the Period (Per) genes constitute critical components. This cell-autonomous molecular clock operates not only within the SCN but also in neurons of other brain regions. However, the phenotype of such neurons and the nature of the phase controlling signal from the pacemaker are largely unknown. We used dual fluorescent in situ hybridization to assess clock function in vasopressin, HCRT and TH cells of the SCN, DMH/LH and LC, respectively, of male Syrian hamsters. In the first experiment, we found that Per1 expression in HCRT and TH oscillated in animals held in constant darkness with a peak phase that lagged that in AVP cells of the SCN by several hours. In the second experiment, hamsters induced to split their locomotor rhythms by exposure to constant light had asymmetric Per1 expression within cells of the middle SCN at 6 h before activity onset (AO) and in HCRT cells 9 h before and at AO. We did not observe evidence of lateralization of Per1 expression in the LC. We conclude that the SCN communicates circadian phase to HCRT cells via lateralized neural projections, and suggests that Per1 expression in the LC may be regulated by signals of a global or bilateral nature. PMID:23826226

  14. Circadian and dark-pulse activation of orexin/hypocretin neurons

    PubMed Central

    Marston, Oliver J; Williams, Rhîannan H; Canal, Maria M; Samuels, Rayna E; Upton, Neil; Piggins, Hugh D

    2008-01-01

    Temporal control of brain and behavioral states emerges as a consequence of the interaction between circadian and homeostatic neural circuits. This interaction permits the daily rhythm of sleep and wake, regulated in parallel by circadian cues originating from the suprachiasmatic nuclei (SCN) and arousal-promoting signals arising from the orexin-containing neurons in the tuberal hypothalamus (TH). Intriguingly, the SCN circadian clock can be reset by arousal-promoting stimuli while activation of orexin/hypocretin neurons is believed to be under circadian control, suggesting the existence of a reciprocal relationship. Unfortunately, since orexin neurons are themselves activated by locomotor promoting cues, it is unclear how these two systems interact to regulate behavioral rhythms. Here mice were placed in conditions of constant light, which suppressed locomotor activity, but also revealed a highly pronounced circadian pattern in orexin neuronal activation. Significantly, activation of orexin neurons in the medial and lateral TH occurred prior to the onset of sustained wheel-running activity. Moreover, exposure to a 6 h dark pulse during the subjective day, a stimulus that promotes arousal and phase advances behavioral rhythms, activated neurons in the medial and lateral TH including those containing orexin. Concurrently, this stimulus suppressed SCN activity while activating cells in the median raphe. In contrast, dark pulse exposure during the subjective night did not reset SCN-controlled behavioral rhythms and caused a transient suppression of neuronal activation in the TH. Collectively these results demonstrate, for the first time, pronounced circadian control of orexin neuron activation and implicate recruitment of orexin cells in dark pulse resetting of the SCN circadian clock. PMID:19055781

  15. Heterogeneous Expression of the Core Circadian Clock Proteins among Neuronal Cell Types in Mouse Retina

    PubMed Central

    Liu, Xiaoqin; Zhang, Zhijing; Ribelayga, Christophe P.

    2012-01-01

    Circadian rhythms in metabolism, physiology, and behavior originate from cell-autonomous circadian clocks located in many organs and structures throughout the body and that share a common molecular mechanism based on the clock genes and their protein products. In the mammalian neural retina, despite evidence supporting the presence of several circadian clocks regulating many facets of retinal physiology and function, the exact cellular location and genetic signature of the retinal clock cells remain largely unknown. Here we examined the expression of the core circadian clock proteins CLOCK, BMAL1, NPAS2, PERIOD 1(PER1), PERIOD 2 (PER2), and CRYPTOCHROME2 (CRY2) in identified neurons of the mouse retina during daily and circadian cycles. We found concurrent clock protein expression in most retinal neurons, including cone photoreceptors, dopaminergic amacrine cells, and melanopsin-expressing intrinsically photosensitive ganglion cells. Remarkably, diurnal and circadian rhythms of expression of all clock proteins were observed in the cones whereas only CRY2 expression was found to be rhythmic in the dopaminergic amacrine cells. Only a low level of expression of the clock proteins was detected in the rods at any time of the daily or circadian cycle. Our observations provide evidence that cones and not rods are cell-autonomous circadian clocks and reveal an important disparity in the expression of the core clock components among neuronal cell types. We propose that the overall temporal architecture of the mammalian retina does not result from the synchronous activity of pervasive identical clocks but rather reflects the cellular and regional heterogeneity in clock function within retinal tissue. PMID:23189207

  16. Drosophila TRPA1 functions in temperature control of circadian rhythm in pacemaker neurons.

    PubMed

    Lee, Youngseok; Montell, Craig

    2013-04-17

    Most animals from flies to humans count on circadian clocks to synchronize their physiology and behaviors. Daily light cycles are well known environmental cues for setting circadian rhythms. Warmer and cooler temperatures that mimic day and night are also effective in entraining circadian activity in most animals. Even vertebrate organisms can be induced to show circadian responses through exposure to temperature cycles. In poikilothermic animals such as Drosophila, temperature differences of only 2-3°C are sufficient to synchronize locomotor rhythms. However, the molecular sensors that participate in temperature regulation of circadian activity in fruit flies or other animals are enigmatic. It is also unclear whether such detectors are limited to the periphery or may be in the central brain. Here, we showed that Drosophila TRPA1 (transient receptor potential cation channel A1) was necessary for normal activity patterns during temperature cycles. The trpA1 gene was expressed in a subset of pacemaker neurons in the central brain. In response to temperature entrainment, loss of trpA1 impaired activity, and altered expression of the circadian clock protein period (Per) in a subset of pacemaker neurons. These findings underscore a role for a thermoTRP in temperature regulation that extends beyond avoidance of noxious or suboptimal temperatures. PMID:23595730

  17. Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms.

    PubMed

    Lee, Ivan T; Chang, Alexander S; Manandhar, Manabu; Shan, Yongli; Fan, Junmei; Izumo, Mariko; Ikeda, Yuichi; Motoike, Toshiyuki; Dixon, Shelley; Seinfeld, Jeffrey E; Takahashi, Joseph S; Yanagisawa, Masashi

    2015-03-01

    Circadian behavior in mammals is orchestrated by neurons within the suprachiasmatic nucleus (SCN), yet the neuronal population necessary for the generation of timekeeping remains unknown. We show that a subset of SCN neurons expressing the neuropeptide neuromedin S (NMS) plays an essential role in the generation of daily rhythms in behavior. We demonstrate that lengthening period within Nms neurons is sufficient to lengthen period of the SCN and behavioral circadian rhythms. Conversely, mice without a functional molecular clock within Nms neurons lack synchronous molecular oscillations and coherent behavioral daily rhythms. Interestingly, we found that mice lacking Nms and its closely related paralog, Nmu, do not lose in vivo circadian rhythms. However, blocking vesicular transmission from Nms neurons with intact cell-autonomous clocks disrupts the timing mechanisms of the SCN, revealing that Nms neurons define a subpopulation of pacemakers that control SCN network synchrony and in vivo circadian rhythms through intercellular synaptic transmission. PMID:25741729

  18. Circadian variation in sensitivity of suprachiasmatic and lateral geniculate neurones to 5-hydroxytryptamine in the rat.

    PubMed Central

    Mason, R

    1986-01-01

    Extracellular single-unit recordings were obtained from neurones in the suprachiasmatic nuclei (s.c.n.) of the rat (a putative circadian pace-maker), the ventral lateral geniculate nucleus (v.l.g.n.) and the hippocampus. These areas receive a 5-hydroxytryptamine (5-HT) innervation from the raphe nuclei. Recording of neuronal activity in the s.c.n., v.l.g.n. and the hippocampus revealed a diurnal variation in the response to the ionophoresis of 5-HT. This variation was manifest as a 2-3-fold increase in post-synaptic sensitivity to 5-HT during the subjective dark (active) phase of the circadian cycle. In contrast there was no apparent circadian variation in the sensitivity of s.c.n., v.l.g.n. or hippocampal neurones to ionophoresed gamma-aminobutyric acid (GABA). Neuronal activity recorded in the s.c.n., v.l.g.n. and hippocampus also exhibited a circadian variation in the recovery from 5-HT-induced suppression of firing. This may reflect reuptake processes as recovery can be prolonged by ionophoresis of uptake blockers (imipramine or fluoxetine). Rats (n = 15) expressing circadian arrhythmicity in their rest-activity behaviour induced by long-term continuous illumination (150-200 lx) showed no apparent circadian variation in 5-HT sensitivity. This loss was accompanied by either the development of a 5-6-fold subsensitivity to ionophoresed 5-HT (eleven out of fifteen rats) or a 2-3-fold supersensitivity to ionophoresed 5-HT (four out of fifteen rats). A similar loss of circadian variation and the development of a subsensitivity to ionophoresed 5-HT was also found in three rats sustaining complete electrolytic lesions of the s.c.n. These changes were not found in rats (n = 4) with partial s.c.n. lesions. These results implicate the s.c.n., or fibres passing through it, in the circadian modulation of 5-HT sensitivity in neurones both intrinsic to the s.c.n. circadian pace-maker itself and in the hippocampus and lateral geniculate nucleus (regions remote from the s

  19. Circadian Modulation of Dopamine Levels and Dopaminergic Neuron Development Contributes to Attention Deficiency and Hyperactive Behavior

    PubMed Central

    Huang, Jian; Zhong, Zhaomin; Wang, Mingyong; Chen, Xifeng; Tan, Yicheng; Zhang, Shuqing; He, Wei; He, Xiong; Huang, Guodong; Lu, Haiping; Wu, Ping; Che, Yi; Yan, Yi-Lin; Postlethwait, John H.; Chen, Wenbiao

    2015-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children and adults. While ADHD patients often display circadian abnormalities, the underlying mechanisms are unclear. Here we found that the zebrafish mutant for the circadian gene period1b (per1b) displays hyperactive, impulsive-like, and attention deficit-like behaviors and low levels of dopamine, reminiscent of human ADHD patients. We found that the circadian clock directly regulates dopamine-related genes monoamine oxidase and dopamine β hydroxylase, and acts via genes important for the development or maintenance of dopaminergic neurons to regulate their number and organization in the ventral diencephalic posterior tuberculum. We then found that Per1 knock-out mice also display ADHD-like symptoms and reduced levels of dopamine, thereby showing highly conserved roles of the circadian clock in ADHD. Our studies demonstrate that disruption of a circadian clock gene elicits ADHD-like syndrome. The circadian model for attention deficiency and hyperactive behavior sheds light on ADHD pathogenesis and opens avenues for exploring novel targets for diagnosis and therapy for this common psychiatric disorder. PMID:25673850

  20. Lmo Mutants Reveal a Novel Role for Circadian Pacemaker Neurons in Cocaine-Induced Behaviors

    PubMed Central

    2004-01-01

    Drosophila has been developed recently as a model system to investigate the molecular and neural mechanisms underlying responses to drugs of abuse. Genetic screens for mutants with altered drug-induced behaviors thus provide an unbiased approach to define novel molecules involved in the process. We identified mutations in the Drosophila LIM-only (LMO) gene, encoding a regulator of LIM-homeodomain proteins, in a genetic screen for mutants with altered cocaine sensitivity. Reduced Lmo function increases behavioral responses to cocaine, while Lmo overexpression causes the opposite effect, reduced cocaine responsiveness. Expression of Lmo in the principal Drosophila circadian pacemaker cells, the PDF-expressing ventral lateral neurons (LNvs), is sufficient to confer normal cocaine sensitivity. Consistent with a role for Lmo in LNv function, Lmo mutants also show defects in circadian rhythms of behavior. However, the role for LNvs in modulating cocaine responses is separable from their role as pacemaker neurons: ablation or functional silencing of the LNvs reduces cocaine sensitivity, while loss of the principal circadian neurotransmitter PDF has no effect. Together, these results reveal a novel role for Lmo in modulating acute cocaine sensitivity and circadian locomotor rhythmicity, and add to growing evidence that these behaviors are regulated by shared molecular mechanisms. The finding that the degree of cocaine responsiveness is controlled by the Drosophila pacemaker neurons provides a neuroanatomical basis for this overlap. We propose that Lmo controls the responsiveness of LNvs to cocaine, which in turn regulate the flies' behavioral sensitivity to the drug. PMID:15550987

  1. Adult-specific electrical silencing of pacemaker neurons uncouples the molecular oscillator from circadian outputs

    PubMed Central

    Depetris-Chauvin, Ana; Berni, Jimena; Aranovich, Ezequiel J.; Muraro, Nara I.; Beckwith, Esteban J.; Ceriani, María Fernanda

    2011-01-01

    Summary Background Circadian rhythms regulate physiology and behavior through transcriptional feedback loops of clock genes running within specific pacemaker cells. In Drosophila, molecular oscillations in the small ventral Lateral Neurons (sLNvs) command rhythmic behavior under free-running conditions releasing the neuropeptide PIGMENT DISPERSING FACTOR (PDF) in a circadian fashion. Electrical activity in the sLNvs is also required for behavioral rhythmicity. Yet, how temporal information is transduced into behavior remains unclear. Results Here we developed a new tool for temporal control of gene expression to obtain adult-restricted electrical silencing of the PDF circuit, which led to reversible behavioral arrhythmicity. Remarkably, PER oscillations during the silenced phase remained unaltered, indicating that arrhythmicity is a direct consequence of the silenced activity. Accordingly, circadian axonal remodeling and PDF accumulation were severely affected during the silenced phase. Conclusions Although electrical activity of the sLNvs is not a clock component it coordinates circuit outputs leading to rhythmic behavior. PMID:22018542

  2. Circadian and other rhythmic activity of neurones in the ventromedial nuclei and lateral hypothalamic area.

    PubMed Central

    Koizumi, K; Nishino, H

    1976-01-01

    1. The frequency of firing was simultaneously recorded from single neurones of the ventromedial nuclei (VMN) and the lateral hypothalamic area (LHA) in urethane anaesthetized rats for many hours. 2. There were circadian changes of VMN and LHA neurone activity. The pattern of this circadian rhythm is as follows: throughout the day LHA neurones show higher activity than that of VMN, as indicated by higher frequency and more fluctuations in their rates of firing. In late afternoon the discharge rate of LHA neurones increases further, showing oscillations of short duration. In the early evening hours LHA neurone activity gradually goes down, as the VMN neurones become active. Throughout the night, VMN neurones are more active than those of LHA, just the opposite of the day period. In early morning hours VMN neurones gradually become quiet, while LHA neurones begin to show activity. 3. Superimposed on the circadian rhythm, at certain periods of the day, VMN and LHA neurones showed short duration oscillations in rate of firing, roughly every 7-15 sec and every 3-5 min. 4. Activities in neurones of the VMN and LHA were reciprocally related; a decrease in firing rate of one was associated with an increase in the other. This phenomenon was shown clearly by analysis of auto- and cross-correlation functions of firing patterns of VMN and LHA neurones. 5. The effects of stimulations of the prefrontal cortex and splanchnic afferents on VMN and LHA neurones depended on the basic firing frequency, thus they varied with the time of day. Definite relationships exist between basic firing frequency of a cell and the magnitude of changes evoked by these stimuli. Reactions of VMN and LHA neurones were the opposite in most instances. Septal stimulations (at more than 10/sec) always produced inhibition of LHA neurone activity. 6. Intravenous injection of glucose inhibited LHA neurones and accelerated firing of VMN cells. This was true during the day period as well as at night when

  3. The Drosophila Circadian Clock Gates Sleep through Time-of-Day Dependent Modulation of Sleep-Promoting Neurons

    PubMed Central

    Cavanaugh, Daniel J.; Vigderman, Abigail S.; Dean, Terry; Garbe, David S.; Sehgal, Amita

    2016-01-01

    Study Objectives: Sleep is under the control of homeostatic and circadian processes, which interact to determine sleep timing and duration, but the mechanisms through which the circadian system modulates sleep are largely unknown. We therefore used adult-specific, temporally controlled neuronal activation and inhibition to identify an interaction between the circadian clock and a novel population of sleep-promoting neurons in Drosophila. Methods: Transgenic flies expressed either dTRPA1, a neuronal activator, or Shibirets1, an inhibitor of synaptic release, in small subsets of neurons. Sleep, as determined by activity monitoring and video tracking, was assessed before and after temperature-induced activation or inhibition using these effector molecules. We compared the effect of these manipulations in control flies and in mutant flies that lacked components of the molecular circadian clock. Results: Adult-specific activation or inhibition of a population of neurons that projects to the sleep-promoting dorsal Fan-Shaped Body resulted in bidirectional control over sleep. Interestingly, the magnitude of the sleep changes were time-of-day dependent. Activation of sleep-promoting neurons was maximally effective during the middle of the day and night, and was relatively ineffective during the day-to-night and night-to-day transitions. These time-ofday specific effects were absent in flies that lacked functional circadian clocks. Conclusions: We conclude that the circadian system functions to gate sleep through active inhibition at specific times of day. These data identify a mechanism through which the circadian system prevents premature sleep onset in the late evening, when homeostatic sleep drive is high. Citation: Cavanaugh DJ, Vigderman AS, Dean T, Garbe DS, Sehgal A. The Drosophila circadian clock gates sleep through time-of-day dependent modulation of sleep-promoting neurons. SLEEP 2016;39(2):345–356. PMID:26350473

  4. Spike firing pattern of output neurons of the Limulus circadian clock.

    PubMed

    Liu, Jiahui S; Passaglia, Christopher L

    2011-08-01

    The lateral eyes of the horseshoe crab (Limulus polyphemus) show a daily rhythm in visual sensitivity that is mediated by efferent nerve signals from a circadian clock in the crab's brain. How these signals communicate circadian messages is not known for this or other animals. Here the authors describe in quantitative detail the spike firing pattern of clock output neurons in living horseshoe crabs and discuss its possible significance to clock organization and function. Efferent fiber spike trains were recorded extracellularly for several hours to days, and in some cases, the electroretinogram was simultaneously acquired to monitor eye sensitivity. Statistical features of single- and multifiber recordings were characterized via interval distribution, serial correlation, and power spectral analysis. The authors report that efferent feedback to the eyes has several scales of temporal structure, consisting of multicellular bursts of spikes that group into clusters and packets of clusters that repeat throughout the night and disappear during the day. Except near dusk and dawn, the bursts occur every 1 to 2 sec in clusters of 10 to 30 bursts separated by a minute or two of silence. Within a burst, each output neuron typically fires a single spike with a preferred order, and intervals between bursts and clusters are positively correlated in length. The authors also report that efferent activity is strongly modulated by light at night and that just a brief flash has lasting impact on clock output. The multilayered firing pattern is likely important for driving circadian rhythms in the eye and other target organs. PMID:21775292

  5. Light activates output from evening neurons and inhibits output from morning neurons in the Drosophila circadian clock.

    PubMed

    Picot, Marie; Cusumano, Paola; Klarsfeld, André; Ueda, Ryu; Rouyer, François

    2007-11-01

    Animal circadian clocks are based on multiple oscillators whose interactions allow the daily control of complex behaviors. The Drosophila brain contains a circadian clock that controls rest-activity rhythms and relies upon different groups of PERIOD (PER)-expressing neurons. Two distinct oscillators have been functionally characterized under light-dark cycles. Lateral neurons (LNs) that express the pigment-dispersing factor (PDF) drive morning activity, whereas PDF-negative LNs are required for the evening activity. In constant darkness, several lines of evidence indicate that the LN morning oscillator (LN-MO) drives the activity rhythms, whereas the LN evening oscillator (LN-EO) does not. Since mutants devoid of functional CRYPTOCHROME (CRY), as opposed to wild-type flies, are rhythmic in constant light, we analyzed transgenic flies expressing PER or CRY in the LN-MO or LN-EO. We show that, under constant light conditions and reduced CRY function, the LN evening oscillator drives robust activity rhythms, whereas the LN morning oscillator does not. Remarkably, light acts by inhibiting the LN-MO behavioral output and activating the LN-EO behavioral output. Finally, we show that PDF signaling is not required for robust activity rhythms in constant light as opposed to its requirement in constant darkness, further supporting the minor contribution of the morning cells to the behavior in the presence of light. We therefore propose that day-night cycles alternatively activate behavioral outputs of the Drosophila evening and morning lateral neurons. PMID:18044989

  6. Phase Shifting Capacity of the Circadian Pacemaker Determined by the SCN Neuronal Network Organization

    PubMed Central

    vanderLeest, Henk Tjebbe; Rohling, Jos H. T.; Michel, Stephan; Meijer, Johanna H.

    2009-01-01

    Background In mammals, a major circadian pacemaker that drives daily rhythms is located in the suprachiasmatic nuclei (SCN), at the base of the hypothalamus. The SCN receive direct light input via the retino-hypothalamic tract. Light during the early night induces phase delays of circadian rhythms while during the late night it leads to phase advances. The effects of light on the circadian system are strongly dependent on the photoperiod to which animals are exposed. An explanation for this phenomenon is currently lacking. Methodology and Principal Findings We recorded running wheel activity in C57 mice and observed large amplitude phase shifts in short photoperiods and small shifts in long photoperiods. We investigated whether these different light responses under short and long days are expressed within the SCN by electrophysiological recordings of electrical impulse frequency in SCN slices. Application of N-methyl-D-aspartate (NMDA) induced sustained increments in electrical activity that were not significantly different in the slices from long and short photoperiods. These responses led to large phase shifts in slices from short days and small phase shifts in slices from long days. An analysis of neuronal subpopulation activity revealed that in short days the amplitude of the rhythm was larger than in long days. Conclusions The data indicate that the photoperiodic dependent phase responses are intrinsic to the SCN. In contrast to earlier predictions from limit cycle theory, we observed large phase shifting responses in high amplitude rhythms in slices from short days, and small shifts in low amplitude rhythms in slices from long days. We conclude that the photoperiodic dependent phase responses are determined by the SCN and propose that synchronization among SCN neurons enhances the phase shifting capacity of the circadian system. PMID:19305510

  7. Transmedulla Neurons in the Sky Compass Network of the Honeybee (Apis mellifera) Are a Possible Site of Circadian Input.

    PubMed

    Zeller, Maximilian; Held, Martina; Bender, Julia; Berz, Annuska; Heinloth, Tanja; Hellfritz, Timm; Pfeiffer, Keram

    2015-01-01

    Honeybees are known for their ability to use the sun's azimuth and the sky's polarization pattern for spatial orientation. Sky compass orientation in bees has been extensively studied at the behavioral level but our knowledge about the underlying neuronal systems and mechanisms is very limited. Electrophysiological studies in other insect species suggest that neurons of the sky compass system integrate information about the polarization pattern of the sky, its chromatic gradient, and the azimuth of the sun. In order to obtain a stable directional signal throughout the day, circadian changes between the sky polarization pattern and the solar azimuth must be compensated. Likewise, the system must be modulated in a context specific way to compensate for changes in intensity, polarization and chromatic properties of light caused by clouds, vegetation and landscape. The goal of this study was to identify neurons of the sky compass pathway in the honeybee brain and to find potential sites of circadian and neuromodulatory input into this pathway. To this end we first traced the sky compass pathway from the polarization-sensitive dorsal rim area of the compound eye via the medulla and the anterior optic tubercle to the lateral complex using dye injections. Neurons forming this pathway strongly resembled neurons of the sky compass pathway in other insect species. Next we combined tracer injections with immunocytochemistry against the circadian neuropeptide pigment dispersing factor and the neuromodulators serotonin, and γ-aminobutyric acid. We identified neurons, connecting the dorsal rim area of the medulla to the anterior optic tubercle, as a possible site of neuromodulation and interaction with the circadian system. These neurons have conspicuous spines in close proximity to pigment dispersing factor-, serotonin-, and GABA-immunoreactive neurons. Our data therefore show for the first time a potential interaction site between the sky compass pathway and the circadian

  8. Transmedulla Neurons in the Sky Compass Network of the Honeybee (Apis mellifera) Are a Possible Site of Circadian Input

    PubMed Central

    Zeller, Maximilian; Held, Martina; Bender, Julia; Berz, Annuska; Heinloth, Tanja; Hellfritz, Timm; Pfeiffer, Keram

    2015-01-01

    Honeybees are known for their ability to use the sun’s azimuth and the sky’s polarization pattern for spatial orientation. Sky compass orientation in bees has been extensively studied at the behavioral level but our knowledge about the underlying neuronal systems and mechanisms is very limited. Electrophysiological studies in other insect species suggest that neurons of the sky compass system integrate information about the polarization pattern of the sky, its chromatic gradient, and the azimuth of the sun. In order to obtain a stable directional signal throughout the day, circadian changes between the sky polarization pattern and the solar azimuth must be compensated. Likewise, the system must be modulated in a context specific way to compensate for changes in intensity, polarization and chromatic properties of light caused by clouds, vegetation and landscape. The goal of this study was to identify neurons of the sky compass pathway in the honeybee brain and to find potential sites of circadian and neuromodulatory input into this pathway. To this end we first traced the sky compass pathway from the polarization-sensitive dorsal rim area of the compound eye via the medulla and the anterior optic tubercle to the lateral complex using dye injections. Neurons forming this pathway strongly resembled neurons of the sky compass pathway in other insect species. Next we combined tracer injections with immunocytochemistry against the circadian neuropeptide pigment dispersing factor and the neuromodulators serotonin, and γ-aminobutyric acid. We identified neurons, connecting the dorsal rim area of the medulla to the anterior optic tubercle, as a possible site of neuromodulation and interaction with the circadian system. These neurons have conspicuous spines in close proximity to pigment dispersing factor-, serotonin-, and GABA-immunoreactive neurons. Our data therefore show for the first time a potential interaction site between the sky compass pathway and the circadian

  9. Synchronization of Biological Clock Neurons by Light and Peripheral Feedback Systems Promotes Circadian Rhythms and Health

    PubMed Central

    Ramkisoensing, Ashna; Meijer, Johanna H.

    2015-01-01

    In mammals, the suprachiasmatic nucleus (SCN) functions as a circadian clock that drives 24-h rhythms in both physiology and behavior. The SCN is a multicellular oscillator in which individual neurons function as cell-autonomous oscillators. The production of a coherent output rhythm is dependent upon mutual synchronization among single cells and requires both synaptic communication and gap junctions. Changes in phase-synchronization between individual cells have consequences on the amplitude of the SCN’s electrical activity rhythm, and these changes play a major role in the ability to adapt to seasonal changes. Both aging and sleep deprivation negatively affect the circadian amplitude of the SCN, whereas behavioral activity (i.e., exercise) has a positive effect on amplitude. Given that the amplitude of the SCN’s electrical activity rhythm is essential for achieving robust rhythmicity in physiology and behavior, the mechanisms that underlie neuronal synchronization warrant further study. A growing body of evidence suggests that the functional integrity of the SCN contributes to health, well-being, cognitive performance, and alertness; in contrast, deterioration of the 24-h rhythm is a risk factor for neurodegenerative disease, cancer, depression, and sleep disorders. PMID:26097465

  10. Synchronization of Biological Clock Neurons by Light and Peripheral Feedback Systems Promotes Circadian Rhythms and Health.

    PubMed

    Ramkisoensing, Ashna; Meijer, Johanna H

    2015-01-01

    In mammals, the suprachiasmatic nucleus (SCN) functions as a circadian clock that drives 24-h rhythms in both physiology and behavior. The SCN is a multicellular oscillator in which individual neurons function as cell-autonomous oscillators. The production of a coherent output rhythm is dependent upon mutual synchronization among single cells and requires both synaptic communication and gap junctions. Changes in phase-synchronization between individual cells have consequences on the amplitude of the SCN's electrical activity rhythm, and these changes play a major role in the ability to adapt to seasonal changes. Both aging and sleep deprivation negatively affect the circadian amplitude of the SCN, whereas behavioral activity (i.e., exercise) has a positive effect on amplitude. Given that the amplitude of the SCN's electrical activity rhythm is essential for achieving robust rhythmicity in physiology and behavior, the mechanisms that underlie neuronal synchronization warrant further study. A growing body of evidence suggests that the functional integrity of the SCN contributes to health, well-being, cognitive performance, and alertness; in contrast, deterioration of the 24-h rhythm is a risk factor for neurodegenerative disease, cancer, depression, and sleep disorders. PMID:26097465

  11. Network-Mediated Encoding of Circadian Time: The Suprachiasmatic Nucleus (SCN) from Genes to Neurons to Circuits, and Back

    PubMed Central

    Enoki, Ryosuke; Mazuski, Cristina N.; Jones, Jeff; Evans, Jennifer A.; Azzi, Abdelhalim

    2014-01-01

    The transcriptional architecture of intracellular circadian clocks is similar across phyla, but in mammals interneuronal mechanisms confer a higher level of circadian integration. The suprachiasmatic nucleus (SCN) is a unique model to study these mechanisms, as it operates as a ∼24 h clock not only in the living animal, but also when isolated in culture. This “clock in a dish” can be used to address fundamental questions, such as how intraneuronal mechanisms are translated by SCN neurons into circuit-level emergent properties and how the circuit decodes, and responds to, light input. This review addresses recent developments in understanding the relationship between electrical activity, [Ca2+]i, and intracellular clocks. Furthermore, optogenetic and chemogenetic approaches to investigate the distinct roles of neurons and glial cells in circuit encoding of circadian time will be discussed, as well as the epigenetic and circuit-level mechanisms that enable the SCN to translate light input into coherent daily rhythms. PMID:25392488

  12. Strong attachment of circadian pacemaker neurons on modified ultrananocrystalline diamond surfaces.

    PubMed

    Voss, Alexandra; Wei, HongYing; Zhang, Yi; Turner, Stuart; Ceccone, Giacomo; Reithmaier, Johann Peter; Stengl, Monika; Popov, Cyril

    2016-07-01

    Diamond is a promising material for a number of bio-applications, including the fabrication of platforms for attachment and investigation of neurons and of neuroprostheses, such as retinal implants. In the current work ultrananocrystalline diamond (UNCD) films were deposited by microwave plasma chemical vapor deposition, modified by UV/O3 treatment or NH3 plasma, and comprehensively characterized with respect to their bulk and surface properties, such as crystallinity, topography, composition and chemical bonding nature. The interactions of insect circadian pacemaker neurons with UNCD surfaces with H-, O- and NH2-terminations were investigated with respect to cell density and viability. The fast and strong attachment achieved without application of adhesion proteins allowed for advantageous modification of dispersion protocols for the preparation of primary cell cultures. Centrifugation steps, which are employed for pelletizing dispersed cells to separate them from dispersing enzymes, easily damage neurons. Now centrifugation can be avoided since dispersed neurons quickly and strongly attach to the UNCD surfaces. Enzyme solutions can be easily washed off without losing many of the dispersed cells. No adverse effects on the cell viability and physiological responses were observed as revealed by calcium imaging. Furthermore, the enhanced attachment of the neurons, especially on the modified UNCD surfaces, was especially advantageous for the immunocytochemical procedures with the cell cultures. The cell losses during washing steps were significantly reduced by one order of magnitude in comparison to controls. In addition, the integration of a titanium grid structure under the UNCD films allowed for individual assignment of physiologically characterized neurons to immunocytochemically stained cells. Thus, employing UNCD surfaces free of foreign proteins improves cell culture protocols and immunocytochemistry with cultured cells. The fast and strong attachment of

  13. The core clock gene Per1 phases molecular and electrical circadian rhythms in SCN neurons

    PubMed Central

    Jones, Jeff R.

    2016-01-01

    The brain’s biological clock, the suprachiasmatic nucleus (SCN), exhibits endogenous 24-hour rhythms in gene expression and spontaneous firing rate; however, the functional relationship between these neuronal rhythms is not fully understood. Here, we used a Per1::GFP transgenic mouse line that allows for the simultaneous quantification of molecular clock state and firing rate in SCN neurons to examine the relationship between these key components of the circadian clock. We find that there is a stable, phased relationship between E-box-driven clock gene expression and spontaneous firing rate in SCN neurons and that these relationships are independent of light input onto the system or of GABAA receptor-mediated synaptic activity. Importantly, the concordant phasing of gene and neural rhythms is disrupted in the absence of the homologous clock gene Per1, but persists in the absence of the core clock gene Per2. These results suggest that Per1 plays a unique, non-redundant role in phasing gene expression and firing rate rhythms in SCN neurons to increase the robustness of cellular timekeeping. PMID:27602274

  14. The core clock gene Per1 phases molecular and electrical circadian rhythms in SCN neurons.

    PubMed

    Jones, Jeff R; McMahon, Douglas G

    2016-01-01

    The brain's biological clock, the suprachiasmatic nucleus (SCN), exhibits endogenous 24-hour rhythms in gene expression and spontaneous firing rate; however, the functional relationship between these neuronal rhythms is not fully understood. Here, we used a Per1::GFP transgenic mouse line that allows for the simultaneous quantification of molecular clock state and firing rate in SCN neurons to examine the relationship between these key components of the circadian clock. We find that there is a stable, phased relationship between E-box-driven clock gene expression and spontaneous firing rate in SCN neurons and that these relationships are independent of light input onto the system or of GABAA receptor-mediated synaptic activity. Importantly, the concordant phasing of gene and neural rhythms is disrupted in the absence of the homologous clock gene Per1, but persists in the absence of the core clock gene Per2. These results suggest that Per1 plays a unique, non-redundant role in phasing gene expression and firing rate rhythms in SCN neurons to increase the robustness of cellular timekeeping. PMID:27602274

  15. A riot of rhythms: neuronal and glial circadian oscillators in the mediobasal hypothalamus

    PubMed Central

    Guilding, Clare; Hughes, Alun TL; Brown, Timothy M; Namvar, Sara; Piggins, Hugh D

    2009-01-01

    Background In mammals, the synchronized activity of cell autonomous clocks in the suprachiasmatic nuclei (SCN) enables this structure to function as the master circadian clock, coordinating daily rhythms in physiology and behavior. However, the dominance of this clock has been challenged by the observations that metabolic duress can over-ride SCN controlled rhythms, and that clock genes are expressed in many brain areas, including those implicated in the regulation of appetite and feeding. The recent development of mice in which clock gene/protein activity is reported by bioluminescent constructs (luciferase or luc) now enables us to track molecular oscillations in numerous tissues ex vivo. Consequently we determined both clock activities and responsiveness to metabolic perturbations of cells and tissues within the mediobasal hypothalamus (MBH), a site pivotal for optimal internal homeostatic regulation. Results Here we demonstrate endogenous circadian rhythms of PER2::LUC expression in discrete subdivisions of the arcuate (Arc) and dorsomedial nuclei (DMH). Rhythms resolved to single cells did not maintain long-term synchrony with one-another, leading to a damping of oscillations at both cell and tissue levels. Complementary electrophysiology recordings revealed rhythms in neuronal activity in the Arc and DMH. Further, PER2::LUC rhythms were detected in the ependymal layer of the third ventricle and in the median eminence/pars tuberalis (ME/PT). A high-fat diet had no effect on the molecular oscillations in the MBH, whereas food deprivation resulted in an altered phase in the ME/PT. Conclusion Our results provide the first single cell resolution of endogenous circadian rhythms in clock gene expression in any intact tissue outside the SCN, reveal the cellular basis for tissue level damping in extra-SCN oscillators and demonstrate that an oscillator in the ME/PT is responsive to changes in metabolism. PMID:19712475

  16. Activation of glycine receptor phase-shifts the circadian rhythm in neuronal activity in the mouse suprachiasmatic nucleus

    PubMed Central

    Mordel, Jérôme; Karnas, Diana; Inyushkin, Alexey; Challet, Etienne; Pévet, Paul; Meissl, Hilmar

    2011-01-01

    Abstract In mammals, the master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is composed of numerous synchronized oscillating cells that drive daily behavioural and physiological processes. Several entrainment pathways, afferent inputs to the SCN with their neurotransmitter and neuromodulator systems, can reset the circadian system regularly and also modulate neuronal activity within the SCN. In the present study, we investigated the function of the inhibitory neurotransmitter glycine on neuronal activity in the mouse SCN and on resetting of the circadian clock. The effects of glycine on the electrical activity of SCN cells from C57Bl/6 mice were studied either by patch-clamp recordings from acute brain slices or by long-term recordings from organotypic brain slices using multi-microelectrode arrays (MEA). Voltage-clamp recordings confirmed the existence of glycine-induced, chloride-selective currents in SCN neurons. These currents were reversibly suppressed by strychnine, phenylbenzene ω-phosphono-α-amino acid (PMBA) or ginkgolide B, selective blockers of glycine receptors (GlyRs). Long-term recordings of the spontaneous activity of SCN neurons revealed that glycine application induces a phase advance during the subjective day and a phase delay during the early subjective night. Both effects were suppressed by strychnine or by PMBA. These results suggest that glycine is able to modulate circadian activity by acting directly on its specific receptors in SCN neurons. PMID:21486797

  17. Activation of glycine receptor phase-shifts the circadian rhythm in neuronal activity in the mouse suprachiasmatic nucleus.

    PubMed

    Mordel, Jérôme; Karnas, Diana; Inyushkin, Alexey; Challet, Etienne; Pévet, Paul; Meissl, Hilmar

    2011-05-01

    In mammals, the master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is composed of numerous synchronized oscillating cells that drive daily behavioural and physiological processes. Several entrainment pathways, afferent inputs to the SCN with their neurotransmitter and neuromodulator systems, can reset the circadian system regularly and also modulate neuronal activity within the SCN. In the present study, we investigated the function of the inhibitory neurotransmitter glycine on neuronal activity in the mouse SCN and on resetting of the circadian clock. The effects of glycine on the electrical activity of SCN cells from C57Bl/6 mice were studied either by patch-clamp recordings from acute brain slices or by long-term recordings from organotypic brain slices using multi-microelectrode arrays(MEA). Voltage-clamp recordings confirmed the existence of glycine-induced, chloride-selective currents in SCN neurons. These currents were reversibly suppressed by strychnine, phenylbenzeneω-phosphono-α-amino acid (PMBA) or ginkgolide B, selective blockers of glycine receptors(GlyRs). Long-term recordings of the spontaneous activity of SCN neurons revealed that glycine application induces a phase advance during the subjective day and a phase delay during the early subjective night. Both effects were suppressed by strychnine or by PMBA. These results suggest that glycine is able to modulate circadian activity by acting directly on its specific receptors in SCN neurons. PMID:21486797

  18. Bmal1 is an essential regulator for circadian cytosolic Ca²⁺ rhythms in suprachiasmatic nucleus neurons.

    PubMed

    Ikeda, Masayuki; Ikeda, Masaaki

    2014-09-01

    The hypothalamic suprachiasmatic nucleus (SCN) plays a pivotal role in the mammalian circadian clock system. Bmal1 is a clock gene that drives transcriptional-translational feedback loops (TTFLs) for itself and other genes, and is expressed in nearly all SCN neurons. Despite strong evidence that Bmal1-null mutant mice display arrhythmic behavior under constant darkness, the function of Bmal1 in neuronal activity is unknown. Recently, periodic changes in the levels of intracellular signaling messengers, such as cytosolic Ca(2+) and cAMP, were suggested to regulate TTFLs. However, the opposite aspect of how clock gene TTFLs regulate cytosolic signaling remains unclear. To investigate intracellular Ca(2+) dynamics under Bmal1 perturbations, we cotransfected some SCN neurons with yellow cameleon together with wild-type or dominant-negative Bmal1 using a gene-gun applied for mouse organotypic cultures. Immunofluorescence staining for a tag protein linked to BMAL1 showed nuclear expression of wild-type BMAL1 and its degradation within 1 week after transfection in SCN neurons. However, dominant-negative BMAL1 did not translocate into the nucleus and the cytosolic signals persisted beyond 1 week. Consistently, circadian Ca(2+) rhythms in SCN neurons were inhibited for longer periods by dominant-negative Bmal1 overexpression. Furthermore, SCN neurons transfected with a Bmal1 shRNA lengthened, whereas those overexpressing wild-type Bmal1 shortened, the periods of Ca(2+) rhythms, with a significant reduction in their amplitude. BMAL1 expression was intact in the majority of neighboring neurons in organotypic cultures. Therefore, we conclude that proper intrinsic Bmal1 expression, but not passive signaling via cell-to-cell interactions, is the determinant of circadian Ca(2+) rhythms in SCN neurons. PMID:25186748

  19. Development of pigment-dispersing hormone-immunoreactive neurons in the American lobster: homology to the insect circadian pacemaker system?

    PubMed Central

    Dircksen, Heinrich; Beltz, Barbara S.

    2011-01-01

    We have examined the development of pigment-dispersing hormone (PDH)-immunoreactive neurons in embryos of the American lobster Homarus americanus Milne Edwards, 1837 (Decapoda, Reptantia, Homarida) by using an antiserum against β-PDH. This peptide is detectable in the terminal medulla of the eyestalks and the protocerebrum where PDH immunoreactivity is present as early as 20% of embryonic development. During ontogenesis, an elaborate system of PDH-immunoreactive neurons and fibres develops in the eyestalks and the protocerebrum, whereas less labelling is present in the deuto- and tritocerebrum and the ventral nerve cord. The sinus gland is innervated by PDH neurites at hatching. This pattern of PDH immunoreactivity has been compared with that found in various insect species. Neurons immunoreactive to pigment-dispersing factor in the medulla have been shown to be a central component of the system that generates the circadian rhythm in insects. Our results indicate that, in view of the position of the neuronal somata and projection patterns of their neurites, the immunolabelled medulla neurons in insects have homologous counterparts in the crustacean eyestalk. Since locomotory and other activities in crustaceans follow distinct circadian rhythms comparable with those observed in insects, we suggest that PDH-immunoreactive medulla neurons in crustaceans are involved in the generation of these rhythms. PMID:19034522

  20. Visual motion-sensitive neurons in the bumblebee brain convey information about landmarks during a navigational task

    PubMed Central

    Mertes, Marcel; Dittmar, Laura; Egelhaaf, Martin; Boeddeker, Norbert

    2014-01-01

    Bees use visual memories to find the spatial location of previously learnt food sites. Characteristic learning flights help acquiring these memories at newly discovered foraging locations where landmarks—salient objects in the vicinity of the goal location—can play an important role in guiding the animal's homing behavior. Although behavioral experiments have shown that bees can use a variety of visual cues to distinguish objects as landmarks, the question of how landmark features are encoded by the visual system is still open. Recently, it could be shown that motion cues are sufficient to allow bees localizing their goal using landmarks that can hardly be discriminated from the background texture. Here, we tested the hypothesis that motion sensitive neurons in the bee's visual pathway provide information about such landmarks during a learning flight and might, thus, play a role for goal localization. We tracked learning flights of free-flying bumblebees (Bombus terrestris) in an arena with distinct visual landmarks, reconstructed the visual input during these flights, and replayed ego-perspective movies to tethered bumblebees while recording the activity of direction-selective wide-field neurons in their optic lobe. By comparing neuronal responses during a typical learning flight and targeted modifications of landmark properties in this movie we demonstrate that these objects are indeed represented in the bee's visual motion pathway. We find that object-induced responses vary little with object texture, which is in agreement with behavioral evidence. These neurons thus convey information about landmark properties that are useful for view-based homing. PMID:25309374

  1. Neuronal activity-regulated gene transcription: how are distant synaptic signals conveyed to the nucleus?

    PubMed Central

    Matamales, Miriam

    2012-01-01

    Synaptic activity can trigger gene expression programs that are required for the stable change of neuronal properties, a process that is essential for learning and memory. Currently, it is still unclear how the stimulation of dendritic synapses can be coupled to transcription in the nucleus in a timely way given that large distances can separate these two cellular compartments. Although several mechanisms have been proposed to explain long distance communication between synapses and the nucleus, the possible co-existence of these models and their relevance in physiological conditions remain elusive. One model suggests that synaptic activation triggers the translocation to the nucleus of certain transcription regulators localised at postsynaptic sites that function as synapto-nuclear messengers. Alternatively, it has been hypothesised that synaptic activity initiates propagating regenerative intracellular calcium waves that spread through dendrites into the nucleus where nuclear transcription machinery is thereby regulated. It has also been postulated that membrane depolarisation of voltage-gated calcium channels on the somatic membrane is sufficient to increase intracellular calcium concentration and activate transcription without the need for transported signals from distant synapses. Here I provide a critical overview of the suggested mechanisms for coupling synaptic stimulation to transcription, the underlying assumptions behind them and their plausible physiological significance. PMID:24327840

  2. dTRPA1 in Non-circadian Neurons Modulates Temperature-dependent Rhythmic Activity in Drosophila melanogaster.

    PubMed

    Das, Antara; Holmes, Todd C; Sheeba, Vasu

    2016-06-01

    In fruit flies Drosophila melanogaster, environmental cycles of light and temperature are known to influence behavioral rhythms through dedicated sensory receptors. But the thermosensory pathways and molecular receptors by which thermal cycles modulate locomotor activity rhythms remain unclear. Here, we report that neurons expressing warmth-activated ion channel Drosophila Transient Receptor Potential-A1 (dTRPA1) modulate distinct aspects of the rhythmic activity/rest rhythm in a light-dependent manner. Under light/dark (LD) cycles paired with constantly warm ambient conditions, flies deficient in dTRPA1 expression are unable to phase morning and evening activity bouts appropriately. Correspondingly, we show that electrical activity of a few neurons targeted by the dTRPA1(SH)-GAL4 driver modulates temperature-dependent phasing of activity/rest rhythm under LD cycles. The expression of dTRPA1 also affects behavior responses to temperature cycles combined with constant dark (DD) or light (LL) conditions. We demonstrate that the mid-day "siesta" exhibited by flies under temperature cycles in DD is dependent on dTRPA1 expression in a small number of neurons that include thermosensory anterior cell neurons. Although a small subset of circadian pacemaker neurons may express dTRPA1, we show that CRY-negative dTRPA1(SH)-GAL4 driven neurons are critical for the suppression of mid-thermophase activity, thus enabling flies to exhibit siesta. In contrast to temperature cycles in DD, under LL, dTRPA1 is not required for exhibiting siesta but is important for phasing of evening peak. Our studies show that activity/rest rhythms are modulated in a temperature-dependent manner via signals from dTRPA1(SH)-GAL4 driven neurons. Taken together, these results emphasize the differential influence of thermoreceptors on rhythmic behavior in fruit flies in coordination with light inputs. PMID:26868037

  3. GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time

    PubMed Central

    Myung, Jihwan; Hong, Sungho; DeWoskin, Daniel; De Schutter, Erik; Forger, Daniel B.; Takumi, Toru

    2015-01-01

    The mammalian suprachiasmatic nucleus (SCN) forms not only the master circadian clock but also a seasonal clock. This neural network of ∼10,000 circadian oscillators encodes season-dependent day-length changes through a largely unknown mechanism. We show that region-intrinsic changes in the SCN fine-tune the degree of network synchrony and reorganize the phase relationship among circadian oscillators to represent day length. We measure oscillations of the clock gene Bmal1, at single-cell and regional levels in cultured SCN explanted from animals raised under short or long days. Coupling estimation using the Kuramoto framework reveals that the network has couplings that can be both phase-attractive (synchronizing) and -repulsive (desynchronizing). The phase gap between the dorsal and ventral regions increases and the overall period of the SCN shortens with longer day length. We find that one of the underlying physiological mechanisms is the modulation of the intracellular chloride concentration, which can adjust the strength and polarity of the ionotropic GABAA-mediated synaptic input. We show that increasing day-length changes the pattern of chloride transporter expression, yielding more excitatory GABA synaptic input, and that blocking GABAA signaling or the chloride transporter disrupts the unique phase and period organization induced by the day length. We test the consequences of this tunable GABA coupling in the context of excitation–inhibition balance through detailed realistic modeling. These results indicate that the network encoding of seasonal time is controlled by modulation of intracellular chloride, which determines the phase relationship among and period difference between the dorsal and ventral SCN. PMID:26130804

  4. Vasoactive Intestinal Polypeptide (VIP)-Expressing Neurons in the Suprachiasmatic Nucleus Provide Sparse GABAergic Outputs to Local Neurons with Circadian Regulation Occurring Distal to the Opening of Postsynaptic GABAA Ionotropic Receptors

    PubMed Central

    Fan, Junmei; Zeng, Hongkui; Olson, David P.; Huber, Kimberly M.

    2015-01-01

    GABAergic synaptic transmission plays an important role in resetting and synchronizing circadian rhythms in the suprachiasmatic nucleus (SCN). Although the circadian modulation of intrinsic membrane currents and biochemical signaling have been examined in the SCN, the modulation of specific synaptic pathways within the SCN is unexplored. In addition, little is known about the functional properties of these pathways, including which ones involve GABAA receptors (GABAA-Rs). In brain slices obtained from mice, we examined synaptic responses originating from the SCN neurons expressing vasoactive intestinal peptide (VIP+ neurons). Focusing on the local projection within the ventromedial SCN, we found that VIP+ afferents provided input onto 49% of neurons with a preference for VIP-negative (VIP−) neurons. Responses were mediated by GABAA-Rs. The projection was sparsely connected and preferentially targeted a subset of SCN neurons unrelated to postsynaptic VIP expression. For most aspects of VIP+ network output, there was no circadian regulation. Excitability and spontaneous firing of the presynaptic VIP+ neurons were unchanged between day and night, and their network connectivity and synaptic function up through the evoked synaptic conductance were also unchanged. On the other hand, VIP+ input onto VIP− neurons became less inhibitory at night suggesting a postsynaptic alteration in the coupling of GABAA-R conductances to action potential firing. These data suggest that components of the VIP network and its synaptic output up through GABAA-R opening are invariant during the circadian cycle, but the effect on action potential firing is modulated by postsynaptic processes occurring after GABAA-R channel opening. PMID:25653351

  5. Parent-of-origin genetic background affects the transcriptional levels of circadian and neuronal plasticity genes following sleep loss

    PubMed Central

    Tinarelli, Federico; Garcia-Garcia, Celina; Nicassio, Francesco; Tucci, Valter

    2014-01-01

    Sleep homoeostasis refers to a process in which the propensity to sleep increases as wakefulness progresses and decreases as sleep progresses. Sleep is tightly organized around the circadian clock and is regulated by genetic and epigenetic mechanisms. The homoeostatic response of sleep, which is classically triggered by sleep deprivation, is generally measured as a rebound effect of electrophysiological measures, for example delta sleep. However, more recently, gene expression changes following sleep loss have been investigated as biomarkers of sleep homoeostasis. The genetic background of an individual may affect this sleep-dependent gene expression phenotype. In this study, we investigated whether parental genetic background differentially modulates the expression of genes following sleep loss. We tested the progeny of reciprocal crosses of AKR/J and DBA/2J mouse strains and we show a parent-of-origin effect on the expression of circadian, sleep and neuronal plasticity genes following sleep deprivation. Thus, we further explored, by in silico, specific functions or upstream mechanisms of regulation and we observed that several upstream mechanisms involving signalling pathways (i.e. DICER1, PKA), growth factors (CSF3 and BDNF) and transcriptional regulators (EGR2 and ELK4) may be differentially modulated by parental effects. This is the first report showing that a behavioural manipulation (e.g. sleep deprivation) in adult animals triggers specific gene expression responses according to parent-of-origin genomic mechanisms. Our study suggests that the same mechanism may be extended to other behavioural domains and that the investigation of gene expression following experimental manipulations should take seriously into account parent-of-origin effects. PMID:24446504

  6. Suprachiasmatic nuclei and Circadian rhythms. The role of suprachiasmatic nuclei on rhythmic activity of neurons in the lateral hypothalamic area, ventromedian nuclei and pineal gland

    NASA Technical Reports Server (NTRS)

    Nishino, H.

    1977-01-01

    Unit activity of lateral hypothalamic area (LHA) and Ventromedian nuclei (VMN) was recorded in urethane anesthetized male rats. A 5 to 10 sec. a 3-5 min and a circadian rhythmicity were observed. In about 15% of all neurons, spontaneous activity of LHA and VMN showed reciprocal relationships. Subthreshold stimuli applied at a slow rate in the septum and the suprachiasmatic nuclei (SCN) suppressed the rhythms without changing firing rates. On the other hand, stimulation of the optic nerve at a rate of 5 to 10/sec increased firing rates in 1/3 of neurons of SCN. Iontophoretically applied acetylcholine increased 80% of tested neurons of SCN, whereas norepinephrine, dopamine and 5 HT inhibited 64, 60 and 75% of SCN neurons respectively. These inhibitions were much stronger in neurons, the activity of which was increased by optic nerve stimulation. Stimulation of the SCN inhibited the tonic activity in cervical sympathetic nerves.

  7. Sensitivity to Interaural Time Differences Conveyed in the Stimulus Envelope: Estimating Inputs of Binaural Neurons Through the Temporal Analysis of Spike Trains.

    PubMed

    Dietz, Mathias; Wang, Le; Greenberg, David; McAlpine, David

    2016-08-01

    Sound-source localization in the horizontal plane relies on detecting small differences in the timing and level of the sound at the two ears, including differences in the timing of the modulated envelopes of high-frequency sounds (envelope interaural time differences (ITDs)). We investigated responses of single neurons in the inferior colliculus (IC) to a wide range of envelope ITDs and stimulus envelope shapes. By a novel means of visualizing neural activity relative to different portions of the periodic stimulus envelope at each ear, we demonstrate the role of neuron-specific excitatory and inhibitory inputs in creating ITD sensitivity (or the lack of it) depending on the specific shape of the stimulus envelope. The underlying binaural brain circuitry and synaptic parameters were modeled individually for each neuron to account for neuron-specific activity patterns. The model explains the effects of envelope shapes on sensitivity to envelope ITDs observed in both normal-hearing listeners and in neural data, and has consequences for understanding how ITD information in stimulus envelopes might be maximized in users of bilateral cochlear implants-for whom ITDs conveyed in the stimulus envelope are the only ITD cues available. PMID:27294694

  8. Folate deprivation modulates the expression of autophagy- and circadian-related genes in HT-22 hippocampal neuron cells through GR-mediated pathway.

    PubMed

    Sun, Qinwei; Yang, Yang; Li, Xi; He, Bin; Jia, Yimin; Zhang, Nana; Zhao, Ruqian

    2016-08-01

    Folic acid (FA) is an extremely important nutrient for brain formation and development. FA deficiency is highly linked to brain degeneration and age-related diseases, which are also associated with autophagic activities and circadian rhythm in hippocampal neurons. However, little is known how autophagy- and circadian-related genes in hippocampal neurons are regulated under FA deficiency. Here, hippocampal neuroncells (HT-22) were employed to determine the effect of FA deprivation (FD) on the expression of relevant genes and to reveal the potential role of glucocorticoid receptor (GR). FD increased autophagic activities in HT-22 cells, associated with significantly (P<0.05) enhanced GR activation indicated by higher ratio of GR phosphorylation. Out of 17 autophagy-related genes determined, 8 was significantly (P<0.05) up-regulated in FD group, which includes ATG2b, ATG3, ATG4c, ATG5, ATG10, ATG12, ATG13 and ATG14. Meanwhile, 4 out of 7 circadian-related genes detected, Clock, Cry1, Cry2 and Per2, were significantly (P<0.05) up-regulated. The protein content of autophagy markers, LC3A and LC3B, was also increased significantly (P<0.05). ChIP assay showed that FD promoted (P<0.05) GR binding to the promoter sequence of ATG3 and Per2. Moreover, MeDIP analysis demonstrated significant (P<0.05) hypomethylation in the promoter sequence of ATG12, ATG13 and Per2 genes. Together, we speculate that FD increases the transcription of autophagy- and circadian-related genes through, at least partly, GR-mediated pathway. Our results provide a basis for future investigations into the intracellular regulatory network in response to folate deficiency. PMID:27133904

  9. Circadian Rhythms

    MedlinePlus

    ... chronobiology. Are circadian rhythms the same thing as biological clocks? No, but they are related. Our biological clocks drive our circadian rhythms. What are biological clocks? The biological clocks that control circadian rhythms ...

  10. Widespread receptivity to neuropeptide PDF throughout the neuronal circadian clock network of Drosophila revealed by real-time cyclic AMP imaging

    PubMed Central

    Shafer, Orie T.; Kim, Dong Jo; Dunbar-Yaffe, Richard; Nikolaev, Viacheslav O.; Lohse, Martin J.; Taghert, Paul H.

    2008-01-01

    Summary The neuropeptide PDF is released by sixteen clock neurons in Drosophila and helps maintain circadian activity rhythms by coordinating a network of ~150 neuronal clocks. Whether PDF acts directly on elements of this neural network remains unknown. We address this question by adapting Epac1-camps, a genetically encoded cAMP FRET sensor, for use in the living brain. We find that a subset of the PDF-expressing neurons respond to PDF with long-lasting cAMP increases, and confirm that such responses require the PDF receptor. In contrast, an unrelated Drosophila neuropeptide, DH 31, stimulates large cAMP increases in all PDF-expressing clock neurons. Thus the network of ~150 clock neurons displays widespread, though not uniform, PDF receptivity. This work introduces a sensitive means of measuring cAMP changes in a living brain with sub-cellular resolution. Specifically, it experimentally confirms the longstanding hypothesis that PDF is a direct modulator of most neurons in the Drosophila clock network. PMID:18439407

  11. A Multi-Oscillatory Circadian System Times Female Reproduction

    PubMed Central

    Simonneaux, Valérie; Bahougne, Thibault

    2015-01-01

    Rhythms in female reproduction are critical to insure that timing of ovulation coincides with oocyte maturation and optimal sexual arousal. This fine tuning of female reproduction involves both the estradiol feedback as an indicator of oocyte maturation, and the master circadian clock of the suprachiasmatic nuclei (SCN) as an indicator of the time of the day. Herein, we are providing an overview of the state of knowledge regarding the differential inhibitory and stimulatory effects of estradiol at different stages of the reproductive axis, and the mechanisms through which the two main neurotransmitters of the SCN, arginine vasopressin, and vasoactive intestinal peptide, convey daily time cues to the reproductive axis. In addition, we will report the most recent findings on the putative functions of peripheral clocks located throughout the reproductive axis [kisspeptin (Kp) neurons, gonadotropin-releasing hormone neurons, gonadotropic cells, the ovary, and the uterus]. This review will point to the critical position of the Kp neurons of the anteroventral periventricular nucleus, which integrate both the stimulatory estradiol signal, and the daily arginine vasopressinergic signal, while displaying a circadian clock. Finally, given the critical role of the light/dark cycle in the synchronization of female reproduction, we will discuss the impact of circadian disruptions observed during shift-work conditions on female reproductive performance and fertility in both animal model and humans. PMID:26539161

  12. Physiology of circadian entrainment.

    PubMed

    Golombek, Diego A; Rosenstein, Ruth E

    2010-07-01

    Mammalian circadian rhythms are controlled by endogenous biological oscillators, including a master clock located in the hypothalamic suprachiasmatic nuclei (SCN). Since the period of this oscillation is of approximately 24 h, to keep synchrony with the environment, circadian rhythms need to be entrained daily by means of Zeitgeber ("time giver") signals, such as the light-dark cycle. Recent advances in the neurophysiology and molecular biology of circadian rhythmicity allow a better understanding of synchronization. In this review we cover several aspects of the mechanisms for photic entrainment of mammalian circadian rhythms, including retinal sensitivity to light by means of novel photopigments as well as circadian variations in the retina that contribute to the regulation of retinal physiology. Downstream from the retina, we examine retinohypothalamic communication through neurotransmitter (glutamate, aspartate, pituitary adenylate cyclase-activating polypeptide) interaction with SCN receptors and the resulting signal transduction pathways in suprachiasmatic neurons, as well as putative neuron-glia interactions. Finally, we describe and analyze clock gene expression and its importance in entrainment mechanisms, as well as circadian disorders or retinal diseases related to entrainment deficits, including experimental and clinical treatments. PMID:20664079

  13. Circadian light-input pathways in Drosophila.

    PubMed

    Yoshii, Taishi; Hermann-Luibl, Christiane; Helfrich-Förster, Charlotte

    2016-01-01

    Light is the most important environmental cue to entrain the circadian clock in most animals. In the fruit fly Drosophila melanogaster, the light entrainment mechanisms of the clock have been well-studied. The Drosophila brain contains approximately 150 neurons that rhythmically express circadian clock genes. These neurons are called "clock neurons" and control behavioral activity rhythms. Many clock neurons express the Cryptochrome (CRY) protein, which is sensitive to UV and blue light, and thus enables clock neurons deep in the brain to directly perceive light. In addition to the CRY protein, external photoreceptors in the Drosophila eyes play an important role in circadian light-input pathways. Recent studies have provided new insights into the mechanisms that integrate these light inputs into the circadian network of the brain. In this review, we will summarize the current knowledge on the light entrainment pathways in the Drosophila circadian clock. PMID:27066180

  14. Prokineticin 2 and circadian clock output

    PubMed Central

    Zhou, Qun-Yong; Cheng, Michelle Y.

    2009-01-01

    Circadian timing from the suprachiasmatic nucleus (SCN) is a critical component of sleep regulation. Animal lesion and genetic studies have indicated an essential interaction between the circadian signals and the homeostatic processes that regulate sleep. Here we summarize the biological functions of prokineticins, a pair of newly discovered regulatory proteins, with focus on the circadian function of prokineticin 2 (PK2) and its potential role in sleep-wake regulation. PK2 has been shown as a candidate SCN output molecule that regulates circadian locomotor behavior. The PK2 molecular rhythm in the SCN is predominantly controlled by the circadian transcriptional/translational loops, but also regulated directly by light. The receptor for PK2 is expressed in the primary SCN output targets that regulate circadian behavior including sleep-wake. The depolarizing effect of PK2 on neurons that express PK2 receptor may represent a possible mechanism for the regulatory role of PK2 in circadian rhythms. PMID:16279936

  15. Phenotyping Circadian Rhythms in Mice.

    PubMed

    Eckel-Mahan, Kristin; Sassone-Corsi, Paolo

    2015-01-01

    Circadian rhythms take place with a periodicity of 24 hr, temporally following the rotation of the earth around its axis. Examples of circadian rhythms are the sleep/wake cycle, feeding, and hormone secretion. Light powerfully entrains the mammalian clock and assists in keeping animals synchronized to the 24-hour cycle of the earth by activating specific neurons in the "central pacemaker" of the brain, the suprachiasmatic nucleus. Absolute periodicity of an animal can deviate slightly from 24 hr as manifest when an animal is placed into constant dark or "free-running" conditions. Simple measurements of an organism's activity in free-running conditions reveal its intrinsic circadian period. Mice are a particularly useful model for studying circadian rhythmicity due to the ease of genetic manipulation, thus identifying molecular contributors to rhythmicity. Furthermore, their small size allows for monitoring locomotion or activity in their homecage environment with relative ease. Several tasks commonly used to analyze circadian periodicity and plasticity in mice are presented here including the process of entrainment, determination of tau (period length) in free-running conditions, determination of circadian periodicity in response to light disruption (e.g., jet lag studies), and evaluation of clock plasticity in non-24-hour conditions (T-cycles). Studying the properties of circadian periods such as their phase, amplitude, and length in response to photic perturbation, can be particularly useful in understanding how humans respond to jet lag, night shifts, rotating shifts, or other transient or chronic disruption of environmental surroundings. PMID:26331760

  16. Molecular Mechanisms of Circadian Regulation During Spaceflight

    NASA Technical Reports Server (NTRS)

    Zanello, S. B.; Boyle, R.

    2012-01-01

    The physiology of both vertebrates and invertebrates follows internal rhythms coordinated in phase with the 24-hour daily light cycle. This circadian clock is governed by a central pacemaker, the suprachiasmatic nucleus (SCN) in the brain. However, peripheral circadian clocks or oscillators have been identified in most tissues. How the central and peripheral oscillators are synchronized is still being elucidated. Light is the main environmental cue that entrains the circadian clock. Under the absence of a light stimulus, the clock continues its oscillation in a free-running condition. In general, three functional compartments of the circadian clock are defined. The vertebrate retina contains endogenous clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis (melatonin and dopamine), rod disk shedding, signalling pathways and gene expression. Neurons with putative local circadian rhythm generation are found among all the major neuron populations in the mammalian retina. In the mouse, clock genes and function are more localized to the inner retinal and ganglion cell layers. The photoreceptor, however, secrete melatonin which may still serve a an important circadian signal. The reception and transmission of the non-visual photic stimulus resides in a small subpopulation (1-3%) or retinal ganglion cells (RGC) that express the pigment melanopsin (Opn4) and are called intrisically photoreceptive RGC (ipRGC). Melanopsin peak absorption is at 420 nm and all the axons of the ipRGC reach the SCN. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate the risk of fatigue and health and performance decrement due to circadian rhythm disruption. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. We hypothesize that spaceflight may affect ip

  17. Central and peripheral circadian clocks in mammals.

    PubMed

    Mohawk, Jennifer A; Green, Carla B; Takahashi, Joseph S

    2012-01-01

    The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism. PMID:22483041

  18. The circadian system: plasticity at many levels.

    PubMed

    Muraro, N I; Pírez, N; Ceriani, M F

    2013-09-01

    Over the years it has become crystal clear that a variety of processes encode time-of-day information, ranging from gene expression, protein stability, or subcellular localization of key proteins, to the fine tuning of network properties and modulation of input signals, ultimately ensuring that physiology and behavior are properly synchronized to a changing environment. The purpose of this review is to put forward examples (as opposed to generate a comprehensive revision of all the available literature) in which the circadian system displays a remarkable degree of plasticity, from cell autonomous to circuit-based levels. In the literature, the term circadian plasticity has been used to refer to different concepts. The obvious one, more literally, refers to any change that follows a circadian (circa=around, diem=day) pattern, i.e. a daily change of a given parameter. The discovery of daily remodeling of neuronal structures will be referred herein as structural circadian plasticity, and represents an additional and novel phenomenon modified daily. Finally, any plasticity that has to do with a circadian parameter would represent a type of circadian plasticity; as an example, adjustments that allow organisms to adapt their daily behavior to the annual changes in photoperiod is a form of circadian plasticity at a higher organizational level, which is an emergent property of the whole circadian system. Throughout this work we will revisit these types of changes by reviewing recent literature delving around circadian control of clock outputs, from the most immediate ones within pacemaker neurons to the circadian modulation of rest-activity cycles. PMID:23727010

  19. On conveying and not conveying expertise.

    PubMed

    Rappert, Brian; Coopmans, Catelijne

    2015-08-01

    This article attends to the movement between disclosing and non-disclosing in accounts of expertise. While referencing discussions about tacit knowledge ('experts know more than they can say') and the politics of non-disclosure ('withholding can help as well as harm the credibility of experts'), in the main it considers how experts move between conveying and not conveying in order to make their proficiencies recognized and accessible to others. The article examines this movement through a form that partakes in it, thus drawing attention to conventions and tensions in how authors make themselves accountable, and their subject matter available, to audiences. It thereby proposes to explore the possibilities of careful, and generative, non-disclosure as part of expert writing practices. PMID:26502661

  20. Phenotyping Circadian Rhythms in Mice

    PubMed Central

    Eckel-Mahan, Kristin; Sassone-Corsi, Paolo

    2015-01-01

    Circadian rhythms take place with a periodicity of twenty-four hours, temporally following the rotation of the earth around its axis. Examples of circadian rhythms are the sleep/wake cycle, feeding, and hormone secretion. Light powerfully entrains the mammalian clock and assists in keeping animals synchronized to the 24-hour cycle of the earth by activating specific neurons in the “central pacemaker” of the brain, the suprachiasmatic nucleus. Absolute periodicity of an animal can deviate slightly from 24 hours as manifest when an animal is placed into constant dark- or “free running”- conditions. Simple measurements of an organism's activity in free running conditions reveal its intrinsic circadian period. Mice are a particularly useful model for studying circadian rhythmicity due to the ease of genetic manipulation, thus identifying molecular contributors to rhythmicity. Furthermore, their small size allows for monitoring locomotion or activity in their home cage environment with relative ease. Several tasks commonly used to analyze circadian periodicity and plasticity in mice are outlined here including the process of entrainment, determination of tau (period length) in free running conditions, determination of circadian periodicity in response to light disruption (i.e. jet lag studies), and evaluation of clock plasticity in non-twenty-four hour conditions (T-cycles). Studying the properties of circadian periods such as their phase, amplitude, and length in response to photic perturbation, can be particularly useful in understanding how humans respond to jet lag, night shifts, rotating shifts, or other transient or chronic disruption of one's environmental surroundings. PMID:26331760

  1. Gut clock: implication of circadian rhythms in the gastrointestinal tract.

    PubMed

    Konturek, P C; Brzozowski, T; Konturek, S J

    2011-04-01

    Circadian and seasonal rhythms are a fundamental feature of all living organisms and their organelles. Biological rhythms are responsible for daily food intake; the period of hunger and satiety is controlled by the central pacemaker, which resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, and communicates with tissues via bidirectional neuronal and humoral pathways. The molecular basis for circadian timing in the gastrointestinal tract (GIT) involves interlocking transcriptional/translational feedback loops which culminate in the rhythmic expression and activity of a set of clock genes and related hormones. Interestingly, it has been found that clocks in the GIT are responsible for the periodic activity (PA) of its various segments and transit along the GIT; they are localized in special interstitial cells, with unstable membrane potentials located between the longitudinal and circular muscle layers. The rhythm of slow waves is controlled in various segments of the GIT: in the stomach (about 3 cycles per min), in the duodenum (12 cycle per min), in the jejunum and ileum (from 7 to 10 cycles per min), and in the colon (12 cycles per min). The migrating motor complex (MMC) starts in the stomach and moves along the gut causing peristaltic contractions when the electrical activity spikes are superimposed on the slow waves. GIT hormones, such as motilin and ghrelin, are involved in the generation of MMCs, while others (gastrin, ghrelin, cholecystokinin, serotonin) are involved in the generation of spikes upon the slow waves, resulting in peristaltic or segmental contractions in the small (duodenum, jejunum ileum) and large bowel (colon). Additionally, melatonin, produced by neuro-endocrine cells of the GIT mucosa, plays an important role in the internal biological clock, related to food intake (hunger and satiety) and the myoelectric rhythm (produced primarily by the pineal gland during the dark period of the light-dark cycle). This appears to be an

  2. Glia-related circadian plasticity in the visual system of Diptera

    PubMed Central

    Górska-Andrzejak, Jolanta

    2012-01-01

    The circadian changes in morphology of the first visual neuropil or lamina of Diptera represent an example of the neuronal plasticity controlled by the circadian clock (circadian plasticity). It is observed in terminals of the compound eye photoreceptor cells, the peripheral oscillators expressing the clock genes. However, it has been found also in their postsynaptic partners, the L1 and L2 monopolar cells, in which the activity of the clock genes have not yet been detected. The circadian input that the L1 and L2 receive seems to originate not only from the retina photoreceptors and from the circadian pacemaker neurons located in the brain, but also from the glial cells that express the clock genes and thus contain circadian oscillators. This paper summarizes the morphological and biochemical rhythms in glia of the optic lobe, shows how they contribute to circadian plasticity, and discusses how glial clocks may modulate circadian rhythms in the lamina. PMID:23986707

  3. NONO couples the circadian clock to the cell cycle

    PubMed Central

    Kowalska, Elzbieta; Ripperger, Juergen A.; Hoegger, Dominik C.; Bruegger, Pascal; Buch, Thorsten; Birchler, Thomas; Mueller, Anke; Albrecht, Urs; Contaldo, Claudio; Brown, Steven A.

    2013-01-01

    Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PERIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-Ink4A cell cycle checkpoint gene and potentiated its circadian activation in a PER protein-dependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-Ink4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization. PMID:23267082

  4. Circadian influences on myocardial infarction.

    PubMed

    Virag, Jitka A I; Lust, Robert M

    2014-01-01

    Components of circadian rhythm maintenance, or "clock genes," are endogenous entrainable oscillations of about 24 h that regulate biological processes and are found in the suprachaismatic nucleus (SCN) and many peripheral tissues, including the heart. They are influenced by external cues, or Zeitgebers, such as light and heat, and can influence such diverse phenomena as cytokine expression immune cells, metabolic activity of cardiac myocytes, and vasodilator regulation by vascular endothelial cells. While it is known that the central master clock in the SCN synchronizes peripheral physiologic rhythms, the mechanisms by which the information is transmitted are complex and may include hormonal, metabolic, and neuronal inputs. Whether circadian patterns are causally related to the observed periodicity of events, or whether they are simply epi-phenomena is not well established, but a few studies suggest that the circadian effects likely are real in their impact on myocardial infarct incidence. Cycle disturbances may be harbingers of predisposition and subsequent response to acute and chronic cardiac injury, and identifying the complex interactions of circadian rhythms and myocardial infarction may provide insights into possible preventative and therapeutic strategies for susceptible populations. PMID:25400588

  5. Circadian influences on myocardial infarction

    PubMed Central

    Virag, Jitka A. I.; Lust, Robert M.

    2014-01-01

    Components of circadian rhythm maintenance, or “clock genes,” are endogenous entrainable oscillations of about 24 h that regulate biological processes and are found in the suprachaismatic nucleus (SCN) and many peripheral tissues, including the heart. They are influenced by external cues, or Zeitgebers, such as light and heat, and can influence such diverse phenomena as cytokine expression immune cells, metabolic activity of cardiac myocytes, and vasodilator regulation by vascular endothelial cells. While it is known that the central master clock in the SCN synchronizes peripheral physiologic rhythms, the mechanisms by which the information is transmitted are complex and may include hormonal, metabolic, and neuronal inputs. Whether circadian patterns are causally related to the observed periodicity of events, or whether they are simply epi-phenomena is not well established, but a few studies suggest that the circadian effects likely are real in their impact on myocardial infarct incidence. Cycle disturbances may be harbingers of predisposition and subsequent response to acute and chronic cardiac injury, and identifying the complex interactions of circadian rhythms and myocardial infarction may provide insights into possible preventative and therapeutic strategies for susceptible populations. PMID:25400588

  6. Circadian Organization of Behavior and Physiology in Drosophila

    PubMed Central

    Allada, Ravi; Chung, Brian Y.

    2010-01-01

    Circadian clocks organize behavior and physiology to adapt to daily environmental cycles. Genetic approaches in the fruit fly, Drosophila melanogaster, have revealed widely conserved molecular gears of these 24-h timers. Yet much less is known about how these cell-autonomous clocks confer temporal information to modulate cellular functions. Here we discuss our current knowledge of circadian clock function in Drosophila, providing an overview of the molecular underpinnings of circadian clocks. We then describe the neural network important for circadian rhythms of locomotor activity, including how these molecular clocks might influence neuronal function. Finally, we address a range of behaviors and physiological systems regulated by circadian clocks, including discussion of specific peripheral oscillators and key molecular effectors where they have been described. These studies reveal a remarkable complexity to circadian pathways in this “simple” model organism. PMID:20148690

  7. Quantification of Circadian Rhythms in Single Cells

    PubMed Central

    Westermark, Pål O.; Welsh, David K.; Okamura, Hitoshi; Herzel, Hanspeter

    2009-01-01

    Bioluminescence techniques allow accurate monitoring of the circadian clock in single cells. We have analyzed bioluminescence data of Per gene expression in mouse SCN neurons and fibroblasts. From these data, we extracted parameters such as damping rate and noise intensity using two simple mathematical models, one describing a damped oscillator driven by noise, and one describing a self-sustained noisy oscillator. Both models describe the data well and enabled us to quantitatively characterize both wild-type cells and several mutants. It has been suggested that the circadian clock is self-sustained at the single cell level, but we conclude that present data are not sufficient to determine whether the circadian clock of single SCN neurons and fibroblasts is a damped or a self-sustained oscillator. We show how to settle this question, however, by testing the models' predictions of different phases and amplitudes in response to a periodic entrainment signal (zeitgeber). PMID:19956762

  8. Circadian Behaviour in Neuroglobin Deficient Mice

    PubMed Central

    Hundahl, Christian A.; Fahrenkrug, Jan; Hay-Schmidt, Anders; Georg, Birgitte; Faltoft, Birgitte; Hannibal, Jens

    2012-01-01

    Neuroglobin (Ngb), a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN). The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt) mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1) and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP) and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night. PMID:22496809

  9. Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators.

    PubMed

    Mohawk, Jennifer A; Takahashi, Joseph S

    2011-07-01

    The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of the master circadian pacemaker in mammals. The individual cells of the SCN are capable of functioning independently from one another and therefore must form a cohesive circadian network through intercellular coupling. The network properties of the SCN lead to coordination of circadian rhythms among its neurons and neuronal subpopulations. There is increasing evidence for multiple interconnected oscillators within the SCN, and in this review we will highlight recent advances in our knowledge of the complex organization and function of the cellular and network-level SCN clock. Understanding the way in which synchrony is achieved between cells in the SCN will provide insight into the means by which this important nucleus orchestrates circadian rhythms throughout the organism. PMID:21665298

  10. Cell Autonomy and Synchrony of Suprachiasmatic Nucleus Circadian Oscillators

    PubMed Central

    Mohawk, Jennifer A.; Takahashi, Joseph S.

    2013-01-01

    The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of the master circadian pacemaker in mammals. The individual cells of the SCN are capable of functioning independently from one another and therefore must form a cohesive circadian network through intercellular coupling. The network properties of the SCN lead to coordination of circadian rhythms among its neurons and neuronal subpopulations. There is increasing evidence for multiple interconnected oscillators within the SCN, and in this Review, we will highlight recent advances in our understanding of the complex organization and function of the cellular and network-level SCN clock. Understanding the way in which synchrony is achieved between cells in the SCN will provide insight into the means by which this important nucleus orchestrates circadian rhythms throughout the organism. PMID:21665298

  11. Impaired circadian photosensitivity in mice lacking glutamate transmission from retinal melanopsin cells.

    PubMed

    Gompf, Heinrich S; Fuller, Patrick M; Hattar, Samer; Saper, Clifford B; Lu, Jun

    2015-02-01

    Intrinsically photoreceptive retinal ganglion cells (ipRGCs) contain the photopigment melanopsin and convey retinal light inputs to the circadian system via the retinohypothalamic tract (RHT) projection to the suprachiasmatic nucleus (SCN). The principal neurotransmitter of this projection is glutamate, and ipRGCs use the vesicular glutamate transporter 2 (VGLUT2) to package glutamate into synaptic vesicles. However, these neurons contain other potential neurotransmitters, such as pituitary adenylate cyclase activating polypeptide (PACAP). To test the role of glutamate in mediating ipRGC light inputs into the SCN, we crossed mice in which Cre-recombinase expression is driven by the melanopsin promotor (Opn4(Cre/+)) with mice in which the second exon of VGLUT2 is flanked by loxP sites (VGLUT2(fl/fl)), producing ipRGCs that are unable to package glutamate into synaptic vesicles. Such mice had free-running circadian rhythms that did not entrain to a 12:12 light-dark (12:12 LD) cycle, nor did they show a phase delay after a 45-min light pulse administered at circadian time (CT) 14. A small subset of the mice did appear to entrain to the 12:12 LD cycle with a positive phase angle to lights-off; a similar entrainment pattern could be achieved in free-running mice if they were exposed to a 12:12 LD cycle with light of a greater intensity. Glutamate transmission from the ipRGCs is necessary for normal light entrainment of the SCN at moderate (0.35 W/m(2)) light levels, but residual transmission (possibly by PACAP in ipRGCs or by other RGCs) can weakly entrain animals, particularly at very high (6.53 W/m(2)) light levels, although it may be less effective at suppressing locomotor activity (light masking). PMID:25512304

  12. p38 MAP kinase regulates circadian rhythms in Drosophila.

    PubMed

    Vrailas-Mortimer, Alysia D; Ryan, Sarah M; Avey, Matthew J; Mortimer, Nathan T; Dowse, Harold; Sanyal, Subhabrata

    2014-12-01

    The large repertoire of circadian rhythms in diverse organisms depends on oscillating central clock genes, input pathways for entrainment, and output pathways for controlling rhythmic behaviors. Stress-activated p38 MAP Kinases (p38K), although sparsely investigated in this context, show circadian rhythmicity in mammalian brains and are considered part of the circadian output machinery in Neurospora. We find that Drosophila p38Kb is expressed in clock neurons, and mutants in p38Kb either are arrhythmic or have a longer free-running periodicity, especially as they age. Paradoxically, similar phenotypes are observed through either transgenic inhibition or activation of p38Kb in clock neurons, suggesting a requirement for optimal p38Kb function for normal free-running circadian rhythms. We also find that p38Kb genetically interacts with multiple downstream targets to regulate circadian locomotor rhythms. More specifically, p38Kb interacts with the period gene to regulate period length and the strength of rhythmicity. In addition, we show that p38Kb suppresses the arrhythmic behavior associated with inhibition of a second p38Kb target, the transcription factor Mef2. Finally, we find that manipulating p38K signaling in free-running conditions alters the expression of another downstream target, MNK/Lk6, which has been shown to cycle with the clock and to play a role in regulating circadian rhythms. These data suggest that p38Kb may affect circadian locomotor rhythms through the regulation of multiple downstream pathways. PMID:25403440

  13. Circadian Clocks and Metabolism

    PubMed Central

    Marcheva, Biliana; Ramsey, Kathryn M.; Peek, Clara B.; Affinati, Alison; Maury, Eleonore; Bass, Joseph

    2014-01-01

    Circadian clocks maintain periodicity in internal cycles of behavior, physiology, and metabolism, enabling organisms to anticipate the 24-h rotation of the Earth. In mammals, circadian integration of metabolic systems optimizes energy harvesting and utilization across the light/dark cycle. Disruption of clock genes has recently been linked to sleep disorders and to the development of cardiometabolic disease. Conversely, aberrant nutrient signaling affects circadian rhythms of behavior. This chapter reviews the emerging relationship between the molecular clock and metabolic systems and examines evidence that circadian disruption exerts deleterious consequences on human health. PMID:23604478

  14. A role for Drosophila ATX2 in activation of PER translation and circadian behavior.

    PubMed

    Zhang, Yong; Ling, Jinli; Yuan, Chunyan; Dubruille, Raphaëlle; Emery, Patrick

    2013-05-17

    A negative transcriptional feedback loop generates circadian rhythms in Drosophila. PERIOD (PER) is a critical state-variable in this mechanism, and its abundance is tightly regulated. We found that the Drosophila homolog of ATAXIN-2 (ATX2)--an RNA-binding protein implicated in human neurodegenerative diseases--was required for circadian locomotor behavior. ATX2 was necessary for PER accumulation in circadian pacemaker neurons and thus determined period length of circadian behavior. ATX2 was required for the function of TWENTY-FOUR (TYF), a crucial activator of PER translation. ATX2 formed a complex with TYF and promoted its interaction with polyadenylate-binding protein (PABP). Our work uncovers a role for ATX2 in circadian timing and reveals that this protein functions as an activator of PER translation in circadian neurons. PMID:23687048

  15. The Arabidopsis Circadian System

    PubMed Central

    McClung, C. Robertson; Salomé, Patrice A.; Michael, Todd P.

    2002-01-01

    Rhythms with periods of approximately 24 hr are widespread in nature. Those that persist in constant conditions are termed circadian rhythms and reflect the activity of an endogenous biological clock. Plants, including Arabidopsis, are richly rhythmic. Expression analysis, most recently on a genomic scale, indicates that the Arabidopsis circadian clock regulates a number of key metabolic pathways and stress responses. A number of sensitive and high-throughput assays have been developed to monitor the Arabidopsis clock. These assays have facilitated the identification of components of plant circadian systems through genetic and molecular biological studies. Although much remains to be learned, the framework of the Arabidopsis circadian system is coming into focus. Dedication This review is dedicated to the memory of DeLill Nasser, a wonderful mentor and an unwavering advocate of both Arabidopsis and circadian rhythms research. PMID:22303209

  16. Short circuiting the circadian system with a new generation of precision tools.

    PubMed

    Loh, Dawn H; Kudo, Takashi; Colwell, Christopher S

    2015-03-01

    Circadian behavior in mammals is coordinated by neurons within the suprachiasmatic nucleus (SCN). In this issue, Lee et al. (2015) and Mieda et al. (2015) applied state-of-the-art genetic tools to dissect the microcircuits within the SCN generating circadian rhythmic behavior. PMID:25741718

  17. miR-124 Regulates the Phase of Drosophila Circadian Locomotor Behavior

    PubMed Central

    Lamba, Pallavi; Guo, Peiyi

    2016-01-01

    Animals use circadian rhythms to anticipate daily environmental changes. Circadian clocks have a profound effect on behavior. In Drosophila, for example, brain pacemaker neurons dictate that flies are mostly active at dawn and dusk. miRNAs are small, regulatory RNAs (≈22 nt) that play important roles in posttranscriptional regulation. Here, we identify miR-124 as an important regulator of Drosophila circadian locomotor rhythms. Under constant darkness, flies lacking miR-124 (miR-124KO) have a dramatically advanced circadian behavior phase. However, whereas a phase defect is usually caused by a change in the period of the circadian pacemaker, this is not the case in miR-124KO flies. Moreover, the phase of the circadian pacemaker in the clock neurons that control rhythmic locomotion is not altered either. Therefore, miR-124 modulates the output of circadian clock neurons rather than controlling their molecular pacemaker. Circadian phase is also advanced under temperature cycles, but a light/dark cycle partially corrects the defects in miR-124KO flies. Indeed, miR-124KO shows a normal evening phase under the latter conditions, but morning behavioral activity is suppressed. In summary, miR-124 controls diurnal activity and determines the phase of circadian locomotor behavior without affecting circadian pacemaker function. It thus provides a potent entry point to elucidate the mechanisms by which the phase of circadian behavior is determined. SIGNIFICANCE STATEMENT In animals, molecular circadian clocks control the timing of behavioral activities to optimize them with the day/night cycle. This is critical for their fitness and survival. The mechanisms by which the phase of circadian behaviors is determined downstream of the molecular pacemakers are not yet well understood. Recent studies indicate that miRNAs are important regulators of circadian outputs. We found that miR-124 shapes diurnal behavioral activity and has a striking impact on the phase of circadian

  18. Circadian Timing in the Lung; A Specific Role for Bronchiolar Epithelial Cells

    PubMed Central

    Gibbs, J. E.; Beesley, S.; Plumb, J.; Singh, D.; Farrow, S.; Ray, D. W.; Loudon, A. S. I.

    2015-01-01

    In addition to the core circadian oscillator, located within the suprachiasmatic nucleus, numerous peripheral tissues possess self-sustaining circadian timers. In vivo these are entrained and temporally synchronized by signals conveyed from the core oscillator. In the present study, we examine circadian timing in the lung, determine the cellular localization of core clock proteins in both mouse and human lung tissue, and establish the effects of glucocorticoids (widely used in the treatment of asthma) on the pulmonary clock. Using organotypic lung slices prepared from transgenic mPER2::Luc mice, luciferase levels, which report PER2 expression, were measured over a number of days. We demonstrate a robust circadian rhythm in the mouse lung that is responsive to glucocorticoids. Immunohistochemical techniques were used to localize specific expression of core clock proteins, and the glucocorticoid receptor, to the epithelial cells lining the bronchioles in both mouse and human lung. In the mouse, these were established to be Clara cells. Murine Clara cells retained circadian rhythmicity when grown as a pure population in culture. Furthermore, selective ablation of Clara cells resulted in the loss of circadian rhythm in lung slices, demonstrating the importance of this cell type in maintaining overall pulmonary circadian rhythmicity. In summary, we demonstrate that Clara cells are critical for maintaining coherent circadian oscillations in lung tissue. Their coexpression of the glucocorticoid receptor and core clock components establishes them as a likely interface between humoral suprachiasmatic nucleus output and circadian lung physiology. PMID:18787022

  19. Biophotonics: Circadian photonics

    NASA Astrophysics Data System (ADS)

    Rea, Mark S.

    2011-05-01

    A growing body of medical evidence suggests that disrupting the body's biological clock can have adverse effects on health. Researchers are now creating the photonic tools to monitor, predict and influence the circadian rhythm.

  20. Circadian clocks and breast cancer.

    PubMed

    Blakeman, Victoria; Williams, Jack L; Meng, Qing-Jun; Streuli, Charles H

    2016-01-01

    Circadian clocks respond to environmental time cues to coordinate 24-hour oscillations in almost every tissue of the body. In the breast, circadian clocks regulate the rhythmic expression of numerous genes. Disrupted expression of circadian genes can alter breast biology and may promote cancer. Here we overview circadian mechanisms, and the connection between the molecular clock and breast biology. We describe how disruption of circadian genes contributes to cancer via multiple mechanisms, and link this to increased tumour risk in women who work irregular shift patterns. Understanding the influence of circadian rhythms on breast cancer could lead to more efficacious therapies, reformed public health policy and improved patient outcome. PMID:27590298

  1. Suprachiasmatic nucleus function and circadian entrainment are modulated by G protein-coupled inwardly rectifying (GIRK) channels

    PubMed Central

    Hablitz, L M; Molzof, H E; Paul, J R; Johnson, R L; Gamble, K L

    2014-01-01

    Abstract G protein signalling within the central circadian oscillator, the suprachiasmatic nucleus (SCN), is essential for conveying time-of-day information. We sought to determine whether G protein-coupled inwardly rectifying potassium channels (GIRKs) modulate SCN physiology and circadian behaviour. We show that GIRK current and GIRK2 protein expression are greater during the day. Pharmacological inhibition of GIRKs and genetic loss of GIRK2 depolarized the day-time resting membrane potential of SCN neurons compared to controls. Behaviourally, GIRK2 knockout (KO) mice failed to shorten free running period in response to wheel access in constant darkness and entrained more rapidly to a 6 h advance of a 12 h:12 h light–dark (LD) cycle than wild-type (WT) littermate controls. We next examined whether these effects were due to disrupted signalling of neuropeptide Y (NPY), which is known to mediate non-photic phase shifts, attenuate photic phase shifts and activate GIRKs. Indeed, GIRK2 KO SCN slices had significantly fewer silent cells in response to NPY, likely contributing to the absence of NPY-induced phase advances of PER2::LUC rhythms in organotypic SCN cultures from GIRK2 KO mice. Finally, GIRK channel activation is sufficient to cause a non-photic-like phase advance of PER2::LUC rhythms on a Per2Luc+/− background. These results suggest that rhythmic regulation of GIRK2 protein and channel function in the SCN contributes to day-time resting membrane potential, providing a mechanism for the fine tuning responses to non-photic and photic stimuli. Further investigation could provide insight into disorders with circadian disruption comorbidities such as epilepsy and addiction, in which GIRK channels have been implicated. PMID:25217379

  2. Circadian organization of the mammalian retina: from gene regulation to physiology and diseases.

    PubMed

    McMahon, Douglas G; Iuvone, P Michael; Tosini, Gianluca

    2014-03-01

    The retinal circadian system represents a unique structure. It contains a complete circadian system and thus the retina represents an ideal model to study fundamental questions of how neural circadian systems are organized and what signaling pathways are used to maintain synchrony of the different structures in the system. In addition, several studies have shown that multiple sites within the retina are capable of generating circadian oscillations. The strength of circadian clock gene expression and the emphasis of rhythmic expression are divergent across vertebrate retinas, with photoreceptors as the primary locus of rhythm generation in amphibians, while in mammals clock activity is most robust in the inner nuclear layer. Melatonin and dopamine serve as signaling molecules to entrain circadian rhythms in the retina and also in other ocular structures. Recent studies have also suggested GABA as an important component of the system that regulates retinal circadian rhythms. These transmitter-driven influences on clock molecules apparently reinforce the autonomous transcription-translation cycling of clock genes. The molecular organization of the retinal clock is similar to what has been reported for the SCN although inter-neural communication among retinal neurons that form the circadian network is apparently weaker than those present in the SCN, and it is more sensitive to genetic disruption than the central brain clock. The melatonin-dopamine system is the signaling pathway that allows the retinal circadian clock to reconfigure retinal circuits to enhance light-adapted cone-mediated visual function during the day and dark-adapted rod-mediated visual signaling at night. Additionally, the retinal circadian clock also controls circadian rhythms in disk shedding and phagocytosis, and possibly intraocular pressure. Emerging experimental data also indicate that circadian clock is also implicated in the pathogenesis of eye disease and compelling experimental data

  3. Identification of a circadian output circuit for rest:activity rhythms in Drosophila

    PubMed Central

    Cavanaugh, Daniel J.; Geratowski, Jill D.; Wooltorton, Julian R. A.; Spaethling, Jennifer M.; Hector, Clare E.; Zheng, Xiangzhong; Johnson, Erik C.; Eberwine, James H.; Sehgal, Amita

    2014-01-01

    SUMMARY Though much is known about the cellular and molecular components of the circadian clock, output pathways that couple clock cells to overt behaviors have not been identified. We conducted a screen for circadian-relevant neurons in the Drosophila brain, and report here that cells of the pars intercerebralis (PI), a functional homologue of the mammalian hypothalamus, comprise an important component of the circadian output pathway for rest:activity rhythms. GRASP analysis demonstrates that PI cells are connected to the clock through a polysynaptic circuit extending from pacemaker cells to PI neurons. Molecular profiling of relevant PI cells identified the corticotropin releasing factor (CRF) homologue, DH44, as a circadian output molecule that is specifically expressed by PI neurons and required for normal rest:activity rhythms. Notably, selective activation or ablation of just 6 DH44+ PI cells causes arrhythmicity. These findings delineate a circuit through which clock cells can modulate locomotor rhythms. PMID:24766812

  4. Circadian Rhythms in Cyanobacteria.

    PubMed

    Cohen, Susan E; Golden, Susan S

    2015-12-01

    Life on earth is subject to daily and predictable fluctuations in light intensity, temperature, and humidity created by rotation of the earth. Circadian rhythms, generated by a circadian clock, control temporal programs of cellular physiology to facilitate adaptation to daily environmental changes. Circadian rhythms are nearly ubiquitous and are found in both prokaryotic and eukaryotic organisms. Here we introduce the molecular mechanism of the circadian clock in the model cyanobacterium Synechococcus elongatus PCC 7942. We review the current understanding of the cyanobacterial clock, emphasizing recent work that has generated a more comprehensive understanding of how the circadian oscillator becomes synchronized with the external environment and how information from the oscillator is transmitted to generate rhythms of biological activity. These results have changed how we think about the clock, shifting away from a linear model to one in which the clock is viewed as an interactive network of multifunctional components that are integrated into the context of the cell in order to pace and reset the oscillator. We conclude with a discussion of how this basic timekeeping mechanism differs in other cyanobacterial species and how information gleaned from work in cyanobacteria can be translated to understanding rhythmic phenomena in other prokaryotic systems. PMID:26335718

  5. Socially synchronized circadian oscillators

    PubMed Central

    Bloch, Guy; Herzog, Erik D.; Levine, Joel D.; Schwartz, William J.

    2013-01-01

    Daily rhythms of physiology and behaviour are governed by an endogenous timekeeping mechanism (a circadian ‘clock’). The alternation of environmental light and darkness synchronizes (entrains) these rhythms to the natural day–night cycle, and underlying mechanisms have been investigated using singly housed animals in the laboratory. But, most species ordinarily would not live out their lives in such seclusion; in their natural habitats, they interact with other individuals, and some live in colonies with highly developed social structures requiring temporal synchronization. Social cues may thus be critical to the adaptive function of the circadian system, but elucidating their role and the responsible mechanisms has proven elusive. Here, we highlight three model systems that are now being applied to understanding the biology of socially synchronized circadian oscillators: the fruitfly, with its powerful array of molecular genetic tools; the honeybee, with its complex natural society and clear division of labour; and, at a different level of biological organization, the rodent suprachiasmatic nucleus, site of the brain's circadian clock, with its network of mutually coupled single-cell oscillators. Analyses at the ‘group’ level of circadian organization will likely generate a more complex, but ultimately more comprehensive, view of clocks and rhythms and their contribution to fitness in nature. PMID:23825203

  6. CCL2 mediates the circadian response to low dose endotoxin.

    PubMed

    Duhart, José M; Brocardo, Lucila; Mul Fedele, Malena L; Guglielmotti, Angelo; Golombek, Diego A

    2016-09-01

    The mammalian circadian system is mainly originated in a master oscillator located in the suprachiasmatic nuclei (SCN) in the hypothalamus. Previous reports from our and other groups have shown that the SCN are sensitive to systemic immune activation during the early night, through a mechanism that relies on the action of proinflammatory factors within this structure. Chemokine (C-C motif) ligand 2 (CCL2) is induced in the brain upon peripheral immune activation, and it has been shown to modulate neuronal physiology. In the present work we tested whether CCL2 might be involved in the response of the circadian clock to peripheral endotoxin administration. The CCL2 receptor, C-C chemokine receptor type 2 (CCR2), was detected in the SCN of mice, with higher levels of expression during the early night, when the clock is sensitive to immune activation. Ccl2 was induced in the SCN upon intraperitoneal lipopolysaccharide (LPS) administration. Furthermore, mice receiving an intracerebroventricular (Icv) administration of a CCL2 synthesis inhibitor (Bindarit), showed a reduction LPS-induced circadian phase changes and Icv delivery of CCL2 led to phase delays in the circadian clock. In addition, we tested the possibility that CCL2 might also be involved in the photic regulation of the clock. Icv administration of Bindarit did not modify the effects of light pulses on the circadian clock. In summary, we found that CCL2, acting at the SCN level is important for the circadian effects of immune activation. PMID:27178133

  7. Circadian regulation of slow waves in human sleep: Topographical aspects

    PubMed Central

    Lazar, Alpar S.; Lazar, Zsolt I.; Dijk, Derk-Jan

    2015-01-01

    Slow waves (SWs, 0.5–4 Hz) in field potentials during sleep reflect synchronized alternations between bursts of action potentials and periods of membrane hyperpolarization of cortical neurons. SWs decline during sleep and this is thought to be related to a reduction of synaptic strength in cortical networks and to be central to sleep's role in maintaining brain function. A central assumption in current concepts of sleep function is that SWs during sleep, and associated recovery processes, are independent of circadian rhythmicity. We tested this hypothesis by quantifying all SWs from 12 EEG derivations in 34 participants in whom 231 sleep periods were scheduled across the circadian cycle in a 10-day forced-desynchrony protocol which allowed estimation of the separate circadian and sleep-dependent modulation of SWs. Circadian rhythmicity significantly modulated the incidence, amplitude, frequency and the slope of the SWs such that the peaks of the circadian rhythms in these slow-wave parameters were located during the biological day. Topographical analyses demonstrated that the sleep-dependent modulation of SW characteristics was most prominent in frontal brain areas whereas the circadian effect was similar to or greater than the sleep-dependent modulation over the central and posterior brain regions. The data demonstrate that circadian rhythmicity directly modulates characteristics of SWs thought to be related to synaptic plasticity and that this modulation depends on topography. These findings have implications for the understanding of local sleep regulation and conditions such as ageing, depression, and neurodegeneration which are associated with changes in SWs, neural plasticity and circadian rhythmicity. PMID:25979664

  8. Circadian regulation of slow waves in human sleep: Topographical aspects.

    PubMed

    Lazar, Alpar S; Lazar, Zsolt I; Dijk, Derk-Jan

    2015-08-01

    Slow waves (SWs, 0.5-4Hz) in field potentials during sleep reflect synchronized alternations between bursts of action potentials and periods of membrane hyperpolarization of cortical neurons. SWs decline during sleep and this is thought to be related to a reduction of synaptic strength in cortical networks and to be central to sleep's role in maintaining brain function. A central assumption in current concepts of sleep function is that SWs during sleep, and associated recovery processes, are independent of circadian rhythmicity. We tested this hypothesis by quantifying all SWs from 12 EEG derivations in 34 participants in whom 231 sleep periods were scheduled across the circadian cycle in a 10-day forced-desynchrony protocol which allowed estimation of the separate circadian and sleep-dependent modulation of SWs. Circadian rhythmicity significantly modulated the incidence, amplitude, frequency and the slope of the SWs such that the peaks of the circadian rhythms in these slow-wave parameters were located during the biological day. Topographical analyses demonstrated that the sleep-dependent modulation of SW characteristics was most prominent in frontal brain areas whereas the circadian effect was similar to or greater than the sleep-dependent modulation over the central and posterior brain regions. The data demonstrate that circadian rhythmicity directly modulates characteristics of SWs thought to be related to synaptic plasticity and that this modulation depends on topography. These findings have implications for the understanding of local sleep regulation and conditions such as ageing, depression, and neurodegeneration which are associated with changes in SWs, neural plasticity and circadian rhythmicity. PMID:25979664

  9. Circadian Rhythm Sleep Disorders

    PubMed Central

    Kim, Min Ju; Lee, Jung Hie; Duffy, Jeanne F.

    2014-01-01

    Objective To review circadian rhythm sleep disorders, including underlying causes, diagnostic considerations, and typical treatments. Methods Literature review and discussion of specific cases. Results Survey studies 1,2 suggest that up to 3% of the adult population suffers from a circadian rhythm sleep disorder (CRSD). However, these sleep disorders are often confused with insomnia, and an estimated 10% of adult and 16% of adolescent sleep disorders patients may have a CRSD 3-6. While some CRSD (such as jet lag) can be self-limiting, others when untreated can lead to adverse medical, psychological, and social consequences. The International Classification of Sleep Disorders classifies CRSD as dyssomnias, with six subtypes: Advanced Sleep Phase Type, Delayed Sleep Phase Type, Irregular Sleep Wake Type, Free Running Type, Jet Lag Type, and Shift Work Type. The primary clinical characteristic of all CRSD is an inability to fall asleep and wake at the desired time. It is believed that CRSD arise from a problem with the internal biological clock (circadian timing system) and/or misalignment between the circadian timing system and the external 24-hour environment. This misalignment can be the result of biological and/or behavioral factors. CRSD can be confused with other sleep or medical disorders. Conclusions Circadian rhythm sleep disorders are a distinct class of sleep disorders characterized by a mismatch between the desired timing of sleep and the ability to fall asleep and remain asleep. If untreated, CRSD can lead to insomnia and excessive daytime sleepiness, with negative medical, psychological, and social consequences. It is important for physicians to recognize potential circadian rhythm sleep disorders so that appropriate diagnosis, treatment, and referral can be made. PMID:25368503

  10. Circadian Disruption in Psychiatric Disorders.

    PubMed

    Jones, Stephanie G; Benca, Ruth M

    2015-12-01

    Evidence suggests that abnormalities in circadian rhythms might prove causally or pathophysiologically significant in psychiatric illness. The circadian regulation of hormonal and behavioral timekeeping processes is often altered in patients with major depression, bipolar disorder, and schizophrenia, and a susceptibility to rhythm instability may contribute to the functional impairment. For some patients, interventions that stabilize or resynchronize circadian rhythms prove therapeutically effective. Circadian disruption in the clinical profiles of most psychiatric illnesses and the treatment efficacy of chronobiological interventions suggest that attention to circadian phenotypes in a range of psychiatric disorders may help to uncover shared pathophysiologic mechanisms. PMID:26568124

  11. Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities

    PubMed Central

    Altimus, C.M.; Güler, A.D.; Alam, N.M.; Arman, A.C.; Prusky, G.T.; Sampath, A.P.; Hattar, S

    2010-01-01

    In mammals, synchronization of the circadian pacemaker in the hypothalamus is achieved through direct input from the eyes conveyed by intrinsically photosensitive retinal ganglion cells (ipRGCs). Circadian photoentrainment can be maintained by rod and cone photoreceptors, but their functional contributions and their retinal circuits that impinge on ipRGCs are not well understood. We demonstrate in genetic mouse models lacking functional rods, or where rods are the only functional photoreceptors, that rods are solely responsible for photoentrainment at scotopic light intensities. Surprisingly, rods were also capable of driving circadian photoentrainment at photopic intensities where they were incapable of supporting a visually–guided behavior. Using animals in which cone photoreceptors were ablated, we demonstrate that rods signal through cones at high light intensities, but not low light intensities. Thus two distinct retinal circuits drive ipRGC function to support circadian photoentrainment across a wide range of light intensities. PMID:20711184

  12. Circadian Clocks, Stress, and Immunity

    PubMed Central

    Dumbell, Rebecca; Matveeva, Olga; Oster, Henrik

    2016-01-01

    In mammals, molecular circadian clocks are present in most cells of the body, and this circadian network plays an important role in synchronizing physiological processes and behaviors to the appropriate time of day. The hypothalamic–pituitary–adrenal endocrine axis regulates the response to acute and chronic stress, acting through its final effectors – glucocorticoids – released from the adrenal cortex. Glucocorticoid secretion, characterized by its circadian rhythm, has an important role in synchronizing peripheral clocks and rhythms downstream of the master circadian pacemaker in the suprachiasmatic nucleus. Finally, glucocorticoids are powerfully anti-inflammatory, and recent work has implicated the circadian clock in various aspects and cells of the immune system, suggesting a tight interplay of stress and circadian systems in the regulation of immunity. This mini-review summarizes our current understanding of the role of the circadian clock network in both the HPA axis and the immune system, and discusses their interactions. PMID:27199894

  13. Synchronization-Induced Rhythmicity of Circadian Oscillators in the Suprachiasmatic Nucleus

    PubMed Central

    Bernard, Samuel; Gonze, Didier; Čajavec, Branka; Herzel, Hanspeter; Kramer, Achim

    2007-01-01

    The suprachiasmatic nuclei (SCN) host a robust, self-sustained circadian pacemaker that coordinates physiological rhythms with the daily changes in the environment. Neuronal clocks within the SCN form a heterogeneous network that must synchronize to maintain timekeeping activity. Coherent circadian output of the SCN tissue is established by intercellular signaling factors, such as vasointestinal polypeptide. It was recently shown that besides coordinating cells, the synchronization factors play a crucial role in the sustenance of intrinsic cellular rhythmicity. Disruption of intercellular signaling abolishes sustained rhythmicity in a majority of neurons and desynchronizes the remaining rhythmic neurons. Based on these observations, the authors propose a model for the synchronization of circadian oscillators that combines intracellular and intercellular dynamics at the single-cell level. The model is a heterogeneous network of circadian neuronal oscillators where individual oscillators are damped rather than self-sustained. The authors simulated different experimental conditions and found that: (1) in normal, constant conditions, coupled circadian oscillators quickly synchronize and produce a coherent output; (2) in large populations, such oscillators either synchronize or gradually lose rhythmicity, but do not run out of phase, demonstrating that rhythmicity and synchrony are codependent; (3) the number of oscillators and connectivity are important for these synchronization properties; (4) slow oscillators have a higher impact on the period in mixed populations; and (5) coupled circadian oscillators can be efficiently entrained by light–dark cycles. Based on these results, it is predicted that: (1) a majority of SCN neurons needs periodic synchronization signal to be rhythmic; (2) a small number of neurons or a low connectivity results in desynchrony; and (3) amplitudes and phases of neurons are negatively correlated. The authors conclude that to understand the

  14. Flexible Conveyance Control System for Agile Manufacturing

    NASA Astrophysics Data System (ADS)

    Uchiyama, Kazuhisa; Uchimura, Keiichi; Yoshikawa, Takeru; Shishino, Satoru; Hu, Zhencheng

    The control of conveyance between processes still relies on the engineer's experience. It is difficult to correspond to the change in the conveyance layout due to the expansion and reduction of production and the breakdown of conveyance devices. In this paper, we propose a conveyance control system that can adapt to changes in the conveyance layout and we aim at the improvement of the amount of total conveyance. First of all, the system is divided into the part where the conveyance layout is made a data base and the part where the conveyance control that uses the congestion index is done. Therefore, it is possible to deal flexibly by changing the data base part without changing the conveyance control part when it is necessary to change the conveyance layout suddenly. In all the combinations of the conveyance layout and the turning on pattern used as a result of the simulation, the proposed conveyance control method became a great result by the amount of total conveyance.

  15. Circadian clock system in the pineal gland.

    PubMed

    Fukada, Yoshitaka; Okano, Toshiyuki

    2002-02-01

    The pineal gland is a neuroendocrine organ that functions as a central circadian oscillator in a variety of nonmammalian vertebrates. In many cases, the pineal gland retains photic input and endocrinal-output pathways both linked tightly to the oscillator. This contrasts well with the mammalian pineal gland equipped only with the output of melatonin production that is subject to neuronal regulation by central circadian oscillator located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Molecular studies on animal clock genes were performed first in Drosophila and later developed in rodents. More recently, clock genes such as Per, Cry, Clock, and Bmal have been found in a variety of vertebrate clock structures including the avian pineal gland. The profiles of the temporal change of the clock gene expression in the avian pineal gland are more similar to those in the mammalian SCN rather than to those in the mammalian pineal gland. Avian pineal gland and mammalian SCN seem to share a fundamental molecular framework of the clock oscillator composed of a transcription/translation-based autoregulatory feedback loop. The circadian time-keeping mechanism also requires several post-translational events, such as protein translocation and degradation processes, in which protein phosphorylation plays a very important role for the stable 24-h cycling of the oscillator and/or the photic-input pathway for entrainment of the clock. PMID:11890455

  16. Biological Clocks & Circadian Rhythms

    ERIC Educational Resources Information Center

    Robertson, Laura; Jones, M. Gail

    2009-01-01

    The study of biological clocks and circadian rhythms is an excellent way to address the inquiry strand in the National Science Education Standards (NSES) (NRC 1996). Students can study these everyday phenomena by designing experiments, gathering and analyzing data, and generating new experiments. As students explore biological clocks and circadian…

  17. Acute Suppressive and Long-Term Phase Modulation Actions of Orexin on the Mammalian Circadian Clock

    PubMed Central

    Belle, Mino D.C.; Hughes, Alun T.L.; Bechtold, David A.; Cunningham, Peter; Pierucci, Massimo; Burdakov, Denis

    2014-01-01

    Circadian and homeostatic neural circuits organize the temporal architecture of physiology and behavior, but knowledge of their interactions is imperfect. For example, neurons containing the neuropeptide orexin homeostatically control arousal and appetitive states, while neurons in the suprachiasmatic nuclei (SCN) function as the brain's master circadian clock. The SCN regulates orexin neurons so that they are much more active during the circadian night than the circadian day, but it is unclear whether the orexin neurons reciprocally regulate the SCN clock. Here we show both orexinergic innervation and expression of genes encoding orexin receptors (OX1 and OX2) in the mouse SCN, with OX1 being upregulated at dusk. Remarkably, we find through in vitro physiological recordings that orexin predominantly suppresses mouse SCN Period1 (Per1)-EGFP-expressing clock cells. The mechanisms underpinning these suppressions vary across the circadian cycle, from presynaptic modulation of inhibitory GABAergic signaling during the day to directly activating leak K+ currents at night. Orexin also augments the SCN clock-resetting effects of neuropeptide Y (NPY), another neurochemical correlate of arousal, and potentiates NPY's inhibition of SCN Per1-EGFP cells. These results build on emerging literature that challenge the widely held view that orexin signaling is exclusively excitatory and suggest new mechanisms for avoiding conflicts between circadian clock signals and homeostatic cues in the brain. PMID:24599460

  18. 36 CFR 17.8 - Conveyance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... less than fair market value. All conveyance of leasehold or freehold interests shall contain such terms... protect the natural, historic, cultural or other values present on the lands. All conveyances shall...

  19. 36 CFR 17.8 - Conveyance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... less than fair market value. All conveyance of leasehold or freehold interests shall contain such terms... protect the natural, historic, cultural or other values present on the lands. All conveyances shall...

  20. PDF receptor signaling in Drosophila contributes to both circadian and geotactic behaviors.

    PubMed

    Mertens, Inge; Vandingenen, Anick; Johnson, Erik C; Shafer, Orie T; Li, W; Trigg, J S; De Loof, Arnold; Schoofs, Liliane; Taghert, Paul H

    2005-10-20

    The neuropeptide Pigment-Dispersing Factor (PDF) is a principle transmitter regulating circadian locomotor rhythms in Drosophila. We have identified a Class II (secretin-related) G protein-coupled receptor (GPCR) that is specifically responsive to PDF and also to calcitonin-like peptides and to PACAP. In response to PDF, the PDF receptor (PDFR) elevates cAMP levels when expressed in HEK293 cells. As predicted by in vivo studies, cotransfection of Neurofibromatosis Factor 1 significantly improves coupling of PDFR to adenylate cyclase. pdfr mutant flies display increased circadian arrhythmicity, and also display altered geotaxis that is epistatic to that of pdf mutants. PDFR immunosignals are expressed by diverse neurons, but only by a small subset of circadian pacemakers. These data establish the first synapse within the Drosophila circadian neural circuit and underscore the importance of Class II peptide GPCR signaling in circadian neural systems. PMID:16242402

  1. 36 CFR 254.24 - Conveyance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 2 2010-07-01 2010-07-01 false Conveyance. 254.24 Section 254.24 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LANDOWNERSHIP ADJUSTMENTS National Forest Townsites § 254.24 Conveyance. (a) Conveyance of the approved tract(s) may be...

  2. 36 CFR 254.24 - Conveyance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 36 Parks, Forests, and Public Property 2 2013-07-01 2013-07-01 false Conveyance. 254.24 Section 254.24 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LANDOWNERSHIP ADJUSTMENTS National Forest Townsites § 254.24 Conveyance. (a) Conveyance of the approved tract(s) may be...

  3. 36 CFR 254.24 - Conveyance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 2 2011-07-01 2011-07-01 false Conveyance. 254.24 Section 254.24 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LANDOWNERSHIP ADJUSTMENTS National Forest Townsites § 254.24 Conveyance. (a) Conveyance of the approved tract(s) may be...

  4. 36 CFR 254.24 - Conveyance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 36 Parks, Forests, and Public Property 2 2012-07-01 2012-07-01 false Conveyance. 254.24 Section 254.24 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LANDOWNERSHIP ADJUSTMENTS National Forest Townsites § 254.24 Conveyance. (a) Conveyance of the approved tract(s) may be...

  5. 36 CFR 254.24 - Conveyance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 36 Parks, Forests, and Public Property 2 2014-07-01 2014-07-01 false Conveyance. 254.24 Section 254.24 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LANDOWNERSHIP ADJUSTMENTS National Forest Townsites § 254.24 Conveyance. (a) Conveyance of the approved tract(s) may be...

  6. 50 CFR 14.107 - Conveyance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... and Birds to the United States § 14.107 Conveyance. (a) The animal cargo space of a conveyance used to transport wild mammals or birds to the United States shall be designed, constructed, and maintained so as to.... (c) No wild mammal or bird shall be placed in a cargo space of a conveyance that does not...

  7. 50 CFR 14.107 - Conveyance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... and Birds to the United States § 14.107 Conveyance. (a) The animal cargo space of a conveyance used to transport wild mammals or birds to the United States shall be designed, constructed, and maintained so as to.... (c) No wild mammal or bird shall be placed in a cargo space of a conveyance that does not...

  8. 47 CFR 13.8 - Authority conveyed.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 1 2010-10-01 2010-10-01 false Authority conveyed. 13.8 Section 13.8 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL COMMERCIAL RADIO OPERATORS General § 13.8 Authority conveyed. Licenses, certificates and permits issued under this part convey authority for the...

  9. Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination.

    PubMed

    Malik, Astha; Kondratov, Roman V; Jamasbi, Roudabeh J; Geusz, Michael E

    2015-01-01

    Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ). Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte proliferation during

  10. Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination

    PubMed Central

    Kondratov, Roman V.; Jamasbi, Roudabeh J.

    2015-01-01

    Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ). Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte proliferation during

  11. How coupling determines the entrainment of circadian clocks

    NASA Astrophysics Data System (ADS)

    Bordyugov, G.; Granada, A. E.; Herzel, H.

    2011-08-01

    Autonomous circadian clocks drive daily rhythms in physiology and behaviour. A network of coupled neurons, the suprachiasmatic nucleus (SCN), serves as a robust self-sustained circadian pacemaker. Synchronization of this timer to the environmental light-dark cycle is crucial for an organism's fitness. In a recent theoretical and experimental study it was shown that coupling governs the entrainment range of circadian clocks. We apply the theory of coupled oscillators to analyse how diffusive and mean-field coupling affects the entrainment range of interacting cells. Mean-field coupling leads to amplitude expansion of weak oscillators and, as a result, reduces the entrainment range. We also show that coupling determines the rigidity of the synchronized SCN network, i.e. the relaxation rates upon perturbation. Our simulations and analytical calculations using generic oscillator models help to elucidate how coupling determines the entrainment of the SCN. Our theoretical framework helps to interpret experimental data.

  12. Circadian clocks and cell division

    PubMed Central

    2010-01-01

    Evolution has selected a system of two intertwined cell cycles: the cell division cycle (CDC) and the daily (circadian) biological clock. The circadian clock keeps track of solar time and programs biological processes to occur at environmentally appropriate times. One of these processes is the CDC, which is often gated by the circadian clock. The intermeshing of these two cell cycles is probably responsible for the observation that disruption of the circadian system enhances susceptibility to some kinds of cancer. The core mechanism underlying the circadian clockwork has been thought to be a transcription and translation feedback loop (TTFL), but recent evidence from studies with cyanobacteria, synthetic oscillators and immortalized cell lines suggests that the core circadian pacemaking mechanism that gates cell division in mammalian cells could be a post-translational oscillator (PTO). PMID:20890114

  13. NPAS2 Compensates for Loss of CLOCK in Peripheral Circadian Oscillators

    PubMed Central

    Landgraf, Dominic; Wang, Lexie L.; Diemer, Tanja; Welsh, David K.

    2016-01-01

    Heterodimers of CLOCK and BMAL1 are the major transcriptional activators of the mammalian circadian clock. Because the paralog NPAS2 can substitute for CLOCK in the suprachiasmatic nucleus (SCN), the master circadian pacemaker, CLOCK-deficient mice maintain circadian rhythms in behavior and in tissues in vivo. However, when isolated from the SCN, CLOCK-deficient peripheral tissues are reportedly arrhythmic, suggesting a fundamental difference in circadian clock function between SCN and peripheral tissues. Surprisingly, however, using luminometry and single-cell bioluminescence imaging of PER2 expression, we now find that CLOCK-deficient dispersed SCN neurons and peripheral cells exhibit similarly stable, autonomous circadian rhythms in vitro. In CLOCK-deficient fibroblasts, knockdown of Npas2 leads to arrhythmicity, suggesting that NPAS2 can compensate for loss of CLOCK in peripheral cells as well as in SCN. Our data overturn the notion of an SCN-specific role for NPAS2 in the molecular circadian clock, and instead indicate that, at the cellular level, the core loops of SCN neuron and peripheral cell circadian clocks are fundamentally similar. PMID:26895328

  14. Ube3a Imprinting Impairs Circadian Robustness in Angelman Syndrome Models

    PubMed Central

    Shi, Shu-qun; Bichell, Terry Jo; Ihrie, Rebecca A.; Johnson, Carl Hirschie

    2015-01-01

    Summary Background The paternal allele of Ube3a is silenced by imprinting in neurons, and Angelman Syndrome (AS) is a disorder arising from a deletion or mutation of the maternal Ube3a allele, which thereby eliminates Ube3a neuronal expression. Sleep disorders such as short sleep duration and increased sleep onset latency are very common in AS. Results We found an unique link between neuronal imprinting of Ube3a and circadian rhythms in two mouse models of AS, including enfeebled circadian activity behavior and slowed molecular rhythms in ex vivo brain tissues. As a consequence of compromised circadian behavior, metabolic homeostasis is also disrupted in AS mice. Unsilencing the paternal Ube3a allele restores functional circadian periodicity in neurons deficient in maternal Ube3a, but does not affect periodicity in peripheral tissues that are not imprinted for uniparental Ube3a expression. The ubiquitin ligase encoded by Ube3a interacts with the central clock components BMAL1 and BMAL2. Moreover, inactivation of Ube3a expression elevates BMAL1 levels in brain regions that control circadian behavior of AS model mice, indicating an important role for Ube3a in modulating BMAL1 turnover. Conclusions Ube3a expression constitutes a direct mechanistic connection between symptoms of a human neurological disorder and the central circadian clock mechanism. The lengthened circadian period leads to delayed phase, which could explain the short sleep duration and increased sleep onset latency of AS subjects. Moreover, we report the pharmacological rescue of an AS phenotype, in this case, altered circadian period. These findings reveal potential treatments for sleep disorders in AS patients. PMID:25660546

  15. Circadian Regulation of Synaptic Plasticity.

    PubMed

    Frank, Marcos G

    2016-01-01

    Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity. PMID:27420105

  16. CIRCADIAN REGULATION OF METABOLISM

    PubMed Central

    Bailey, Shannon M.; Udoh, Uduak S.; Young, Martin E.

    2014-01-01

    In association with sleep/wake and fasting/feeding cycles, organisms experience dramatic oscillations in energetic demands and nutrient supply. It is therefore not surprising that various metabolic parameters, ranging from the activity status of molecular energy sensors to circulating nutrient levels, oscillate in time-of-day-dependent manners. It has become increasingly clear that rhythms in metabolic processes are not simply in response to daily environmental/behavioral influences, but are driven in part by cell autonomous circadian clocks. By synchronizing the cell with its environment, clocks modulate a host of metabolic processes in a temporally appropriate manner. The purpose of this article is to review current understanding of the interplay between circadian clocks and metabolism, in addition to the pathophysiologic consequences of disruption of this molecular mechanism, in terms of cardiometabolic disease development. PMID:24928941

  17. Sleep and circadian rhythms

    NASA Technical Reports Server (NTRS)

    Monk, Timothy H.

    1991-01-01

    Three interacting processes are involved in the preservation of circadian rhythms: (1) endogenous rhythm generation mechanisms, (2) entrainment mechanisms to keep these rhythms 'on track', and (3) exogenous masking processes stemming from changes in environment and bahavior. These processes, particularly the latter two, can be dramatically affected in individuals of advanced age and in space travelers, with a consequent disruption in sleep and daytime functioning. This paper presents results of a phase-shift experiment investigating the age-related effects of the exogeneous component of circadian rhythms in various physiological and psychological functions by comparing these functions in middle aged and old subjects. Dramatic differences were found between the two age groups in measures of sleep, mood, activation, and performance efficiency.

  18. Postoperative circadian disturbances.

    PubMed

    Gögenur, Ismail

    2010-12-01

    An increasing number of studies have shown that circadian variation in the excretion of hormones, the sleep wake circle, the core body temperature rhythm, the tone of the autonomic nervous system and the activity rhythm are important both in health and in disease processes. An increasing attention has also been directed towards the circadian variation in endogenous rhythms in relation to surgery. The attention has been directed to the question whether the circadian variation in endogenous rhythms can affect postoperative recovery, morbidity and mortality. Based on the lack of studies where these endogenous rhythms have been investigated in relation to surgery we performed a series of studies exploring different endogenous rhythms and factors affecting these rhythms. We also wanted to examine whether the disturbances in the postoperative circadian rhythms could be correlated to postoperative recovery parameters, and if pharmacological administration of chronobiotics could improve postoperative recovery. Circadian rhythm disturbances were found in all the examined endogenous rhythms. A delay was found in the endogenous rhythm of plasma melatonin and excretion of the metabolite of melatonin (AMT6s) in urine the first night after both minor and major surgery. This delay after major surgery was correlated to the duration of surgery. The amplitude in the melatonin rhythm was unchanged the first night but increased in the second night after major surgery. The amplitude in AMT6s was reduced the first night after minimally invasive surgery. The core body temperature rhythm was disturbed after both major and minor surgery. There was a change in the sleep wake cycle with a significantly increased duration of REM-sleep in the day and evening time after major surgery compared with preoperatively. There was also a shift in the autonomic nervous balance after major surgery with a significantly increased number of myocardial ischaemic episodes during the nighttime period. The

  19. Sensitivity and integration in a visual pathway for circadian entrainment in the hamster (Mesocricetus auratus).

    PubMed Central

    Nelson, D E; Takahashi, J S

    1991-01-01

    1. Light-induced phase shifts of the circadian rhythm of wheel-running activity were used to measure the photic sensitivity of a circadian pacemaker and the visual pathway that conveys light information to it in the golden hamster (Mesocricetus auratus). The sensitivity to stimulus irradiance and duration was assessed by measuring the magnitude of phase-shift responses to photic stimuli of different irradiance and duration. The visual sensitivity was also measured at three different phases of the circadian rhythm. 2. The stimulus-response curves measured at different circadian phases suggest that the maximum phase-shift is the only aspect of visual responsivity to change as a function of the circadian day. The half-saturation constants (sigma) for the stimulus-response curves are not significantly different over the three circadian phases tested. The photic sensitivity to irradiance (1/sigma) appears to remain constant over the circadian day. 3. The hamster circadian pacemaker and the photoreceptive system that subserves it are more sensitive to the irradiance of longer-duration stimuli than to irradiance of briefer stimuli. The system is maximally sensitive to the irradiance of stimuli of 300 s and longer in duration. A quantitative model is presented to explain the changes that occur in the stimulus-response curves as a function of photic stimulus duration. 4. The threshold for photic stimulation of the hamster circadian pacemaker is also quite high. The threshold irradiance (the minimum irradiance necessary to induce statistically significant responses) is approximately 10(11) photons cm-2 s-1 for optimal stimulus durations. This threshold is equivalent to a luminance at the cornea of 0.1 cd m-2. 5. We also measured the sensitivity of this visual pathway to the total number of photons in a stimulus. This system is maximally sensitive to photons in stimuli between 30 and 3600 s in duration. The maximum quantum efficiency of photic integration occurs in 300 s

  20. Circadian gene variants in cancer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostas...

  1. Circadian Disorganization Alters Intestinal Microbiota

    PubMed Central

    Voigt, Robin M.; Forsyth, Christopher B.; Green, Stefan J.; Mutlu, Ece; Engen, Phillip; Vitaterna, Martha H.; Turek, Fred W.; Keshavarzian, Ali

    2014-01-01

    Intestinal dysbiosis and circadian rhythm disruption are associated with similar diseases including obesity, metabolic syndrome, and inflammatory bowel disease. Despite the overlap, the potential relationship between circadian disorganization and dysbiosis is unknown; thus, in the present study, a model of chronic circadian disruption was used to determine the impact on the intestinal microbiome. Male C57BL/6J mice underwent once weekly phase reversals of the light:dark cycle (i.e., circadian rhythm disrupted mice) to determine the impact of circadian rhythm disruption on the intestinal microbiome and were fed either standard chow or a high-fat, high-sugar diet to determine how diet influences circadian disruption-induced effects on the microbiome. Weekly phase reversals of the light:dark (LD) cycle did not alter the microbiome in mice fed standard chow; however, mice fed a high-fat, high-sugar diet in conjunction with phase shifts in the light:dark cycle had significantly altered microbiota. While it is yet to be established if some of the adverse effects associated with circadian disorganization in humans (e.g., shift workers, travelers moving across time zones, and in individuals with social jet lag) are mediated by dysbiosis, the current study demonstrates that circadian disorganization can impact the intestinal microbiota which may have implications for inflammatory diseases. PMID:24848969

  2. The ROP vesicle release factor is required in adult Drosophila glia for normal circadian behavior

    PubMed Central

    Ng, Fanny S.; Jackson, F. Rob

    2015-01-01

    We previously showed that endocytosis and/or vesicle recycling mechanisms are essential in adult Drosophila glial cells for the neuronal control of circadian locomotor activity. In this study, our goal was to identify specific glial vesicle trafficking, recycling, or release factors that are required for rhythmic behavior. From a glia-specific, RNAi-based genetic screen, we identified eight glial factors that are required for normally robust circadian rhythms in either a light-dark cycle or in constant dark conditions. In particular, we show that conditional knockdown of the ROP vesicle release factor in adult glial cells results in arrhythmic behavior. Immunostaining for ROP reveals reduced protein in glial cell processes and an accumulation of the Par Domain Protein 1ε (PDP1ε) clock output protein in the small lateral clock neurons. These results suggest that glia modulate rhythmic circadian behavior by secretion of factors that act on clock neurons to regulate a clock output factor. PMID:26190976

  3. Drosophila spaghetti and doubletime link the circadian clock and light to caspases, apoptosis and tauopathy.

    PubMed

    Means, John C; Venkatesan, Anandakrishnan; Gerdes, Bryan; Fan, Jin-Yuan; Bjes, Edward S; Price, Jeffrey L

    2015-05-01

    While circadian dysfunction and neurodegeneration are correlated, the mechanism for this is not understood. It is not known if age-dependent circadian dysfunction leads to neurodegeneration or vice-versa, and the proteins that mediate the effect remain unidentified. Here, we show that the knock-down of a regulator (spag) of the circadian kinase Dbt in circadian cells lowers Dbt levels abnormally, lengthens circadian rhythms and causes expression of activated initiator caspase (Dronc) in the optic lobes during the middle of the day or after light pulses at night. Likewise, reduced Dbt activity lengthens circadian period and causes expression of activated Dronc, and a loss-of-function mutation in Clk also leads to expression of activated Dronc in a light-dependent manner. Genetic epistasis experiments place Dbt downstream of Spag in the pathway, and Spag-dependent reductions of Dbt are shown to require the proteasome. Importantly, activated Dronc expression due to reduced Spag or Dbt activity occurs in cells that do not express the spag RNAi or dominant negative Dbt and requires PDF neuropeptide signaling from the same neurons that support behavioral rhythms. Furthermore, reduction of Dbt or Spag activity leads to Dronc-dependent Drosophila Tau cleavage and enhanced neurodegeneration produced by human Tau in a fly eye model for tauopathy. Aging flies with lowered Dbt or Spag function show markers of cell death as well as behavioral deficits and shortened lifespans, and even old wild type flies exhibit Dbt modification and activated caspase at particular times of day. These results suggest that Dbt suppresses expression of activated Dronc to prevent Tau cleavage, and that the circadian clock defects confer sensitivity to expression of activated Dronc in response to prolonged light. They establish a link between the circadian clock factors, light, cell death pathways and Tau toxicity, potentially via dysregulation of circadian neuronal remodeling in the optic lobes

  4. Visualizing and Quantifying Intracellular Behavior and Abundance of the Core Circadian Clock Protein PERIOD2.

    PubMed

    Smyllie, Nicola J; Pilorz, Violetta; Boyd, James; Meng, Qing-Jun; Saer, Ben; Chesham, Johanna E; Maywood, Elizabeth S; Krogager, Toke P; Spiller, David G; Boot-Handford, Raymond; White, Michael R H; Hastings, Michael H; Loudon, Andrew S I

    2016-07-25

    Transcriptional-translational feedback loops (TTFLs) are a conserved molecular motif of circadian clocks. The principal clock in mammals is the suprachiasmatic nucleus (SCN) of the hypothalamus. In SCN neurons, auto-regulatory feedback on core clock genes Period (Per) and Cryptochrome (Cry) following nuclear entry of their protein products is the basis of circadian oscillation [1, 2]. In Drosophila clock neurons, the movement of dPer into the nucleus is subject to a circadian gate that generates a delay in the TTFL, and this delay is thought to be critical for oscillation [3, 4]. Analysis of the Drosophila clock has strongly influenced models of the mammalian clock, and such models typically infer complex spatiotemporal, intracellular behaviors of mammalian clock proteins. There are, however, no direct measures of the intracellular behavior of endogenous circadian proteins to support this: dynamic analyses have been limited and often have no circadian dimension [5-7]. We therefore generated a knockin mouse expressing a fluorescent fusion of native PER2 protein (PER2::VENUS) for live imaging. PER2::VENUS recapitulates the circadian functions of wild-type PER2 and, importantly, the behavior of PER2::VENUS runs counter to the Drosophila model: it does not exhibit circadian gating of nuclear entry. Using fluorescent imaging of PER2::VENUS, we acquired the first measures of mobility, molecular concentration, and localization of an endogenous circadian protein in individual mammalian cells, and we showed how the mobility and nuclear translocation of PER2 are regulated by casein kinase. These results provide new qualitative and quantitative insights into the cellular mechanism of the mammalian circadian clock. PMID:27374340

  5. Integrating Beneficiation into Regolith Conveyance Systems

    NASA Technical Reports Server (NTRS)

    Metzger, Philip T.; Mantovani, James H.; Townsend, I. I.; Mueller, Robert P.

    2010-01-01

    Regolith conveyance includes hauler/dumpers, hoppers, augers, pneumatic transport subsystems, and other elements. The features of the conveyance and the time the material stream spend in conveyance may be used synergistically to perform beneficiation, pre-processing (such as heating), and other tasks, thus reducing the mass and complexity of the overall ISRU system. Since the cost of spaceflight is largely driven by the cost of launching mass out of Earth's gravity well, the conveyance system should be leveraged in this way to the maximum extent.

  6. Architecture of retinal projections to the central circadian pacemaker.

    PubMed

    Fernandez, Diego Carlos; Chang, Yi-Ting; Hattar, Samer; Chen, Shih-Kuo

    2016-05-24

    The suprachiasmatic nucleus (SCN) receives direct retinal input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) for circadian photoentrainment. Interestingly, the SCN is the only brain region that receives equal inputs from the left and right eyes. Despite morphological assessments showing that axonal fibers originating from ipRGCs cover the entire SCN, physiological evidence suggests that only vasoactive intestinal polypeptide (VIP)/gastrin-releasing peptide (GRP) cells located ventrally in the SCN receive retinal input. It is still unclear, therefore, which subpopulation of SCN neurons receives synaptic input from the retina and how the SCN receives equal inputs from both eyes. Here, using single ipRGC axonal tracing and a confocal microscopic analysis in mice, we show that ipRGCs have elaborate innervation patterns throughout the entire SCN. Unlike conventional retinal ganglion cells (RGCs) that innervate visual targets either ipsilaterally or contralaterally, a single ipRGC can bilaterally innervate the SCN. ipRGCs form synaptic contacts with major peptidergic cells of the SCN, including VIP, GRP, and arginine vasopressin (AVP) neurons, with each ipRGC innervating specific subdomains of the SCN. Furthermore, a single SCN-projecting ipRGC can send collateral inputs to many other brain regions. However, the size and complexity of the axonal arborizations in non-SCN regions are less elaborate than those in the SCN. Our results provide a better understanding of how retinal neurons connect to the central circadian pacemaker to synchronize endogenous circadian clocks with the solar day. PMID:27162356

  7. Circadian Control of Neuroendocrine Circuits Regulating Female Reproductive Function

    PubMed Central

    Williams, Wilbur P.; Kriegsfeld, Lance J.

    2012-01-01

    Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary–gonadal (HPG) axis functioning. In mammals, the master circadian pacemaker in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus coordinates reproductively relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene) lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the gonadotropin-releasing hormone (GnRH) system in control of the preovulatory luteinizing hormone (LH) surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge. PMID:22661968

  8. Ontogenetic development of the mammalian circadian system.

    PubMed

    Weinert, Dietmar

    2005-01-01

    This review summarizes the current knowledge about the ontogenetic development of the circadian system in mammals. The developmental changes of overt rhythms are discussed, although the main focus of the review is the underlying neuronal and molecular mechanisms. In addition, the review describes ontogenetic development, not only as a process of morpho-functional maturation. The need of repeated adaptations and readaptations due to changing developmental stage and environmental conditions is also considered. The review analyzes mainly rodent data, obtained from the literature and from the author's own studies. Results from other species, including humans, are presented to demonstrate common features and species-dependent differences. The review first describes the development of the suprachiasmatic nuclei as the central pacemaker system and shows that intrinsic circadian rhythms are already generated in the mammalian fetus. As in adult organisms, the period length is different from 24 h and needs continuous correction by environmental periodicities, or zeitgebers. The investigation of the ontogenetic development of the mechanisms of entrainment reveals that, at prenatal and early postnatal stages, non-photic cues deriving from the mother are effective. Light-dark entrainment develops later. At a certain age, both photic and non-photic zeitgebers may act in parallel, even though the respective time information is 12 h out of phase. That leads to a temporary internal desynchronization. Because rhythmic information needs to be transferred to effector organs, the corresponding neural and humoral signalling pathways are also briefly described. Finally, to be able to transform a rhythmic signal into an overt rhythm, the corresponding effector organs must be functionally mature. As many of these organs are able to generate their own intrinsic rhythms, another aspect of the review is dedicated to the development of peripheral oscillators and mechanisms of their entrainment

  9. Circadian gene variants in cancer

    PubMed Central

    Kettner, Nicole M.; Katchy, Chinenye A.; Fu, Loning

    2014-01-01

    Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment. PMID:24901356

  10. Disrupted reproduction, estrous cycle, and circadian rhythms in female vasoactive intestinal peptide deficient mice

    PubMed Central

    Loh, Dawn Hsiao-Wei; Kuljis, Dika Ana; Azuma, Lauren; Wu, Yingfei; Truong, Danny; Wang, Huei-Bin; Colwell, Christopher Scott

    2015-01-01

    The female reproductive cycle is gated by the circadian timing system and may be vulnerable to disruptions in the circadian system. Prior work suggests that vasoactive intestinal peptide (VIP) expressing neurons in the suprachiasmatic nucleus (SCN) are one pathway by which the circadian clock can influence the estrous cycle but the impact of the loss of this peptide on reproduction has not been assessed. In the present study, we first examine the impact of the genetic loss of the neuropeptide VIP on the reproductive success of female mice. Significantly, mutant females produced about half the offspring of their wild type sisters even when mated to the same males. We also find that VIP-deficient females exhibit a disrupted estrous cycle i.e. ovulation occurs less frequently and results in the release of fewer oocytes compared to controls. Circadian rhythms of wheel running activity are disrupted in the female mutant mice as are the spontaneous electrical activity of dorsal SCN neurons. On a molecular level, the VIP-deficient SCN tissue exhibit lower amplitude oscillations with altered phase relationships between the SCN and peripheral oscillators as measured by PER2-driven bioluminescence. The simplest explanation of our data is that the loss of VIP results in a weakened SCN oscillator which reduces the synchronization of the female circadian system. These results clarify one of the mechanisms by which disruption of the circadian system reduces female reproductive success. PMID:25252712

  11. GW182 controls Drosophila circadian behavior and PDF-receptor signaling.

    PubMed

    Zhang, Yong; Emery, Patrick

    2013-04-10

    The neuropeptide PDF is crucial for Drosophila circadian behavior: it keeps circadian neurons synchronized. Here, we identify GW182 as a key regulator of PDF signaling. Indeed, GW182 downregulation results in phenotypes similar to those of Pdf and Pdf-receptor (Pdfr) mutants. gw182 genetically interacts with Pdfr and cAMP signaling, which is essential for PDFR function. GW182 mediates miRNA-dependent gene silencing through its interaction with AGO1. Consistently, GW182's AGO1 interaction domain is required for GW182's circadian function. Moreover, our results indicate that GW182 modulates PDFR signaling by silencing the expression of the cAMP phosphodiesterase DUNCE. Importantly, this repression is under photic control, and GW182 activity level--which is limiting in circadian neurons--influences the responses of the circadian neural network to light. We propose that GW182's gene silencing activity functions as a rheostat for PDFR signaling and thus profoundly impacts the circadian neural network and its response to environmental inputs. PMID:23583112

  12. Circadian rhythms and the suprachiasmatic nucleus in perinatal development, aging and Alzheimer's disease.

    PubMed

    Mirmiran, M; Swaab, D F; Kok, J H; Hofman, M A; Witting, W; Van Gool, W A

    1992-01-01

    Circadian rhythms are already present in the fetus. At a certain stage of pre-natal hypothalamic development (around 30 weeks of gestation) the fetus becomes responsive to maternal circadian signals. Moreover, recent studies showed that the fetal biological clock is able to generate circadian rhythms, as exemplified by the rhythms of body temperature and heart rate of pre-term babies in the absence of maternal or environmental entrainment factors. Pre-term babies that are deprived of maternal entrainment and kept under constant environmental conditions (e.g., continuous light) in the neonatal intensive care unit run the risk of developing a biological clock dysfunctioning. However, the fact should be acknowledged that at least in mice the development of the circadian pacemaker (i.e., SCN) does not depend on environmental influences (Davis and Menaker, 1981), although other data suggest that severe disruption of the maternal circadian rhythm indeed abolishes the circadian rhythm of the fetal SCN (Shibata and Moore, 1988). During aging and in particular in AD circadian rhythms are disturbed. These disturbances include phase advance and reduced period and amplitude, as well as an increased intradaily variability and a decreased interdaily stability of the rhythm. Among the factors underlying these changes the loss of SCN neurons seems to play a central role. Other contributory factors may be reduced amount of light, degenerative changes in the visual system and the level of activity and decreased melatonin. PMID:1480747

  13. Endocrine Effects of Circadian Disruption.

    PubMed

    Bedrosian, Tracy A; Fonken, Laura K; Nelson, Randy J

    2016-01-01

    Disruption of circadian rhythms, provoked by artificial lighting at night, inconsistent sleep-wake schedules, and transmeridian air travel, is increasingly prevalent in modern society. Desynchrony of biological rhythms from environmental light cycles has dramatic consequences for human health. In particular, disrupting homeostatic oscillations in endocrine tissues and the hormones that these tissues regulate can have cascading effects on physiology and behavior. Accumulating evidence suggests that chronic disruption of circadian organization of endocrine function may lead to metabolic, reproductive, sleep, and mood disorders. This review discusses circadian control of endocrine systems and the consequences of distorting rhythmicity of these systems. PMID:26208951

  14. Nocturia: The circadian voiding disorder

    PubMed Central

    Moon, Young Tae; Kim, Kyung Do

    2016-01-01

    Nocturia is a prevalent condition of waking to void during the night. The concept of nocturia has evolved from being a symptomatic aspect of disease associated with the prostate or bladder to a form of lower urinary tract disorder. However, recent advances in circadian biology and sleep science suggest that it might be important to consider nocturia as a form of circadian dysfunction. In the current review, nocturia is reexamined with an introduction to sleep disorders and recent findings in circadian biology in an attempt to highlight the importance of rediscovering nocturia as a problem of chronobiology. PMID:27195315

  15. Neurobiology of Circadian Rhythm Regulation.

    PubMed

    Rosenwasser, Alan M; Turek, Fred W

    2015-12-01

    Over the past few decades, multilevel research has elucidated the basic neuroanatomy, neurochemistry, and molecular neurobiology of the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). The circadian timing system is composed of a large number of cellular oscillators located in the SCN, in non-SCN brain structures, and throughout the body. Cellular-level oscillations are generated by a molecular feedback loop in which circadian clock genes rhythmically regulate their own transcription, as well as that of hundreds of clock-controlled genes. The maintenance of proper coordination within this network of cellular- and tissue-level clocks is essential for health and well-being. PMID:26568118

  16. Nocturia: The circadian voiding disorder.

    PubMed

    Kim, Jin Wook; Moon, Young Tae; Kim, Kyung Do

    2016-05-01

    Nocturia is a prevalent condition of waking to void during the night. The concept of nocturia has evolved from being a symptomatic aspect of disease associated with the prostate or bladder to a form of lower urinary tract disorder. However, recent advances in circadian biology and sleep science suggest that it might be important to consider nocturia as a form of circadian dysfunction. In the current review, nocturia is reexamined with an introduction to sleep disorders and recent findings in circadian biology in an attempt to highlight the importance of rediscovering nocturia as a problem of chronobiology. PMID:27195315

  17. Casein Kinase 1 Promotes Synchrony of the Circadian Clock Network

    PubMed Central

    Zheng, Xiangzhong; Sowcik, Mallory; Chen, Dechun

    2014-01-01

    Casein kinase 1, known as DOUBLETIME (DBT) in Drosophila melanogaster, is a critical component of the circadian clock that phosphorylates and promotes degradation of the PERIOD (PER) protein. However, other functions of DBT in circadian regulation are not clear, in part because severe reduction of dbt causes preadult lethality. Here we report the molecular and behavioral phenotype of a viable dbtEY02910 loss-of-function mutant. We found that DBT protein levels are dramatically reduced in adult dbtEY02910 flies, and the majority of mutant flies display arrhythmic behavior, with a few showing weak, long-period (∼32 h) rhythms. Peak phosphorylation of PER is delayed, and both hyper- and hypophosphorylated forms of the PER and CLOCK proteins are present throughout the day. In addition, molecular oscillations of the circadian clock are dampened. In the central brain, PER and TIM expression is heterogeneous and decoupled in the canonical clock neurons of the dbtEY02910 mutants. We also report an interaction between dbt and the signaling pathway involving pigment dispersing factor (PDF), a synchronizing peptide in the clock network. These data thus demonstrate that overall reduction of DBT causes long and arrhythmic behavior, and they reveal an unexpected role of DBT in promoting synchrony of the circadian clock network. PMID:24820422

  18. Casein kinase 1 promotes synchrony of the circadian clock network.

    PubMed

    Zheng, Xiangzhong; Sowcik, Mallory; Chen, Dechun; Sehgal, Amita

    2014-07-01

    Casein kinase 1, known as DOUBLETIME (DBT) in Drosophila melanogaster, is a critical component of the circadian clock that phosphorylates and promotes degradation of the PERIOD (PER) protein. However, other functions of DBT in circadian regulation are not clear, in part because severe reduction of dbt causes preadult lethality. Here we report the molecular and behavioral phenotype of a viable dbt(EY02910) loss-of-function mutant. We found that DBT protein levels are dramatically reduced in adult dbt(EY02910) flies, and the majority of mutant flies display arrhythmic behavior, with a few showing weak, long-period (∼32 h) rhythms. Peak phosphorylation of PER is delayed, and both hyper- and hypophosphorylated forms of the PER and CLOCK proteins are present throughout the day. In addition, molecular oscillations of the circadian clock are dampened. In the central brain, PER and TIM expression is heterogeneous and decoupled in the canonical clock neurons of the dbt(EY02910) mutants. We also report an interaction between dbt and the signaling pathway involving pigment dispersing factor (PDF), a synchronizing peptide in the clock network. These data thus demonstrate that overall reduction of DBT causes long and arrhythmic behavior, and they reveal an unexpected role of DBT in promoting synchrony of the circadian clock network. PMID:24820422

  19. Role of cardiomyocyte circadian clock in myocardial metabolic adaptation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Marked circadian rhythmicities in cardiovascular physiology and pathophysiology exist. The cardiomyocyte circadian clock has recently been linked to circadian rhythms in myocardial gene expression, metabolism, and contractile function. For instance, the cardiomyocyte circadian clock is essential f...

  20. Daily variation in the electrophysiological activity of mouse medial habenula neurones

    PubMed Central

    Sakhi, Kanwal; Belle, Mino D C; Gossan, Nicole; Delagrange, Philippe; Piggins, Hugh D

    2014-01-01

    AbstractIntrinsic daily or circadian rhythms arise through the outputs of the master circadian clock in the brain's suprachiasmatic nuclei (SCN) as well as circadian oscillators in other brain sites and peripheral tissues. SCN neurones contain an intracellular molecular clock that drives these neurones to exhibit pronounced day–night differences in their electrical properties. The epithalamic medial habenula (MHb) expresses clock genes, but little is known about the bioelectric properties of mouse MHb neurones and their potential circadian characteristics. Therefore, in this study we used a brain slice preparation containing the MHb to determine the basic electrical properties of mouse MHb neurones with whole-cell patch clamp electrophysiology, and investigated whether these vary across the day–night cycle. MHb neurones (n = 230) showed heterogeneity in electrophysiological state, ranging from highly depolarised cells (∼ −25 to −30 mV) that are silent with no membrane activity or display depolarised low-amplitude membrane oscillations, to neurones that were moderately hyperpolarised (∼40 mV) and spontaneously discharging action potentials. These electrical states were largely intrinsically regulated and were influenced by the activation of small-conductance calcium-activated potassium channels. When considered as one population, MHb neurones showed significant circadian variation in their spontaneous firing rate and resting membrane potential. However, in recordings of MHb neurones from mice lacking the core molecular circadian clock, these temporal differences in MHb activity were absent, indicating that circadian clock signals actively regulate the timing of MHb neuronal states. These observations add to the extracellularly recorded rhythms seen in other brain areas and establish that circadian mechanisms can influence the membrane properties of neurones in extra-SCN sites. Collectively, the results of this study indicate that the MHb may

  1. Rhythmic expression of cryptochrome induces the circadian clock of arrhythmic suprachiasmatic nuclei through arginine vasopressin signaling.

    PubMed

    Edwards, Mathew D; Brancaccio, Marco; Chesham, Johanna E; Maywood, Elizabeth S; Hastings, Michael H

    2016-03-01

    Circadian rhythms in mammals are coordinated by the suprachiasmatic nucleus (SCN). SCN neurons define circadian time using transcriptional/posttranslational feedback loops (TTFL) in which expression of Cryptochrome (Cry) and Period (Per) genes is inhibited by their protein products. Loss of Cry1 and Cry2 stops the SCN clock, whereas individual deletions accelerate and decelerate it, respectively. At the circuit level, neuronal interactions synchronize cellular TTFLs, creating a spatiotemporal wave of gene expression across the SCN that is lost in Cry1/2-deficient SCN. To interrogate the properties of CRY proteins required for circadian function, we expressed CRY in SCN of Cry-deficient mice using adeno-associated virus (AAV). Expression of CRY1::EGFP or CRY2::EGFP under a minimal Cry1 promoter was circadian and rapidly induced PER2-dependent bioluminescence rhythms in previously arrhythmic Cry1/2-deficient SCN, with periods appropriate to each isoform. CRY1::EGFP appropriately lengthened the behavioral period in Cry1-deficient mice. Thus, determination of specific circadian periods reflects properties of the respective proteins, independently of their phase of expression. Phase of CRY1::EGFP expression was critical, however, because constitutive or phase-delayed promoters failed to sustain coherent rhythms. At the circuit level, CRY1::EGFP induced the spatiotemporal wave of PER2 expression in Cry1/2-deficient SCN. This was dependent on the neuropeptide arginine vasopressin (AVP) because it was prevented by pharmacological blockade of AVP receptors. Thus, our genetic complementation assay reveals acute, protein-specific induction of cell-autonomous and network-level circadian rhythmicity in SCN never previously exposed to CRY. Specifically, Cry expression must be circadian and appropriately phased to support rhythms, and AVP receptor signaling is required to impose circuit-level circadian function. PMID:26903624

  2. Circadian Control of Global Transcription

    PubMed Central

    Li, Shujing; Zhang, Luoying

    2015-01-01

    Circadian rhythms exist in most if not all organisms on the Earth and manifest in various aspects of physiology and behavior. These rhythmic processes are believed to be driven by endogenous molecular clocks that regulate rhythmic expression of clock-controlled genes (CCGs). CCGs consist of a significant portion of the genome and are involved in diverse biological pathways. The transcription of CCGs is tuned by rhythmic actions of transcription factors and circadian alterations in chromatin. Here, we review the circadian control of CCG transcription in five model organisms that are widely used, including cyanobacterium, fungus, plant, fruit fly, and mouse. Comparing the similarity and differences in the five organisms could help us better understand the function of the circadian clock, as well as its output mechanisms adapted to meet the demands of diverse environmental conditions. PMID:26682214

  3. Endocrine regulation of circadian physiology.

    PubMed

    Tsang, Anthony H; Astiz, Mariana; Friedrichs, Maureen; Oster, Henrik

    2016-07-01

    Endogenous circadian clocks regulate 24-h rhythms of behavior and physiology to align with external time. The endocrine system serves as a major clock output to regulate various biological processes. Recent findings suggest that some of the rhythmic hormones can also provide feedback to the circadian system at various levels, thus contributing to maintaining the robustness of endogenous rhythmicity. This delicate balance of clock-hormone interaction is vulnerable to modern lifestyle factors such as shiftwork or high-calorie diets, altering physiological set points. In this review, we summarize the current knowledge on the communication between the circadian timing and endocrine systems, with a focus on adrenal glucocorticoids and metabolic peptide hormones. We explore the potential role of hormones as systemic feedback signals to adjust clock function and their relevance for the maintenance of physiological and metabolic circadian homeostasis. PMID:27106109

  4. Embryonic development of circadian clocks in the mammalian suprachiasmatic nuclei

    PubMed Central

    Landgraf, Dominic; Koch, Christiane E.; Oster, Henrik

    2014-01-01

    In most species, self-sustained molecular clocks regulate 24-h rhythms of behavior and physiology. In mammals, a circadian pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN) receives photic signals from the retina and synchronizes subordinate clocks in non-SCN tissues. The emergence of circadian rhythmicity during development has been extensively studied for many years. In mice, neuronal development in the presumptive SCN region of the embryonic hypothalamus occurs on days 12–15 of gestation. Intra-SCN circuits differentiate during the following days and retinal projections reach the SCN, and thus mediate photic entrainment, only after birth. In contrast the genetic components of the clock gene machinery are expressed much earlier and during midgestation SCN explants and isolated neurons are capable of generating molecular oscillations in culture. In vivo metabolic rhythms in the SCN, however, are observed not earlier than the 19th day of rat gestation, and rhythmic expression of clock genes is hardly detectable until after birth. Together these data indicate that cellular coupling and, thus, tissue-wide synchronization of single-cell rhythms, may only develop very late during embryogenesis. In this mini-review we describe the developmental origin of the SCN structure and summarize our current knowledge about the functional initiation and entrainment of the circadian pacemaker during embryonic development. PMID:25520627

  5. Colour as a signal for entraining the mammalian circadian clock.

    PubMed

    Walmsley, Lauren; Hanna, Lydia; Mouland, Josh; Martial, Franck; West, Alexander; Smedley, Andrew R; Bechtold, David A; Webb, Ann R; Lucas, Robert J; Brown, Timothy M

    2015-04-01

    Twilight is characterised by changes in both quantity ("irradiance") and quality ("colour") of light. Animals use the variation in irradiance to adjust their internal circadian clocks, aligning their behaviour and physiology with the solar cycle. However, it is currently unknown whether changes in colour also contribute to this entrainment process. Using environmental measurements, we show here that mammalian blue-yellow colour discrimination provides a more reliable method of tracking twilight progression than simply measuring irradiance. We next use electrophysiological recordings to demonstrate that neurons in the mouse suprachiasmatic circadian clock display the cone-dependent spectral opponency required to make use of this information. Thus, our data show that some clock neurons are highly sensitive to changes in spectral composition occurring over twilight and that this input dictates their response to changes in irradiance. Finally, using mice housed under photoperiods with simulated dawn/dusk transitions, we confirm that spectral changes occurring during twilight are required for appropriate circadian alignment under natural conditions. Together, these data reveal a new sensory mechanism for telling time of day that would be available to any mammalian species capable of chromatic vision. PMID:25884537

  6. Circadian rhythm of temperature preference and its neural control in Drosophila

    PubMed Central

    Kaneko, Haruna; Head, Lauren M.; Ling, Jinli; Tang, Xin; Liu, Yilin; Hardin, Paul E.; Emery, Patrick; Hamada, Fumika N.

    2012-01-01

    A daily body temperature rhythm (BTR) is critical for the maintenance of homeostasis in mammals. While mammals use internal energy to regulate body temperature, ectotherms typically regulate body temperature behaviorally [1]. Some ectotherms maintain homeostasis via a daily temperature preference rhythm (TPR) [2], but the underlying mechanisms are largely unknown. Here, we show that Drosophila exhibit a daily circadian clock dependent TPR that resembles mammalian BTR. Pacemaker neurons critical for locomotor activity are not necessary for TPR; instead, the dorsal neuron 2s (DN2s), whose function was previously unknown, is sufficient. This indicates that TPR, like BTR, is controlled independently from locomotor activity. Therefore, the mechanisms controlling temperature fluctuations in fly TPR and mammalian BTR may share parallel features. Taken together, our results reveal the existence of a novel DN2- based circadian neural circuit that specifically regulates TPR; thus, understanding the mechanisms of TPR will shed new light on the function and neural control of circadian rhythms. PMID:22981774

  7. Dynamic instability of ducts conveying fluid

    NASA Technical Reports Server (NTRS)

    Yu, Y. Y.

    1975-01-01

    A finite element analysis was used to study dynamic instability in ducts conveying high speed fluids. Ducts examined include cantilevered curved, flexibly supported, arbitrarily shaped, and composite duct systems. Partial differential equations were used to study the duct systems.

  8. Depression-like behaviour in mice is associated with disrupted circadian rhythms in nucleus accumbens and periaqueductal grey.

    PubMed

    Landgraf, Dominic; Long, Jaimie E; Welsh, David K

    2016-05-01

    An association between circadian rhythms and mood regulation is well established, and disturbed circadian clocks are believed to contribute to the development of mood disorders, including major depressive disorder. The circadian system is coordinated by the suprachiasmatic nucleus (SCN), the master pacemaker in the hypothalamus that receives light input from the retina and synchronizes circadian oscillators in other brain regions and peripheral tissues. Lacking the tight neuronal network that couples single-cell oscillators in the SCN, circadian clocks outside the SCN may be less stable and more susceptible to disturbances, for example by clock gene mutations or uncontrollable stress. However, non-SCN circadian clocks have not been studied extensively in rodent models of mood disorders. In the present study, it was hypothesized that disturbances of local circadian clocks in mood-regulating brain areas are associated with depression-like behaviour in mice. Using the learned helplessness procedure, depression-like behaviour was evoked in mice bearing the PER2::LUC circadian reporter, and then circadian rhythms of PER2 expression were examined in brain slices from these mice using luminometry and bioluminescence imaging. It was found that helplessness is associated with absence of circadian rhythms in the nucleus accumbens and the periaqueductal grey, two of the most critical brain regions within the reward circuit. The current study provides evidence that susceptibility of mice to depression-like behaviour is associated with disturbed local circadian clocks in a subset of mood-regulating brain areas, but the direction of causality remains to be determined. PMID:26414405

  9. Assessment of Circadian and Light-Entrainable Parameters in Mice Using Wheel-Running Activity.

    PubMed

    Banks, Gareth T; Nolan, Patrick M

    2011-01-01

    In most organisms, physiological variables are regulated by an internal clock. This endogenous circadian (∼24-hr) clock enables organisms to anticipate daily environmental changes and modify behavioral and physiological functions appropriately. Processes regulated by the circadian clock include sleep-wake and locomotor activity, core body temperature, metabolism, water/food intake, and available hormone levels. At the core of the mammalian circadian system are molecular oscillations within the hypothalamic suprachiasmatic nucleus. These oscillations are modifiable by signals from the environment (so called zeitgebers or time-givers) and, once integrated within the suprachiasmatic nucleus, are conveyed to remote neural circuits where output rhythms are regulated. Disrupting any of a number of neural processes can affect how rhythms are generated and relayed to the periphery and disturbances in circadian/entrainment parameters are associated with numerous human conditions. These non-invasive protocols can be used to determine whether circadian/entrainment parameters are affected in mouse mutants or treatment groups. Curr. Protoc. Mouse Biol. 1:369-381 © 2011 by John Wiley & Sons, Inc. PMID:26068996

  10. A mechanosensory pathway to the Drosophila circadian clock.

    PubMed

    Simoni, Alekos; Wolfgang, Werner; Topping, Matthew P; Kavlie, Ryan G; Stanewsky, Ralf; Albert, Joerg T

    2014-01-31

    Circadian clocks attune the physiology of virtually all living organisms to the diurnal cycles of their environments. In metazoan animals, multiple sensory input pathways have been linked to clock synchronization with the environmental cycle (entrainment). Extrinsic entrainment cues include light and temperature. We show that (12-hour:12-hour) cycles of vibration and silence (VS) are sufficient to synchronize the daily locomotor activity of wild-type Drosophila melanogaster. Behavioral synchronization to VS cycles required a functional clock and functional chordotonal organs and was accompanied by phase-shifts of the daily oscillations of PERIOD protein concentrations in brain clock neurons. The feedback from mechanosensory-and particularly, proprioceptive-organs may help an animal to keep its circadian clock in sync with its own, stimulus-induced activities. PMID:24482478

  11. Nutrition and the circadian system.

    PubMed

    Potter, Gregory D M; Cade, Janet E; Grant, Peter J; Hardie, Laura J

    2016-08-01

    The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partitions incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24-h day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation, and thereby contributes to adverse metabolic consequences and chronic disease development. 'High-fat diets' (HFD) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFD in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases. PMID:27221157

  12. Circadian regulation of renal function.

    PubMed

    Firsov, Dmitri; Bonny, Olivier

    2010-10-01

    Urinary excretion of water and all major electrolytes exhibit robust circadian oscillations. The 24-h periodicity has been well documented for several important determinants of urine formation, including renal blood flow, glomerular filtration, tubular reabsorption, and tubular secretion. Disturbance of the renal circadian rhythms is increasingly recognized as a risk factor for hypertension, polyuria, and other diseases and may contribute to renal fibrosis. The origin of these rhythms has been attributed to the reactive response of the kidney to circadian changes in volume and/or in the composition of extracellular fluids that are entrained by rest/activity and feeding/fasting cycles. However, numerous studies have shown that most of the renal excretory rhythms persist for long periods of time, even in the absence of periodic environmental cues. These observations led to the hypothesis of the existence of a self-sustained mechanism, enabling the kidney to anticipate various predictable circadian challenges to homeostasis. The molecular basis of this mechanism remained unknown until the recent discovery of the mammalian circadian clock made of a system of autoregulatory transcriptional/translational feedback loops, which have been found in all tissues studied, including the kidney. Here, we present a review of the growing evidence showing the involvement of the molecular clock in the generation of renal excretory rhythms. PMID:20664559

  13. Nutrition and the Circadian System

    PubMed Central

    Potter, Gregory D M; Cade, Janet E; Grant, Peter J; Hardie, Laura J

    2016-01-01

    The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partition incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24 hour day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation and thereby contributes to adverse metabolic consequences and chronic disease development. ‘High-fat diets’ (HFDs) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFDs in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases. PMID:27221157

  14. Analysis of Circadian Leaf Movements.

    PubMed

    Müller, Niels A; Jiménez-Gómez, José M

    2016-01-01

    The circadian clock is a molecular timekeeper that controls a wide variety of biological processes. In plants, clock outputs range from the molecular level, with rhythmic gene expression and metabolite content, to physiological processes such as stomatal conductance or leaf movements. Any of these outputs can be used as markers to monitor the state of the circadian clock. In the model plant Arabidopsis thaliana, much of the current knowledge about the clock has been gained from time course experiments profiling expression of endogenous genes or reporter constructs regulated by the circadian clock. Since these methods require labor-intensive sample preparation or transformation, monitoring leaf movements is an interesting alternative, especially in non-model species and for natural variation studies. Technological improvements both in digital photography and image analysis allow cheap and easy monitoring of circadian leaf movements. In this chapter we present a protocol that uses an autonomous point and shoot camera and free software to monitor circadian leaf movements in tomato. PMID:26867616

  15. Protein Phosphatase 1 (PP1) Is a Post-Translational Regulator of the Mammalian Circadian Clock

    PubMed Central

    Schmutz, Isabelle; Wendt, Sabrina; Schnell, Anna; Kramer, Achim; Mansuy, Isabelle M.; Albrecht, Urs

    2011-01-01

    Circadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an important role in regulating activity, stability and intracellular localization of clock components. Several protein kinases were characterized as regulators of the circadian clock. However, the function of protein phosphatases, which balance phosphorylation events, in the mammalian clock mechanism is less well understood. Here, we identify protein phosphatase 1 (PP1) as regulator of period and light-induced resetting of the mammalian circadian clock. Down-regulation of PP1 activity in cells by RNA interference and in vivo by expression of a specific inhibitor in the brain of mice tended to lengthen circadian period. Moreover, reduction of PP1 activity in the brain altered light-mediated clock resetting behavior in mice, enhancing the phase shifts in either direction. At the molecular level, diminished PP1 activity increased nuclear accumulation of the clock component PER2 in neurons. Hence, PP1, may reduce PER2 phosphorylation thereby influencing nuclear localization of this protein. This may at least partially influence period and phase shifting properties of the mammalian circadian clock. PMID:21712997

  16. Design and Analysis of Temperature Preference Behavior and its Circadian Rhythm in Drosophila

    PubMed Central

    Goda, Tadahiro; Leslie, Jennifer R.; Hamada, Fumika N.

    2014-01-01

    The circadian clock regulates many aspects of life, including sleep, locomotor activity, and body temperature (BTR) rhythms1,2. We recently identified a novel Drosophila circadian output, called the temperature preference rhythm (TPR), in which the preferred temperature in flies rises during the day and falls during the night 3. Surprisingly, the TPR and locomotor activity are controlled through distinct circadian neurons3. Drosophila locomotor activity is a well known circadian behavioral output and has provided strong contributions to the discovery of many conserved mammalian circadian clock genes and mechanisms4. Therefore, understanding TPR will lead to the identification of hitherto unknown molecular and cellular circadian mechanisms. Here, we describe how to perform and analyze the TPR assay. This technique not only allows for dissecting the molecular and neural mechanisms of TPR, but also provides new insights into the fundamental mechanisms of the brain functions that integrate different environmental signals and regulate animal behaviors. Furthermore, our recently published data suggest that the fly TPR shares features with the mammalian BTR3. Drosophila are ectotherms, in which the body temperature is typically behaviorally regulated. Therefore, TPR is a strategy used to generate a rhythmic body temperature in these flies5-8. We believe that further exploration of Drosophila TPR will facilitate the characterization of the mechanisms underlying body temperature control in animals. PMID:24457268

  17. CRTC Potentiates Light-independent timeless Transcription to Sustain Circadian Rhythms in Drosophila

    PubMed Central

    Kim, Minkyung; Lee, Hoyeon; Hur, Jin-Hoe; Choe, Joonho; Lim, Chunghun

    2016-01-01

    Light is one of the strongest environmental time cues for entraining endogenous circadian rhythms. Emerging evidence indicates that CREB-regulated transcription co-activator 1 (CRTC1) is a key player in this pathway, stimulating light-induced Period1 (Per1) transcription in mammalian clocks. Here, we demonstrate a light-independent role of Drosophila CRTC in sustaining circadian behaviors. Genomic deletion of the crtc locus causes long but poor locomotor rhythms in constant darkness. Overexpression or RNA interference-mediated depletion of CRTC in circadian pacemaker neurons similarly impairs the free-running behavioral rhythms, implying that Drosophila clocks are sensitive to the dosage of CRTC. The crtc null mutation delays the overall phase of circadian gene expression yet it remarkably dampens light-independent oscillations of TIMELESS (TIM) proteins in the clock neurons. In fact, CRTC overexpression enhances CLOCK/CYCLE (CLK/CYC)-activated transcription from tim but not per promoter in clock-less S2 cells whereas CRTC depletion suppresses it. Consistently, TIM overexpression partially but significantly rescues the behavioral rhythms in crtc mutants. Taken together, our data suggest that CRTC is a novel co-activator for the CLK/CYC-activated tim transcription to coordinate molecular rhythms with circadian behaviors over a 24-hour time-scale. We thus propose that CRTC-dependent clock mechanisms have co-evolved with selective clock genes among different species. PMID:27577611

  18. Clk post-transcriptional control denoises circadian transcription in time and space

    PubMed Central

    Wolfson, Victoria; Menet, Jerome S; Weissbein, Uri; Afik, Shaked; Haimovich, Daniel; Gafni, Chen; Friedman, Nir; Rosbash, Michael; Kadener, Sebastian

    2016-01-01

    The transcription factor CLOCK (CLK) is essential for the development and maintenance of circadian rhythms in Drosophila. However, little is known about how CLK levels are controlled. Here, we show that Clk mRNA is strongly regulated post-transcriptionally through its 3’UTR. Flies expressing Clk transgenes missing their normal 3’UTR, exhibited variable CLK-driven transcription and circadian behavior, as well as ectopic expression of CLK-target genes in the brain. Surprisingly, in these flies, the numbers of the key circadian neurons differs stochastically between individuals and within the two hemispheres of the same brain. In addition, flies carrying Clk transgenes with deletions in the binding sites for the miRNA bantam have stochastic number of pacemaker neurons, suggesting that this miRNA mediates the deterministic expression of CLK. Overall our results demonstrate a key role of Clk post-transcriptional control in stabilizing circadian transcription, which is essential for proper development and maintenance of circadian rhythms in Drosophila. PMID:25952406

  19. CRTC Potentiates Light-independent timeless Transcription to Sustain Circadian Rhythms in Drosophila.

    PubMed

    Kim, Minkyung; Lee, Hoyeon; Hur, Jin-Hoe; Choe, Joonho; Lim, Chunghun

    2016-01-01

    Light is one of the strongest environmental time cues for entraining endogenous circadian rhythms. Emerging evidence indicates that CREB-regulated transcription co-activator 1 (CRTC1) is a key player in this pathway, stimulating light-induced Period1 (Per1) transcription in mammalian clocks. Here, we demonstrate a light-independent role of Drosophila CRTC in sustaining circadian behaviors. Genomic deletion of the crtc locus causes long but poor locomotor rhythms in constant darkness. Overexpression or RNA interference-mediated depletion of CRTC in circadian pacemaker neurons similarly impairs the free-running behavioral rhythms, implying that Drosophila clocks are sensitive to the dosage of CRTC. The crtc null mutation delays the overall phase of circadian gene expression yet it remarkably dampens light-independent oscillations of TIMELESS (TIM) proteins in the clock neurons. In fact, CRTC overexpression enhances CLOCK/CYCLE (CLK/CYC)-activated transcription from tim but not per promoter in clock-less S2 cells whereas CRTC depletion suppresses it. Consistently, TIM overexpression partially but significantly rescues the behavioral rhythms in crtc mutants. Taken together, our data suggest that CRTC is a novel co-activator for the CLK/CYC-activated tim transcription to coordinate molecular rhythms with circadian behaviors over a 24-hour time-scale. We thus propose that CRTC-dependent clock mechanisms have co-evolved with selective clock genes among different species. PMID:27577611

  20. The Circadian System: A Regulatory Feedback Network of Periphery and Brain.

    PubMed

    Buijs, Frederik N; León-Mercado, Luis; Guzmán-Ruiz, Mara; Guerrero-Vargas, Natali N; Romo-Nava, Francisco; Buijs, Ruud M

    2016-05-01

    Circadian rhythms are generated by the autonomous circadian clock, the suprachiasmatic nucleus (SCN), and clock genes that are present in all tissues. The SCN times these peripheral clocks, as well as behavioral and physiological processes. Recent studies show that frequent violations of conditions set by our biological clock, such as shift work, jet lag, sleep deprivation, or simply eating at the wrong time of the day, may have deleterious effects on health. This infringement, also known as circadian desynchronization, is associated with chronic diseases like diabetes, hypertension, cancer, and psychiatric disorders. In this review, we will evaluate evidence that these diseases stem from the need of the SCN for peripheral feedback to fine-tune its output and adjust physiological processes to the requirements of the moment. This feedback can vary from neuronal or hormonal signals from the liver to changes in blood pressure. Desynchronization renders the circadian network dysfunctional, resulting in a breakdown of many functions driven by the SCN, disrupting core clock rhythms in the periphery and disorganizing cellular processes that are normally driven by the synchrony between behavior and peripheral signals with neuronal and humoral output of the hypothalamus. Consequently, we propose that the loss of synchrony between the different elements of this circadian network as may occur during shiftwork and jet lag is the reason for the occurrence of health problems. PMID:27053731

  1. Evidence for a Putative Circadian Kiss-Clock in the Hypothalamic AVPV in Female Mice.

    PubMed

    Chassard, David; Bur, Isabelle; Poirel, Vincent-Joseph; Mendoza, Jorge; Simonneaux, Valérie

    2015-08-01

    The kisspeptin (Kp) neurons in the anteroventral periventricular nucleus (AVPV) are essential for the preovulatory LH surge, which is gated by circulating estradiol (E2) and the time of day. We investigated whether AVPV Kp neurons in intact female mice may be the site in which both E2 and daily signals are integrated and whether these neurons may host a circadian oscillator involved in the timed LH surge. In the afternoon of proestrous day, Kp immunoreactivity displayed a marked and transient decrease 2 hours before the LH surge. In contrast, Kp content was stable throughout the day of diestrus, when LH levels are constantly low. AVPV Kp neurons expressed the clock protein period 1 (PER1) with a daily rhythm that is phase delayed compared with the PER1 rhythm measured in the main clock of the suprachiasmatic nuclei (SCN). PER1 rhythm in the AVPV, but not in the SCN, exhibited a significant phase delay of 2.8 hours in diestrus as compared with proestrus. Isolated Kp-expressing AVPV explants from PER2::LUCIFERASE mice displayed sustained circadian oscillations of bioluminescence with a circadian period (23.2 h) significantly shorter than that of SCN explants (24.5 h). Furthermore, in AVPV explants incubated with E2 (10 nM to 1 μM), the circadian period was lengthened by 1 hour, whereas the SCN clock remained unaltered. In conclusion, these findings indicate that AVPV Kp neurons display an E2-dependent daily rhythm, which may possibly be driven by an intrinsic circadian clock acting in combination with the SCN timing signal. PMID:25993523

  2. Manipulations of amyloid precursor protein cleavage disrupt the circadian clock in aging Drosophila.

    PubMed

    Blake, Matthew R; Holbrook, Scott D; Kotwica-Rolinska, Joanna; Chow, Eileen S; Kretzschmar, Doris; Giebultowicz, Jadwiga M

    2015-05-01

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by severe cognitive deterioration. While causes of AD pathology are debated, a large body of evidence suggests that increased cleavage of Amyloid Precursor Protein (APP) producing the neurotoxic Amyloid-β (Aβ) peptide plays a fundamental role in AD pathogenesis. One of the detrimental behavioral symptoms commonly associated with AD is the fragmentation of sleep-activity cycles with increased nighttime activity and daytime naps in humans. Sleep-activity cycles, as well as physiological and cellular rhythms, which may be important for neuronal homeostasis, are generated by a molecular system known as the circadian clock. Links between AD and the circadian system are increasingly evident but not well understood. Here we examined whether genetic manipulations of APP-like (APPL) protein cleavage in Drosophila melanogaster affect rest-activity rhythms and core circadian clock function in this model organism. We show that the increased β-cleavage of endogenous APPL by the β-secretase (dBACE) severely disrupts circadian behavior and leads to reduced expression of clock protein PER in central clock neurons of aging flies. Our data suggest that behavioral rhythm disruption is not a product of APPL-derived Aβ production but rather may be caused by a mechanism common to both α and β-cleavage pathways. Specifically, we show that increased production of the endogenous Drosophila Amyloid Intracellular Domain (dAICD) caused disruption of circadian rest-activity rhythms, while flies overexpressing endogenous APPL maintained stronger circadian rhythms during aging. In summary, our study offers a novel entry point toward understanding the mechanism of circadian rhythm disruption in Alzheimer's disease. PMID:25766673

  3. Circadian Clock, Cancer, and Chemotherapy

    PubMed Central

    2015-01-01

    The circadian clock is a global regulatory system that interfaces with most other regulatory systems and pathways in mammalian organisms. Investigations of the circadian clock–DNA damage response connections have revealed that nucleotide excision repair, DNA damage checkpoints, and apoptosis are appreciably influenced by the clock. Although several epidemiological studies in humans and a limited number of genetic studies in mouse model systems have indicated that clock disruption may predispose mammals to cancer, well-controlled genetic studies in mice have not supported the commonly held view that circadian clock disruption is a cancer risk factor. In fact, in the appropriate genetic background, clock disruption may instead aid in cancer regression by promoting intrinsic and extrinsic apoptosis. Finally, the clock may affect the efficacy of cancer treatment (chronochemotherapy) by modulating the pharmacokinetics and pharmacodynamics of chemotherapeutic drugs as well as the activity of the DNA repair enzymes that repair the DNA damage caused by anticancer drugs. PMID:25302769

  4. Calretinin Neurons in the Rat Suprachiasmatic Nucleus.

    PubMed

    Moore, Robert Y

    2016-08-01

    The hypothalamic suprachiasmatic nucleus (SCN), a circadian pacemaker, is present in all mammalian brains. It has a complex organization of peptide-containing neurons that is similar among species, but calcium-binding proteins are expressed variably. Neurons containing calretinin have been described in the SCN in a number of species but not with association to circadian function. The objective of the present study is to characterize a calretinin neuron (CAR) group in the rat anterior hypothalamus anatomically and functionally with a detailed description of its location and a quantitative analysis of neuronal calretinin immunoreactivity at 3 times of day, 0600, 1400, and 1900 h, from animals in either light-dark or constant dark conditions. CAR neurons occupy a region in the dorsal and lateral SCN with a circadian rhythm in CAR immunoreactivity with a peak at 0600 h and a rhythm in cytoplasmic CAR distribution with a peak at 1400 h. CAR neurons should be viewed as an anatomical and functional component of the rat SCN that expands the definition from observations with cell stains. CAR neurons are likely to modulate temporal regulation of calcium in synaptic transmission. PMID:27330050

  5. Effects of chronic administration and withdrawal of antidepressant agents on circadian activity rhythms in rats.

    PubMed

    Wollnik, F

    1992-10-01

    play a significant role in the neuronal control of behavioral state and circadian rhythmicity. Although the present study found that some antidepressives affect parameters of circadian rhythmicity, it could not demonstrate a common effect of all classes of antidepressives. PMID:1438492

  6. Disruption of circadian clocks has ramifications for metabolism, brain, and behavior

    PubMed Central

    Karatsoreos, Ilia N.; Bhagat, Sarah; Bloss, Erik B.; Morrison, John H.; McEwen, Bruce S.

    2011-01-01

    Circadian (daily) rhythms are present in almost all plants and animals. In mammals, a brain clock located in the hypothalamic suprachiasmatic nucleus maintains synchrony between environmental light/dark cycles and physiology and behavior. Over the past 100 y, especially with the advent of electric lighting, modern society has resulted in a round-the-clock lifestyle, in which natural connections between rest/activity cycles and environmental light/dark cycles have been degraded or even broken. Instances in which rapid changes to sleep patterns are necessary, such as transmeridian air travel, demonstrate negative effects of acute circadian disruption on physiology and behavior. However, the ramifications of chronic disruption of the circadian clock for mental and physical health are not yet fully understood. By housing mice in 20-h light/dark cycles, incongruous with their endogenous ∼24-h circadian period, we were able to model the effects of chronic circadian disruption noninvasively. Housing in these conditions results in accelerated weight gain and obesity, as well as changes in metabolic hormones. In the brain, circadian-disrupted mice exhibit a loss of dendritic length and decreased complexity of neurons in the prelimbic prefrontal cortex, a brain region important in executive function and emotional control. Disrupted animals show decreases in cognitive flexibility and changes in emotionality consistent with the changes seen in neural architecture. How our findings translate to humans living and working in chronic circadian disruption is unknown, but we believe that this model can provide a foundation to understand how environmental disruption of circadian rhythms impacts the brain, behavior, and physiology. PMID:21220317

  7. Circadian Insights into Motivated Behavior.

    PubMed

    Antle, Michael C; Silver, Rae

    2016-01-01

    For an organism to be successful in an evolutionary sense, it and its offspring must survive. Such survival depends on satisfying a number of needs that are driven by motivated behaviors, such as eating, sleeping, and mating. An individual can usually only pursue one motivated behavior at a time. The circadian system provides temporal structure to the organism's 24 hour day, partitioning specific behaviors to particular times of the day. The circadian system also allows anticipation of opportunities to engage in motivated behaviors that occur at predictable times of the day. Such anticipation enhances fitness by ensuring that the organism is physiologically ready to make use of a time-limited resource as soon as it becomes available. This could include activation of the sympathetic nervous system to transition from sleep to wake, or to engage in mating, or to activate of the parasympathetic nervous system to facilitate transitions to sleep, or to prepare the body to digest a meal. In addition to enabling temporal partitioning of motivated behaviors, the circadian system may also regulate the amplitude of the drive state motivating the behavior. For example, the circadian clock modulates not only when it is time to eat, but also how hungry we are. In this chapter we explore the physiology of our circadian clock and its involvement in a number of motivated behaviors such as sleeping, eating, exercise, sexual behavior, and maternal behavior. We also examine ways in which dysfunction of circadian timing can contribute to disease states, particularly in psychiatric conditions that include adherent motivational states. PMID:26419240

  8. 24 CFR 203.402 - Items included in payment-conveyed and non-conveyed properties.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 24 Housing and Urban Development 2 2012-04-01 2012-04-01 false Items included in payment-conveyed and non-conveyed properties. 203.402 Section 203.402 Housing and Urban Development Regulations... items: (a) Taxes, ground rents, water rates, and utility charges that are liens prior to the...

  9. 24 CFR 203.402 - Items included in payment-conveyed and non-conveyed properties.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 24 Housing and Urban Development 2 2013-04-01 2013-04-01 false Items included in payment-conveyed and non-conveyed properties. 203.402 Section 203.402 Housing and Urban Development Regulations... items: (a) Taxes, ground rents, water rates, and utility charges that are liens prior to the...

  10. 24 CFR 203.402 - Items included in payment-conveyed and non-conveyed properties.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 2 2014-04-01 2014-04-01 false Items included in payment-conveyed and non-conveyed properties. 203.402 Section 203.402 Housing and Urban Development Regulations... items: (a) Taxes, ground rents, water rates, and utility charges that are liens prior to the...

  11. In vitro circadian rhythms: imaging and electrophysiology.

    PubMed

    Beaulé, Christian; Granados-Fuentes, Daniel; Marpegan, Luciano; Herzog, Erik D

    2011-06-30

    In vitro assays have localized circadian pacemakers to individual cells, revealed genetic determinants of rhythm generation, identified molecular players in cell-cell synchronization and determined physiological events regulated by circadian clocks. Although they allow strict control of experimental conditions and reduce the number of variables compared with in vivo studies, they also lack many of the conditions in which cellular circadian oscillators normally function. The present review highlights methods to study circadian timing in cultured mammalian cells and how they have shaped the hypothesis that all cells are capable of circadian rhythmicity. PMID:21819387

  12. In vitro circadian rhythms: imaging and electrophysiology

    PubMed Central

    Beaulé, Christian; Granados-Fuentes, Daniel; Marpegan, Luciano; Herzog, Erik D.

    2013-01-01

    In vitro assays have localized circadian pacemakers to individual cells, revealed genetic determinants of rhythm generation, identified molecular players in cell-cell synchronization and determined physiological events regulated by circadian clocks. Although they allow strict control of experimental conditions and reduce the number of variables compared with in vivo studies, they also lack many of the conditions in which cellular circadian oscillators normally function. The present review highlights methods to study circadian timing in cultured mammalian cells and how they have shaped the hypothesis that all cells are capable of circadian rhythmicity. PMID:21819387

  13. PDP1ε functions downstream of the circadian oscillator to mediate behavioral rhythms Abbreviated title: PDP1ε function in the circadian clock

    PubMed Central

    Benito, Juliana; Zheng, Hao; Hardin, Paul E.

    2007-01-01

    The Drosophila circadian oscillator is comprised of autoregulatory period/timeless (per/tim) and Clock (Clk) feedback loops that control rhythmic transcription. In the Clk loop, CLOCK-CYCLE (CLK-CYC) heterodimers activate vrille (vri) and PAR domain protein 1ε (Pdp1ε) transcription, then sequential repression by VRI and activation by PDP1ε mediate rhythms in Clk transcription. Since VRI and PDP1ε bind the same regulatory element, the VRI/PDP1ε ratio is thought to control the level of Clk transcription. Thus, constant high or low PDP1ε levels in clock cells should eliminate Clk mRNA cycling and disrupt circadian oscillator function. Here we show that reducing PDP1ε levels in clock cells by ~70% via RNA interference or increasing PDP1ε levels by ~10-fold in clock cells does not alter Clk mRNA cycling or circadian oscillator function. However, constant low or high PDP1ε levels in clock cells disrupt locomotor activity rhythms despite persistent circadian oscillator function in brain pacemaker neurons that extend morphologically normal projections into the dorsal brain. These results demonstrate that the VRI/PDP1ε ratio neither controls Clk mRNA cycling nor circadian oscillator function, and argue that PDP1ε is not essential for Clk activation. PDP1ε is nevertheless required for behavioral rhythmicity, which suggests that it functions to regulate oscillator output. PMID:17344391

  14. 27 CFR 19.477 - Use of bulk conveyances.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Use of bulk conveyances... § 19.477 Use of bulk conveyances. If a bulk conveyance meets the construction requirements of § 19.478 or is approved under § 19.473(b), a proprietor may use the bulk conveyance on bonded premises for...

  15. 43 CFR 2720.4 - Issuance of document of conveyance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... MANAGEMENT, DEPARTMENT OF THE INTERIOR LAND RESOURCE MANAGEMENT (2000) CONVEYANCE OF FEDERALLY-OWNED MINERAL INTERESTS Conveyance of Federally-Owned Mineral Interests § 2720.4 Issuance of document of conveyance. Upon... shall issue the necessary document conveying to the applicant the mineral interests of the United...

  16. DEVICE FOR CONVEYING AND ROTATING OBJECTS

    DOEpatents

    Frantz, C.E.; Roslund, J.

    1958-01-21

    A device is described for conveying cylindrical material with a combined rotary and axial motion. The material rides on a series of balls which are retained in a guide plate and rotated by bearing against a rotating drum. The drum has a series of conical sections or grooves cut in its outer surface on which the balls ride. The grooves and balls match in such a way that all the balls are caused to rotate about an axis at an angle to the drum axis. This skewed rotation of the ball imparts a longitudinal as well as a rotary motion to the cylinders being conveyed.

  17. Circadian rhythm and its role in malignancy

    PubMed Central

    2010-01-01

    Circadian rhythms are daily oscillations of multiple biological processes directed by endogenous clocks. The circadian timing system comprises peripheral oscillators located in most tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian genes and the proteins produced by these genes constitute the molecular components of the circadian oscillator which form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends beyond clock genes to involve various clock-controlled genes (CCGs) including various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. Different lines of evidence in mice and humans suggest that cancer may be a circadian-related disorder. The genetic or functional disruption of the molecular circadian clock has been found in various cancers including breast, ovarian, endometrial, prostate and hematological cancers. The acquisition of current data in circadian clock mechanism may help chronotherapy, which takes into consideration the biological time to improve treatments by devising new therapeutic approaches for treating circadian-related disorders, especially cancer. PMID:20353609

  18. Circadian Rhythm Disruption Promotes Lung Tumorigenesis.

    PubMed

    Papagiannakopoulos, Thales; Bauer, Matthew R; Davidson, Shawn M; Heimann, Megan; Subbaraj, Lakshmipriya; Bhutkar, Arjun; Bartlebaugh, Jordan; Vander Heiden, Matthew G; Jacks, Tyler

    2016-08-01

    Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression. PMID:27476975

  19. Circadian rhythms: basic neurobiology and clinical applications.

    PubMed

    Moore, R Y

    1997-01-01

    Circadian rhythms are major features of adaptation to our environment. In mammals, circadian rhythms are generated and regulated by a circadian timing system. This system consists of entertainment pathways, pacemakers, and pace-maker output to effector systems that are under circadian control. The primary entertainment pathway is the retinohypothalamic tract, which terminates in the circadian pacemakers, the suprachiasmatic nuclei of the hypothalamus. The output of the suprachiasmatic nuclei is principally to the hypothalamus, the midline thalamus, and the basal forebrain. This provides a temporal organization to the sleep-wake cycle, to many physiological and endocrine functions, and to psychomotor performance functions. Disorders of circadian timing primarily affect entertainment and pacemaker functions. The pineal hormone, melatonin, appears to be promising agent for therapy of some circadian timing disorders. PMID:9046960

  20. Metabolism and the Circadian Clock Converge

    PubMed Central

    Eckel-Mahan, Kristin

    2013-01-01

    Circadian rhythms occur in almost all species and control vital aspects of our physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. Epidemiological studies from recent decades have supported a unique role for circadian rhythm in metabolism. As evidenced by individuals working night or rotating shifts, but also by rodent models of circadian arrhythmia, disruption of the circadian cycle is strongly associated with metabolic imbalance. Some genetically engineered mouse models of circadian rhythmicity are obese and show hallmark signs of the metabolic syndrome. Whether these phenotypes are due to the loss of distinct circadian clock genes within a specific tissue versus the disruption of rhythmic physiological activities (such as eating and sleeping) remains a cynosure within the fields of chronobiology and metabolism. Becoming more apparent is that from metabolites to transcription factors, the circadian clock interfaces with metabolism in numerous ways that are essential for maintaining metabolic homeostasis. PMID:23303907

  1. A Novel Quantitative Trait Locus on Mouse Chromosome 18, “era1,” Modifies the Entrainment of Circadian Rhythms

    PubMed Central

    Wisor, Jonathan P.; Striz, Martin; DeVoss, Jason; Murphy, Greer M.; Edgar, Dale M.; O'Hara, Bruce F.

    2007-01-01

    Study Objectives: The mammalian circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus conveys 24-h rhythmicity to sleep-wake cycles, locomotor activity, and other behavioral and physiological processes. The timing of rhythms relative to the light/dark (LD12:12) cycle is influenced in part by the endogenous circadian period and the time of day specific sensitivity of the clock to light. We now describe a novel circadian rhythm phenotype, and a locus influencing that phenotype, in a segregating population of mice. Methods: By crossbreeding 2 genetically distinct nocturnal strains of mice (Cast/Ei and C57BL/6J) and backcrossing the resulting progeny to Cast/Ei, we have produced a novel circadian phenotype, called early runner mice. Results: Early runner mice entrain to a light/dark cycle at an advanced phase, up to 9 hours before dark onset. This phenotype is not significantly correlated with circadian period in constant darkness and is not associated with disruption of molecular circadian rhythms in the SCN, as assessed by analysis of period gene expression. We have identified a genomic region that regulates this phenotype—a major quantitative trait locus on chromosome 18 (near D18Mit184) that we have named era1 for Early Runner Activity locus one. Phase delays caused by light exposure early in the subjective night were of smaller magnitude in backcross offspring that were homozygous Cast/Ei at D18Mit184 than in those that were heterozygous at this locus. Conclusion: Genetic variability in the circadian response to light may, in part, explain the variance in phase angle of entrainment in this segregating mouse population. Citation: Wisor JP; Striz M; DeVoss J; Murphy GM; Edgar DM; O'Hara BF. A novel quantitative trait locus on mouse chromosome 18, “era1,” modifies the entrainment of circadian rhythms. SLEEP 2007;30(10):1255-1263. PMID:17969459

  2. Environmental Circadian Disruption Worsens Neurologic Impairment and Inhibits Hippocampal Neurogenesis in Adult Rats After Traumatic Brain Injury.

    PubMed

    Li, Dongpeng; Ma, Shanshan; Guo, Dewei; Cheng, Tian; Li, Hongwei; Tian, Yi; Li, Jianbin; Guan, Fangxia; Yang, Bo; Wang, Jian

    2016-10-01

    Circadian rhythms modulate many physiologic processes and behaviors. Therefore, their disruption causes a variety of potential adverse effects in humans and animals. Circadian disruption induced by constant light exposure has been discovered to produce pathophysiologic consequences after brain injury. However, the underlying mechanisms that lead to more severe impairment and disruption of neurophysiologic processes are not well understood. Here, we evaluated the effect of constant light exposure on the neurobehavioral impairment and survival of neurons in rats after traumatic brain injury (TBI). Sixty adult male Sprague-Dawley rats were subjected to a weight-drop model of TBI and then exposed to either a standard 12-/12-h light/dark cycle or a constant 24-h light/light cycle for 14 days. Our results showed that 14 days of constant light exposure after TBI significantly worsened the sensorimotor and cognitive deficits, which were associated with decreased body weight, impaired water and food intake, increased cortical lesion volume, and decreased neuronal survival. Furthermore, environmental circadian disruption inhibited cell proliferation and newborn cell survival and decreased immature cell production in rats subjected to the TBI model. We conclude that circadian disruption induced by constant light exposure worsens histologic and neurobehavioral impairment and inhibits neurogenesis in adult TBI rats. Our novel findings suggest that light exposure should be decreased and circadian rhythm reestablished in hospitalized TBI patients and that drugs and strategies that maintain circadian rhythm would offer a novel therapeutic option. PMID:26886755

  3. Glucocorticoids as entraining signals for peripheral circadian oscillators.

    PubMed

    Pezük, Pinar; Mohawk, Jennifer A; Wang, Laura A; Menaker, Michael

    2012-10-01

    Mammalian circadian organization is governed by pacemaker neurons in the brain that communicate with oscillators in peripheral tissues. Adrenal glucocorticoids are important time-giving signals to peripheral circadian oscillators. We investigated the rhythm of Per1-luc expression in pineal, pituitary, salivary glands, liver, lung, kidney, cornea as well as suprachiasmatic nucleus from adrenalectomized and sham-operated rats kept under light-dark cycles, or exposed to single 6-h phase delays or advances of their light cycles. Adrenalectomy shifted the phases of Per1-luc in liver, kidney, and cornea and caused phase desynchrony and significant dampening in the rhythmicity of cornea. Treatment with hydrocortisone shifted the phases of Per1-luc in most of the tissues examined, even those that were not affected by adrenalectomy. The rhythm in cornea recovered in animals given hydrocortisone in vivo or when corneas were treated with dexamethasone in vitro. Adrenalectomy increased the rate of reentrainment after phase shifts in liver, kidney, cornea, pineal, lung, and suprachiasmatic nucleus but not in pituitary and salivary glands. Our data show that glucocorticoids act as strong entraining signals for peripheral circadian oscillators and may feed back on central oscillators as well. PMID:22893723

  4. Vasoactive intestinal polypeptide entrains circadian rhythms in astrocytes.

    PubMed

    Marpegan, Luciano; Krall, Thomas J; Herzog, Erik D

    2009-04-01

    Many mammalian cell types show daily rhythms in gene expression driven by a circadian pacemaker. For example, cultured astrocytes display circadian rhythms in Period1 and Period2 expression. It is not known, however, how or which intercellular factors synchronize and sustain rhythmicity in astrocytes. Because astrocytes are highly sensitive to vasoactive intestinal polypeptide (VIP), a neuropeptide released by neurons and important for the coordination of daily cycling, the authors hypothesized that VIP entrains circadian rhythms in astrocytes. They used astrocyte cultures derived from knock-in mice containing a bioluminescent reporter of PERIOD2 (PER2) protein, to assess the effects of VIP on the rhythmic properties of astrocytes. VIP induced a dose-dependent increase in the peak-to-trough amplitude of the ensemble rhythms of PER2 expression with maximal effects near 100 nM VIP and threshold values between 0.1 and 1 nM. VIP also induced dose- and phase-dependent shifts in PER2 rhythms and daily VIP administration entrained bioluminescence rhythms of astrocytes to a predicted phase angle. This is the first demonstration that a neuropeptide can entrain glial cells to a phase predicted by a phase-response curve. The authors conclude that VIP potently entrains astrocytes in vitro and is a candidate for coordinating daily rhythms among glia in the brain. PMID:19346450

  5. Vasoactive intestinal polypeptide entrains circadian rhythms in astrocytes

    PubMed Central

    Marpegan, Luciano; Krall, Thomas J.; Herzog, Erik D.

    2009-01-01

    Many mammalian cell types show daily rhythms in gene expression driven by a circadian pacemaker. For example, cultured astrocytes display circadian rhythms in Period1 and Period2 expression. It is not known, however, how or which intercellular factors synchronize and sustain rhythmicity in astrocytes. Because astrocytes are highly sensitive to vasoactive intestinal polypeptide (VIP), a neuropeptide released by neurons and important for the coordination of daily cycling, we hypothesized that VIP entrains circadian rhythms in astrocytes. We used astrocyte cultures derived from knock-in mice containing a bioluminescent reporter of PERIOD2 (PER2) protein, to assess the effects of VIP on the rhythmic properties of astrocytes. VIP induced a dose-dependent increase in the peak-to-trough amplitude of the ensemble rhythms of PER2 expression with maximal effects near 100nM VIP and threshold values between 0.1 and 1 nM. VIP also induced dose- and phase-dependent shifts in PER2 rhythms and daily VIP administration entrained bioluminescence rhythms of astrocytes to a predicted phase angle. This is the first demonstration that a neuropeptide can entrain glial cells to a phase predicted by a phase response curve. We conclude that VIP potently entrains astrocytes in vitro and is a candidate for coordinating daily rhythms among glia in the brain. PMID:19346450

  6. Class IIa Histone Deacetylases Are Conserved Regulators of Circadian Function*

    PubMed Central

    Fogg, Paul C. M.; O'Neill, John S.; Dobrzycki, Tomasz; Calvert, Shaun; Lord, Emma C.; McIntosh, Rebecca L. L.; Elliott, Christopher J. H.; Sweeney, Sean T.; Hastings, Michael H.; Chawla, Sangeeta

    2014-01-01

    Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca2+ and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. PMID:25271152

  7. Pneumatic conveying of pulverized solvent refined coal

    DOEpatents

    Lennon, Dennis R.

    1984-11-06

    A method for pneumatically conveying solvent refined coal to a burner under conditions of dilute phase pneumatic flow so as to prevent saltation of the solvent refined coal in the transport line by maintaining the transport fluid velocity above approximately 95 ft/sec.

  8. 50 CFR 14.107 - Conveyance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... maintained so as to prevent the harmful ingress of engine exhaust fumes and gases produced by the conveyance... sufficient air for it to breathe normally. Primary enclosures shall be positioned in a cargo space in such a manner that each animal has access to sufficient air for normal breathing. (d) The interior of an...

  9. 50 CFR 14.107 - Conveyance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... maintained so as to prevent the harmful ingress of engine exhaust fumes and gases produced by the conveyance... sufficient air for it to breathe normally. Primary enclosures shall be positioned in a cargo space in such a manner that each animal has access to sufficient air for normal breathing. (d) The interior of an...

  10. 50 CFR 14.107 - Conveyance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... maintained so as to prevent the harmful ingress of engine exhaust fumes and gases produced by the conveyance... sufficient air for it to breathe normally. Primary enclosures shall be positioned in a cargo space in such a manner that each animal has access to sufficient air for normal breathing. (d) The interior of an...

  11. 33 CFR 211.80 - Conveyance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 3 2012-07-01 2012-07-01 false Conveyance. 211.80 Section 211.80 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE REAL ESTATE ACTIVITIES OF THE CORPS OF ENGINEERS IN CONNECTION WITH CIVIL WORKS PROJECTS Sale of Lands in Reservoir...

  12. 33 CFR 211.80 - Conveyance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Conveyance. 211.80 Section 211.80 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE REAL ESTATE ACTIVITIES OF THE CORPS OF ENGINEERS IN CONNECTION WITH CIVIL WORKS PROJECTS Sale of Lands in Reservoir...

  13. 33 CFR 211.80 - Conveyance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Conveyance. 211.80 Section 211.80 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE REAL ESTATE ACTIVITIES OF THE CORPS OF ENGINEERS IN CONNECTION WITH CIVIL WORKS PROJECTS Sale of Lands in Reservoir...

  14. 33 CFR 211.80 - Conveyance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 3 2013-07-01 2013-07-01 false Conveyance. 211.80 Section 211.80 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE REAL ESTATE ACTIVITIES OF THE CORPS OF ENGINEERS IN CONNECTION WITH CIVIL WORKS PROJECTS Sale of Lands in Reservoir...

  15. 33 CFR 211.147 - Conveyance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Conveyance. 211.147 Section 211.147 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE REAL ESTATE ACTIVITIES OF THE CORPS OF ENGINEERS IN CONNECTION WITH CIVIL WORKS PROJECTS...

  16. The circadian rhythm induced by the heterogeneous network structure of the suprachiasmatic nucleus.

    PubMed

    Gu, Changgui; Yang, Huijie

    2016-05-01

    In mammals, the master clock is located in the suprachiasmatic nucleus (SCN), which is composed of about 20 000 nonidentical neuronal oscillators expressing different intrinsic periods. These neurons are coupled through neurotransmitters to form a network consisting of two subgroups, i.e., a ventrolateral (VL) subgroup and a dorsomedial (DM) subgroup. The VL contains about 25% SCN neurons that receive photic input from the retina, and the DM comprises the remaining 75% SCN neurons which are coupled to the VL. The synapses from the VL to the DM are evidently denser than that from the DM to the VL, in which the VL dominates the DM. Therefore, the SCN is a heterogeneous network where the neurons of the VL are linked with a large number of SCN neurons. In the present study, we mimicked the SCN network based on Goodwin model considering four types of networks including an all-to-all network, a Newman-Watts (NW) small world network, an Erdös-Rényi (ER) random network, and a Barabási-Albert (BA) scale free network. We found that the circadian rhythm was induced in the BA, ER, and NW networks, while the circadian rhythm was absent in the all-to-all network with weak cellular coupling, where the amplitude of the circadian rhythm is largest in the BA network which is most heterogeneous in the network structure. Our finding provides an alternative explanation for the induction or enhancement of circadian rhythm by the heterogeneity of the network structure. PMID:27249952

  17. Temporal Requirements of the Fragile X Mental Retardation Protein in Modulating Circadian Clock Circuit Synaptic Architecture

    PubMed Central

    Gatto, Cheryl L.; Broadie, Kendal

    2009-01-01

    Loss of fragile X mental retardation 1 (FMR1) gene function is the most common cause of inherited mental retardation and autism spectrum disorders, characterized by attention disorder, hyperactivity and disruption of circadian activity cycles. Pursuit of effective intervention strategies requires determining when the FMR1 product (FMRP) is required in the regulation of neuronal circuitry controlling these behaviors. In the well-characterized Drosophila disease model, loss of the highly conserved dFMRP causes circadian arrhythmicity and conspicuous abnormalities in the circadian clock circuitry. Here, a novel Sholl Analysis was used to quantify over-elaborated synaptic architecture in dfmr1-null small ventrolateral neurons (sLNvs), a key subset of clock neurons. The transgenic Gene-Switch system was employed to drive conditional neuronal dFMRP expression in the dfmr1-null mutant background in order to dissect temporal requirements within the clock circuit. Introduction of dFMRP during early brain development, including the stages of neurogenesis, neuronal fate specification and early pathfinding, provided no rescue of dfmr1 mutant phenotypes. Similarly, restoring normal dFMRP expression in the adult failed to restore circadian circuit architecture. In sharp contrast, supplying dFMRP during a transient window of very late brain development, wherein synaptogenesis and substantial subsequent synaptic reorganization (e.g. use-dependent pruning) occur, provided strong morphological rescue to reestablish normal sLNvs synaptic arbors. We conclude that dFMRP plays a developmentally restricted role in sculpting synaptic architecture in these neurons that cannot be compensated for by later reintroduction of the protein at maturity. PMID:19738924

  18. The circadian rhythm induced by the heterogeneous network structure of the suprachiasmatic nucleus

    NASA Astrophysics Data System (ADS)

    Gu, Changgui; Yang, Huijie

    2016-05-01

    In mammals, the master clock is located in the suprachiasmatic nucleus (SCN), which is composed of about 20 000 nonidentical neuronal oscillators expressing different intrinsic periods. These neurons are coupled through neurotransmitters to form a network consisting of two subgroups, i.e., a ventrolateral (VL) subgroup and a dorsomedial (DM) subgroup. The VL contains about 25% SCN neurons that receive photic input from the retina, and the DM comprises the remaining 75% SCN neurons which are coupled to the VL. The synapses from the VL to the DM are evidently denser than that from the DM to the VL, in which the VL dominates the DM. Therefore, the SCN is a heterogeneous network where the neurons of the VL are linked with a large number of SCN neurons. In the present study, we mimicked the SCN network based on Goodwin model considering four types of networks including an all-to-all network, a Newman-Watts (NW) small world network, an Erdös-Rényi (ER) random network, and a Barabási-Albert (BA) scale free network. We found that the circadian rhythm was induced in the BA, ER, and NW networks, while the circadian rhythm was absent in the all-to-all network with weak cellular coupling, where the amplitude of the circadian rhythm is largest in the BA network which is most heterogeneous in the network structure. Our finding provides an alternative explanation for the induction or enhancement of circadian rhythm by the heterogeneity of the network structure.

  19. Circadian rhythm dissociation in an environment with conflicting temporal information

    NASA Technical Reports Server (NTRS)

    Sulzman, F. M.; Fuller, C. A.; Hiles, L. G.; Moore-Ede, M. C.

    1978-01-01

    The relative contributions of light-dark (LD) cycles and eating-fasting (EF) cycles in providing temporal information to the circadian time-keeping system were examined in chair-acclimatized squirrel monkeys (Saimiri sciureus). The circadian rhythms of drinking, colonic temperature, urine volume, and urinary potassium excretion were measured with the LD and EF cycles providing either conflicting phases or periods. In conflicting phase experiments, animals were exposed to 24-hr LD cycles consisting of 12 hr of 600 lx followed by 12 hr of less than 1 lx and concurrent 24-hr EF cycles in which the animals ate for 3 hr and then fasted for 21 hr. One group had food available at the beginning and a second group at the end of the light period. In conflicting period experiments, monkeys were exposed to 23-hr LD cycles and 24-hr EF cycles. Analysis of the rhythms showed that both phase and period information were conveyed to the drinking and urinary rhythms by the EF cycle, and to the temperature rhythm by the LD cycle.

  20. The neurochemical basis of photic entrainment of the circadian pacemaker

    NASA Technical Reports Server (NTRS)

    Rea, Michael A.; Buckley, Becky; Lutton, Lewis M.

    1992-01-01

    Circadian rhythmicity in mammals is controlled by the action of a light-entrainable hypothalamus, in association with two cell clusters known as the supra chiasmatic nuclei (SCN). In the absence of temporal environmental clues, this pacemaker continues to measure time by an endogenous mechanism (clock), driving biochemical, physiological, and behavioral rhythms that reflect the natural period of the pacemaker oscillation. This endogenous period usually differs slightly from 24 hours (i.e., circadian). When mammals are maintained under a 24 hour light-dark (LD) cycle, the pacemaker becomes entrained such that the period of the pacemaker oscillation matches that of the LD cycle. Potentially entraining photic information is conveyed to the SCN via a direct retinal projection, the retinohypothalamic tract (RHT). RHT neurotransmission is thought to be mediated by the release of excitatory amino acids (EAA) in the SCN. In support of this hypothesis, recent experiments using nocturnal rodents have shown that EAA antagonists block the effects of light on pacemaker-driven behavioral rhythms, and attenuate light induced gene expression in SCN cells. An understanding of the neurochemical basis of the photic entrainment process would facilitate the development of pharmacological strategies for maintaining synchrony among shift workers in environments, such as the Space Station, which provide unreliable or conflicting temporal photic clues.

  1. Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour

    PubMed Central

    Doi, Masao; Murai, Iori; Kunisue, Sumihiro; Setsu, Genzui; Uchio, Naohiro; Tanaka, Rina; Kobayashi, Sakurako; Shimatani, Hiroyuki; Hayashi, Hida; Chao, Hsu-Wen; Nakagawa, Yuuki; Takahashi, Yukari; Hotta, Yunhong; Yasunaga, Jun-ichirou; Matsuoka, Masao; Hastings, Michael H.; Kiyonari, Hiroshi; Okamura, Hitoshi

    2016-01-01

    G-protein-coupled receptors (GPCRs) participate in a broad range of physiological functions. A priority for fundamental and clinical research, therefore, is to decipher the function of over 140 remaining orphan GPCRs. The suprachiasmatic nucleus (SCN), the brain's circadian pacemaker, governs daily rhythms in behaviour and physiology. Here we launch the SCN orphan GPCR project to (i) search for murine orphan GPCRs with enriched expression in the SCN, (ii) generate mutant animals deficient in candidate GPCRs, and (iii) analyse the impact on circadian rhythms. We thereby identify Gpr176 as an SCN-enriched orphan GPCR that sets the pace of circadian behaviour. Gpr176 is expressed in a circadian manner by SCN neurons, and molecular characterization reveals that it represses cAMP signalling in an agonist-independent manner. Gpr176 acts independently of, and in parallel to, the Vipr2 GPCR, not through the canonical Gi, but via the unique G-protein subclass Gz. PMID:26882873

  2. Using light to tell the time of day: sensory coding in the mammalian circadian visual network.

    PubMed

    Brown, Timothy M

    2016-06-15

    Circadian clocks are a near-ubiquitous feature of biology, allowing organisms to optimise their physiology to make the most efficient use of resources and adjust behaviour to maximise survival over the solar day. To fulfil this role, circadian clocks require information about time in the external world. This is most reliably obtained by measuring the pronounced changes in illumination associated with the earth's rotation. In mammals, these changes are exclusively detected in the retina and are relayed by direct and indirect neural pathways to the master circadian clock in the hypothalamic suprachiasmatic nuclei. Recent work reveals a surprising level of complexity in this sensory control of the circadian system, including the participation of multiple photoreceptive pathways conveying distinct aspects of visual and/or time-of-day information. In this Review, I summarise these important recent advances, present hypotheses as to the functions and neural origins of these sensory signals, highlight key challenges for future research and discuss the implications of our current knowledge for animals and humans in the modern world. PMID:27307539

  3. Using light to tell the time of day: sensory coding in the mammalian circadian visual network

    PubMed Central

    2016-01-01

    ABSTRACT Circadian clocks are a near-ubiquitous feature of biology, allowing organisms to optimise their physiology to make the most efficient use of resources and adjust behaviour to maximise survival over the solar day. To fulfil this role, circadian clocks require information about time in the external world. This is most reliably obtained by measuring the pronounced changes in illumination associated with the earth's rotation. In mammals, these changes are exclusively detected in the retina and are relayed by direct and indirect neural pathways to the master circadian clock in the hypothalamic suprachiasmatic nuclei. Recent work reveals a surprising level of complexity in this sensory control of the circadian system, including the participation of multiple photoreceptive pathways conveying distinct aspects of visual and/or time-of-day information. In this Review, I summarise these important recent advances, present hypotheses as to the functions and neural origins of these sensory signals, highlight key challenges for future research and discuss the implications of our current knowledge for animals and humans in the modern world. PMID:27307539

  4. Ribosomal S6 Kinase Cooperates with Casein Kinase 2 to Modulate the Drosophila Circadian Molecular Oscillator

    PubMed Central

    Akten, Bikem; Tangredi, Michelle M.; Jauch, Eike; Roberts, Mary A.; Ng, Fanny; Raabe, Thomas; Jackson, F. Rob

    2009-01-01

    There is a universal requirement for post-translational regulatory mechanisms in circadian clock systems. Previous work in Drosophila has identified several kinases, phosphatases and an E3 ligase that are critical for determining the nuclear translocation and/or stability of clock proteins. The present study evaluated the function of p90 ribosomal S6 kinase (RSK) in the Drosophila circadian system. In mammals, RSK1 is a light- and clock-regulated kinase known to be activated by the MAPK pathway, but there is no direct evidence that it functions as a component of the circadian system. Here, we show that Drosophila S6KII RNA displays rhythms in abundance, indicative of circadian control. Importantly, an S6KII null mutant exhibits a short-period circadian phenotype that can be rescued by expression of the wild-type gene in clock neurons, indicating a role for S6KII in the molecular oscillator. Peak PER clock protein expression is elevated in the mutant, indicative of enhanced stability, whereas per mRNA level is decreased, consistent with enhanced feedback repression. Gene reporter assays show that decreased S6KII is associated with increased PER repression. Surprisingly, we demonstrate a physical interaction between S6KII and the Casein Kinase 2 regulatory subunit (CK2β), suggesting a functional relationship between the two kinases. In support of such a relationship, there are genetic interactions between S6KII and CK2 mutations, in vivo, which indicate that CK2 activity is required for S6KII action. We propose that the two kinases cooperate within clock neurons to fine-tune circadian period, improving the precision of the clock mechanism. PMID:19144847

  5. CIRCADIAN RHYTHM REPROGRAMMING DURING LUNG INFLAMMATION

    PubMed Central

    Haspel, Jeffrey A.; Chettimada, Sukrutha; Shaik, Rahamthulla S.; Chu, Jen-Hwa; Raby, Benjamin A.; Cernadas, Manuela; Carey, Vincent; Process, Vanessa; Hunninghake, G. Matthew; Ifedigbo, Emeka; Lederer, James A.; Englert, Joshua; Pelton, Ashley; Coronata, Anna; Fredenburgh, Laura E.; Choi, Augustine M. K.

    2014-01-01

    Circadian rhythms are known to regulate immune responses in healthy animals, but it is unclear whether they persist during acute illnesses where clock gene expression is disrupted by systemic inflammation. Here, we use a genome-wide approach to investigate circadian gene and metabolite expression in the lungs of endotoxemic mice and find that novel cellular and molecular circadian rhythms are elicited in this setting. The endotoxin-specific circadian program exhibits unique features, including a divergent group of rhythmic genes and metabolites compared to the basal state and a distinct periodicity and phase distribution. At the cellular level endotoxin treatment also alters circadian rhythms of leukocyte counts within the lung in a bmal1-dependent manner, such that granulocytes rather than lymphocytes become the dominant oscillating cell type. Our results show that inflammation produces a complex reorganization of cellular and molecular circadian rhythms that are relevant to early events in lung injury. PMID:25208554

  6. Mechanism of the circadian clock in physiology

    PubMed Central

    Richards, Jacob

    2013-01-01

    It has been well established that the circadian clock plays a crucial role in the regulation of almost every physiological process. It also plays a critical role in pathophysiological states including those of obesity and diabetes. Recent evidence has highlighted the potential for targeting the circadian clock as a potential drug target. New studies have also demonstrated the existence of “clock-independent effects” of the circadian proteins, leading to exciting new avenues of research in the circadian clock field in physiology. The goal of this review is to provide an introduction to and overview of the circadian clock in physiology, including mechanisms, targets, and role in disease states. The role of the circadian clocks in the regulation of the cardiovascular system, renal function, metabolism, the endocrine system, immune, and reproductive systems will be discussed. PMID:23576606

  7. Role of Circadian Rhythms in Potassium Homeostasis

    PubMed Central

    Gumz, Michelle L.; Rabinowitz, Lawrence

    2013-01-01

    It has been known for decades that urinary potassium excretion varies with a circadian pattern. In this review, we consider the historical evidence for this phenomenon and present an overview of recent developments in the field. Extensive evidence from the latter part of the last century clearly demonstrates that circadian potassium excretion does not depend on endogenous aldosterone. Of note is the recent discovery that the expression of several renal potassium transporters varies with a circadian pattern that appears to be consistent with substantial clinical data regarding daily fluctuations in urinary potassium levels. We propose the circadian clock mechanism as a key regulator of renal potassium transporters, and consequently renal potassium excretion. Further investigation into the mechanism of regulation of renal potassium transport by the circadian clock is warranted in order to increase our understanding of the clinical relevance of circadian rhythms to potassium homeostasis. PMID:23953800

  8. Metabolic and Nontranscriptional Circadian Clocks: Eukaryotes

    PubMed Central

    Reddy, Akhilesh B.; Rey, Guillaume

    2016-01-01

    Circadian clocks are cellular timekeeping mechanisms that coordinate behavior and physiology around the 24-h day in most living organisms. Misalignment of an organism’s clock with its environment is associated with long-term adverse fitness consequences, as exemplified by the link between circadian disruption and various age-related diseases in humans. Current eukaryotic models of the circadian oscillator rely on transcription/translation feedback loop mechanisms, supplemented with accessory cytosolic loops that connect them to cellular physiology. However, there is mounting evidence questioning the absolute necessity of transcription-based oscillators for circadian rhythmicity, supported by the recent discovery of oxidation-reduction cycles of peroxiredoxin proteins, which persist even in the absence of transcription. A more fundamental mechanism based on metabolic cycles could thus underlie circadian transcriptional and cytosolic rhythms, thereby promoting circadian oscillations to integral properties of cellular metabolism. PMID:24606143

  9. WIDE AWAKE mediates the circadian timing of sleep onset.

    PubMed

    Liu, Sha; Lamaze, Angelique; Liu, Qili; Tabuchi, Masashi; Yang, Yong; Fowler, Melissa; Bharadwaj, Rajnish; Zhang, Julia; Bedont, Joseph; Blackshaw, Seth; Lloyd, Thomas E; Montell, Craig; Sehgal, Amita; Koh, Kyunghee; Wu, Mark N

    2014-04-01

    How the circadian clock regulates the timing of sleep is poorly understood. Here, we identify a Drosophila mutant, wide awake (wake), that exhibits a marked delay in sleep onset at dusk. Loss of WAKE in a set of arousal-promoting clock neurons, the large ventrolateral neurons (l-LNvs), impairs sleep onset. WAKE levels cycle, peaking near dusk, and the expression of WAKE in l-LNvs is Clock dependent. Strikingly, Clock and cycle mutants also exhibit a profound delay in sleep onset, which can be rescued by restoring WAKE expression in LNvs. WAKE interacts with the GABAA receptor Resistant to Dieldrin (RDL), upregulating its levels and promoting its localization to the plasma membrane. In wake mutant l-LNvs, GABA sensitivity is decreased and excitability is increased at dusk. We propose that WAKE acts as a clock output molecule specifically for sleep, inhibiting LNvs at dusk to promote the transition from wake to sleep. PMID:24631345

  10. Pipes Conveying Fluid: A Model Dynamical Problem

    NASA Astrophysics Data System (ADS)

    Païdoussis, M. P.; Li, G. X.

    1993-02-01

    This paper reviews the dynamics of pipes conveying fluid and presents a selective review of the research undertaken on it. It is endeavoured to show that this system is fast becoming a new paradigm in dynamics, on a par with, for instance, the classical problem of the column subjected to compressive loading, but one capable of displaying much richer dynamical behaviour. The dynamics of pipes with supported ends, cantilevered pipes or with unusual boundary conditions; continuously flexible pipes or articulated ones; pipe conveying incompressible or compressible fluid, with steady or unsteady flow velocity; pipes thin enough to be treated as thin shells; linear, nonlinear and chaotic dynamics; these and many more are some of the aspects of the problem considered. An Appendix is provided for those unfamiliar with the modern methods of nonlinear analysis.

  11. Putative Pacemakers in the Eyestalk and Brain of the Crayfish Procambarus clarkii Show Circadian Oscillations in Levels of mRNA for Crustacean Hyperglycemic Hormone

    PubMed Central

    Nelson-Mora, Janikua; Prieto-Sagredo, Julio; Loredo-Ranjel, Rosaura; Fanjul-Moles, María Luisa

    2013-01-01

    Crustacean hyperglycemic hormone (CHH) synthesizing cells in the optic lobe, one of the pacemakers of the circadian system, have been shown to be present in crayfish. However, the presence of CHH in the central brain, another putative pacemaker of the multi-oscillatory circadian system, of this decapod and its circadian transcription in the optic lobe and brain have yet to be explored. Therefore, using qualitative and quantitative PCR, we isolated and cloned a CHH mRNA fragment from two putative pacemakers of the multi-oscillatory circadian system of Procambarus clarkii, the optic lobe and the central brain. This CHH transcript synchronized to daily light-dark cycles and oscillated under dark, constant conditions demonstrating statistically significant daily and circadian rhythms in both structures. Furthermore, to investigate the presence of the peptide in the central brain of this decapod, we used immunohistochemical methods. Confocal microscopy revealed the presence of CHH-IR in fibers and cells of the protocerebral and tritocerebal clusters and neuropiles, particularly in some neurons located in clusters 6, 14, 15 and 17. The presence of CHH positive neurons in structures of P. clarkii where clock proteins have been reported suggests a relationship between the circadian clockwork and CHH. This work provides new insights into the circadian regulation of CHH, a pleiotropic hormone that regulates many physiological processes such as glucose metabolism and osmoregulatory responses to stress. PMID:24391849

  12. Plasticity of circadian clocks and consequences for metabolism.

    PubMed

    Coomans, C P; Lucassen, E A; Kooijman, S; Fifel, K; Deboer, T; Rensen, P C N; Michel, S; Meijer, J H

    2015-09-01

    The increased prevalence of metabolic disorders and obesity in modern society, together with the widespread use of artificial light at night, have led researchers to investigate whether altered patterns of light exposure contribute to metabolic disorders. This article discusses the experimental evidence that perturbed environmental cycles induce rhythm disorders in the circadian system, thus leading to metabolic disorders. This notion is generally supported by animal studies. Distorted environmental cycles, including continuous exposure to light, affect the neuronal organization of the central circadian pacemaker in the suprachiasmatic nucleus (SCN), its waveform and amplitude of the rhythm in electrical activity. Moreover, repeated exposure to a shifted light cycle or the application of dim light at night are environmental cues that cause a change in SCN function. The effects on the SCN waveform are the result of changes in synchronization among the SCN's neuronal cell population, which lead consistently to metabolic disturbances. Furthermore, we discuss the effects of sleep deprivation and the time of feeding on metabolism, as these factors are associated with exposure to disturbed environmental cycles. Finally, we suggest that these experimental studies reveal a causal relationship between the rhythm disorders and the metabolic disorders observed in epidemiological studies performed in humans. PMID:26332970

  13. Distinct visual pathways mediate Drosophila larval light avoidance and circadian clock entrainment.

    PubMed

    Keene, Alex C; Mazzoni, Esteban O; Zhen, Jamie; Younger, Meg A; Yamaguchi, Satoko; Blau, Justin; Desplan, Claude; Sprecher, Simon G

    2011-04-27

    Visual organs perceive environmental stimuli required for rapid initiation of behaviors and can also entrain the circadian clock. The larval eye of Drosophila is capable of both functions. Each eye contains only 12 photoreceptors (PRs), which can be subdivided into two subtypes. Four PRs express blue-sensitive rhodopsin5 (rh5) and eight express green-sensitive rhodopsin6 (rh6). We found that either PR-subtype is sufficient to entrain the molecular clock by light, while only the Rh5-PR subtype is essential for light avoidance. Acetylcholine released from PRs confers both functions. Both subtypes of larval PRs innervate the main circadian pacemaker neurons of the larva, the neuropeptide PDF (pigment-dispersing factor)-expressing lateral neurons (LNs), providing sensory input to control circadian rhythms. However, we show that PDF-expressing LNs are dispensable for light avoidance, and a distinct set of three clock neurons is required. Thus we have identified distinct sensory and central circuitry regulating light avoidance behavior and clock entrainment. Our findings provide insights into the coding of sensory information for distinct behavioral functions and the underlying molecular and neuronal circuitry. PMID:21525293

  14. The circadian clock gene period extends healthspan in aging Drosophila melanogaster

    PubMed Central

    Krishnan, Natraj; Kretzschmar, Doris; Rakshit, Kuntol; Chow, Eileen; Giebultowicz, Jadwiga M.

    2009-01-01

    There is increasing evidence that aging is affected by biological (circadian) clocks - the internal mechanisms that coordinate daily changes in gene expression, physiological functions and behavior with external day/night cycles. Recent data suggest that disruption of the mammalian circadian clock results in accelerated aging and increased age-related pathologies such as cancer; however, the links between loss of daily rhythms and aging are not understood. We sought to determine whether disruption of the circadian clock affects lifespan and healthspan in the model organism Drosophila melanogaster. We examined effects of a null mutation in the circadian clock gene period (per01) on the fly healthspan by challenging aging flies with short-term oxidative stress (24h hyperoxia) and investigating their response in terms of mortality hazard, levels of oxidative damage, and functional senescence. Exposure to 24h hyperoxia during middle age significantly shortened the life expectancy in per01 but not in control flies. This homeostatic challenge also led to significantly higher accumulation of oxidative damage in per01 flies compared to controls. In addition, aging per01 flies showed accelerated functional decline, such as lower climbing ability and increased neuronal degeneration compared to age-matched controls. Together, these data suggest that impaired stress defense pathways may contribute to accelerated aging in the per mutant. In addition, we show that the expression of per gene declines in old wild type flies, suggesting that the circadian regulatory network becomes impaired with age. PMID:20157575

  15. Dose-Dependent Effects of Androgens on the Circadian Timing System and Its Response to Light

    PubMed Central

    Butler, Matthew P.; Karatsoreos, Ilia N.; LeSauter, Joseph

    2012-01-01

    The hypothalamic suprachiasmatic nucleus (SCN) is the locus of a master clock that regulates circadian rhythms in physiology and behavior. Gonadectomy in male mice lengthens the period of circadian rhythms and increases the day-to-day variability of activity onset time. Both of these responses are rescued by the nonaromatizable androgen dihydrotestosterone. Androgen receptors (AR) are localized in SCN neurons that receive direct retinal input. To explore how androgens affect circadian clock function and its responsiveness to photic cues, we measured wheel-running behavior and SCN AR expression in intact, gonadectomized, and testosterone-replaced mice, held under various photic conditions. Gonadectomy lengthened circadian period in constant dim light but not in constant darkness. Increasing intensities of constant light parametrically increased circadian period, and this was potentiated at all intensities by gonadectomy. In contrast, gonadectomy did not alter light-induced pupil constriction, suggesting a nonretinal locus of hormone action. In hormone-replaced animals housed in constant darkness, T concentration was positively correlated with precision of activity onset and with SCN AR expression and negatively correlated with duration of activity. We infer the existence of two androgenic mechanisms: one modulates SCN responsiveness to light, and the second modulates SCN timekeeping and locomotor activity in a dose-dependent manner. Finally, the effects of androgens on period are a result of hormonal modulation of the SCN's response to photic input rather than to a change in the inherent period of oscillators in the absence of light. PMID:22492303

  16. Hippocampal PER1: a circadian sentinel controlling RSKy activity during memory formation.

    PubMed

    Yoo, Seung-Hee; Eckel-Mahan, Kristin

    2016-09-01

    Studies have demonstrated a pronounced dependence of memory formation on circadian time; however, the numerous mechanisms underlying this reliance are only beginning to be understood. While the 24-h cellular clock controls various aspects of hippocampal memory formation, its consolidation in particular (i.e., its conversion from short-term to long-term memory), appears to be heavily dependent on circadian activity in hippocampal neurons. Hippocampal memory consolidation requires phosphorylation of the cAMP Response Element-Binding protein, CREB, which upon phosphorylation promotes the transcription of genes necessary for long-term memory formation. Rhythmic cAMP/ERK-MAPK activity upstream of CREB is a necessary component. This Editorial highlights a study by Rawashdeh and coworkers, in which the authors establish the circadian clock gene Period1 (Per1) as a regulator of CREB phosphorylation in the mouse hippocampus, and thus reveal a functional link between circadian rhythms and learning efficiency. Read the highlighted article 'Period1 gates the circadian modulation of memory-relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pP90RSK' on page 731. PMID:27554418

  17. Optimizing pneumatic conveying of biomass materials

    NASA Astrophysics Data System (ADS)

    DiCianni, Matthew Edward Michael

    2011-12-01

    Biomass is a readily available but underutilized energy resource. One of the main challenges is the inability of biomass feed stocks like corn stover or wood chips to flow freely without intermittent jamming. This research integrated an automated pneumatic conveying system to efficiently transport biomass into a biomass reactor. Material was held in a storage container until an end effector attached to a 3-axis controller engaged the material to flow through pneumatic vacuum in the carrier fluid of air. The material was disengaged from the carrier fluid through centripetal forces induced by a cyclone separator. As the air was pulled out of the cyclone, the biomass drops out the bottom due to gravitational forces and fell into a secondary storage hopper. The second storage container was for testing purposes only, where the actual apparatus would use a vertically oriented lock hopper to feed material into the biomass reactor. In the experimental test apparatus, sensors measured the storage hopper weight (mass-flow rate), pressure drop from the blower, and input power consumption of the motor. Parameters that were adjusted during testing include pipe diameter, material type, and motor speed. Testing indicated that decreasing the motor speed below its maximum still allows for conveyance of the material without blockage forming in the piping. The data shows that the power consumption of the system can be reduced based on the size and weight of the material introduced to the conveying pipe. Also, conveying certain materials proved to be problematic with particular duct diameters. Ultimately, an optimal duct diameter that can perform efficiently for a broad range of materials was chosen for the given system. Through these improvements, the energy return on investment will be improved for biomass feed stocks, which is taking a step in the right direction to secure the nation's energy independence.

  18. Circadian clocks: lessons from fish.

    PubMed

    Idda, M Laura; Bertolucci, Cristiano; Vallone, Daniela; Gothilf, Yoav; Sánchez-Vázquez, Francisco Javier; Foulkes, Nicholas S

    2012-01-01

    Our understanding of the molecular and cellular organization of the circadian timing system in vertebrates has increased enormously over the past decade. In large part, progress has been based on genetic studies in the mouse as well as on fundamental similarities between vertebrate and Drosophila clocks. The zebrafish was initially considered as a potentially attractive genetic model for identifying vertebrate clock genes. However, instead, fish have ultimately proven to be valuable complementary models for studying various aspects of clock biology. For example, many fish can shift from diurnal to nocturnal activity implying specific flexibility in their clock function. We have learned much about the function of light input pathways, and the ontogeny and function of the pineal organ, the fish central pacemaker. Finally, blind cavefish have also provided new insight into the evolution of the circadian clock under extreme environmental conditions. PMID:22877658

  19. Circadian Rhythm Control: Neurophysiological Investigations

    NASA Technical Reports Server (NTRS)

    Glotzbach, S. F.

    1985-01-01

    The suprachiasmatic nucleus (SCN) was implicated as a primary component in central nervous system mechanisms governing circadian rhythms. Disruption of the normal synchronization of temperature, activity, and other rhythms is detrimental to health. Sleep wake disorders, decreases in vigilance and performance, and certain affective disorders may result from or be exacerbated by such desynchronization. To study the basic neurophysiological mechanisms involved in entrainment of circadian systems by the environment, Parylene-coated, etched microwire electrode bundles were used to record extracellular action potentials from the small somata of the SCN and neighboring hypothalamic nuclei in unanesthetized, behaving animals. Male Wistar rats were anesthetized and chronically prepared with EEG ane EMG electrodes in addition to a moveable microdrive assembly. The majority of cells had firing rates 10 Hz and distinct populations of cells which had either the highest firing rate or lowest firing rate during sleep were seen.

  20. Circadian rhythmometry of mammalian radiosensitivity

    NASA Technical Reports Server (NTRS)

    Haus, E.; Halberg, F.; Loken, M. K.; Kim, Y. S.

    1974-01-01

    In the case of human bone marrow, the largest number of mitoses is seen in the evening in diurnally active men, mitotic activity being at a minimum in the morning. The opposite pattern is observed for nocturnal animals such as rats and mice on a regimen of light during the daytime alternating with darkness during the night hours. The entirety of these rhythms plays an important role in the organism's responses to environmental stimuli, including its resistance to potentially harmful agents. Conditions under which circadian rhythms can be observed and validated by inferential statistical means are discussed while emphasizing how artifacts of the laboratory environment can be shown to obscure circadian periodic variations in radiosensitivity.

  1. Intrinsic and extrinsic cues regulate the daily profile of mouse lateral habenula neuronal activity

    PubMed Central

    Sakhi, Kanwal; Wegner, Sven; Belle, Mino D C; Howarth, Michael; Delagrange, Philippe; Brown, Timothy M; Piggins, Hugh D

    2014-01-01

    The epithalamic lateral habenula (LHb) is implicated as part of the mammalian brain's circadian system. Anatomical evidence suggests that the LHb receives extrinsic circadian timing cues from retinal ganglion cells and the master clock in the suprachiasmatic nuclei (SCN). Intriguingly, some LHb neurones contain the molecular circadian clock, but it is unclear if and how intrinsic and extrinsic circadian processes influence neuronal activity in the mouse LHb. Here, using an in vitro brain slice preparation isolating the LHb from the SCN, we show through whole-cell patch-clamp recordings that LHb neurones exhibit heterogeneity in their resting state, but the majority spontaneously fire action potentials (APs). Discharge rate of APs varied from low firing in the early day to higher firing later in the day and was absent in LHb brain slices prepared from Cry1−/−Cry2−/− mice that lack a functional molecular clock. Low amplitude circadian oscillations in the molecular circadian clock were also monitored in LHb brain slices, but were absent in Cry1−/−Cry2−/− LHb brain tissue. A putative neurochemical output signal of the SCN, prokineticin 2 (PK2), inhibited some LHb neurones by elevating the frequency of GABA release in the LHb. Using multi-electrode recordings in vivo, we found that LHb neurones sluggishly respond to retinal illumination, suggesting that they receive such information through polysynaptic processes. In summary, our results show for the first time that intrinsic circadian signals are important for regulating LHb neuronal state, while the SCN-derived signal PK2 is less influential. Moreover, we demonstrate that mouse LHb neurones have access to and can respond to visual input, but such signals are unlikely to be directly communicated to the LHb. Broadly, these findings raise the possibility that intrinsic circadian signals are likely to be influential in shaping LHb contributions to cognition and emotionality. PMID:25194046

  2. Circadian rhythms: glucocorticoids and arthritis.

    PubMed

    Cutolo, Maurizio; Sulli, Alberto; Pizzorni, Carmen; Secchi, Maria Elena; Soldano, Stefano; Seriolo, Bruno; Straub, Rainer H; Otsa, Kati; Maestroni, Georges J

    2006-06-01

    Circadian rhythms are driven by biological clocks and are endogenous in origin. Therefore, circadian changes in the metabolism or secretion of endogenous glucocorticoids are certainly responsible in part for the time-dependent changes observed in the inflammatory response and arthritis. More recently, melatonin (MLT), another circadian hormone that is the secretory product of the pineal gland, has been found implicated in the time-dependent inflammatory reaction with effects opposite those of cortisol. Interestingly, cortisol and MLT show an opposite response to the light. The light conditions in the early morning have a strong impact on the morning cortisol peak, whereas MLT is synthesized in a strictly nocturnal pattern. Recently, a diurnal rhythmicity in healthy humans between cellular (Th1 type) or humoral (Th2 type) immune responses has been found and related to immunomodulatory actions of cortisol and MLT. The interferon (IFN)-gamma/interleukin (IL)-10 ratio peaked during the early morning and correlated negatively with plasma cortisol and positively with plasma MLT. Accordingly, the intensity of the arthritic pain varies consistently as a function of the hour of the day: pain is greater after waking up in the morning than in the afternoon or evening. The reduced cortisol and adrenal androgen secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with glucocoticoids, should be clearly considered as a "relative adrenal insufficiency" in the presence of a sustained inflammatory process, and allows Th1 type cytokines to be produced in higher amounts during the late night. In conclusion, the right timing (early morning) for the glucocorticoid therapy in arthritis is fundamental and well justified by the circadian rhythms of the inflammatory mechanisms. PMID:16855156

  3. Circadian rhythms and cancer chemotherapy.

    PubMed

    Wood, P A; Hrushesky, W J

    1996-01-01

    Temporal coordination of biologic processes with an approximately 24-h cycle (circadian) is common throughout the animal and plant kingdom and even in some prokaryotic organisms. In all organisms studied, the capability to keep biologic time is an inherited characteristic located intracellularly. These biological clocks anticipate and get the organism ready for regular environmental changes. This indicates both the ubiquity and the weight of the selective environmental pressure to keep time accurately. Several molecular strategies for biologic time keeping have apparently arisen independently several times throughout evolution. The anatomic, biochemical, and molecular mechanisms of the clock are in the process of being defined. This temporal organization at the cellular, organ, and organismic levels results in predictable differences in the capacity of plants, animals, and human beings to respond to therapeutic interventions administered at different times throughout important biologic cycles (e.g., circadian timed therapy). In the treatment of the cancer bearing host, circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, enhanced tumor control, and improved host survival. The routine clinical application of such principles is facilitated by the availability of programmable drug delivery devices. Rhythm frequency ranges other than 24-h (e.g., low frequency: menstrual; high frequency: 10 to 120 min) may also be important to understanding health and disease and to designing successful therapy in diseases as diverse as cancer, infertility, and diabetes. PMID:8959371

  4. A PNEUMATIC CONVEYING TEST RIG FOR MUNICIPAL SOLID WASTE FRACTIONS

    EPA Science Inventory

    This report analyzes the material properties and system parameters relevant to the pneumatic conveying of municipal solid waste and its processed fractions. Comparisons are made with the conveying of conventional industrial feedstocks, and a rationale for sizing and specification...

  5. The Circadian Timing System and Environmental Circadian Disruption: From Follicles to Fertility.

    PubMed

    Sen, Aritro; Sellix, Michael T

    2016-09-01

    The internal or circadian timing system is deeply integrated in female reproductive physiology. Considerable details of rheostatic timing function in the neuroendocrine control of pituitary hormone secretion, adenohypophyseal hormone gene expression and secretion, gonadal steroid hormone biosynthesis and secretion, ovulation, implantation, and parturition have been reported. The molecular clock, an autonomous feedback loop oscillator of interacting transcriptional regulators, dictates the timing and amplitude of gene expression in each tissue of the female hypothalamic-pituitary-gonadal (HPG) axis. Although multiple targets of the molecular clock have been identified, many associated with critical physiological functions in the HPG axis, the full extent of clock-driven gene expression and physiology in this critical system remains unknown. Environmental circadian disruption (ECD), the disturbance of temporal relationships within and between internal clocks (brain and periphery), and external timing cues (eg, light, nutrients, social cues) due to rotating/night shift work or transmeridian travel have been linked to reproductive dysfunction and subfertility. Moreover, ECD resulting from exposure to endocrine disrupting chemicals, environmental toxins, and/or irregular hormone levels during sexual development can also reduce fertility. Thus, perturbations that disturb clock function at the molecular, cellular or systemic level correlate with significant declines in female reproductive function. Here we briefly review the evidence for molecular clock function in each tissue of the female HPG axis (GnRH neuron, pituitary, uterus, oviduct, and ovary), describe the human epidemiological and animal data supporting the negative effects of ECD on fertility, and explore the potential for novel chronotherapeutics in women's health and fertility. PMID:27501186

  6. 32 CFR 174.9 - Economic development conveyances.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Economic development conveyances. 174.9 Section... Economic development conveyances. (a) The Secretary concerned may transfer real property and personal... Development Conveyance (EDC). (b) For installations having a date of approval for closure after January...

  7. 32 CFR 174.9 - Economic development conveyances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 false Economic development conveyances. 174.9 Section... Economic development conveyances. (a) The Secretary concerned may transfer real property and personal... Development Conveyance (EDC). (b) For installations having a date of approval for closure after January...

  8. 30 CFR 56.19065 - Lowering conveyances by the brakes.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Lowering conveyances by the brakes. 56.19065... Hoisting Hoisting Procedures § 56.19065 Lowering conveyances by the brakes. Conveyances shall not be lowered by the brakes alone except during emergencies....

  9. 30 CFR 57.19065 - Lowering conveyances by the brakes.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Lowering conveyances by the brakes. 57.19065... Hoisting Hoisting Procedures § 57.19065 Lowering conveyances by the brakes. Conveyances shall not be lowered by the brakes alone except during emergencies....

  10. 38 CFR 36.4323 - Election to convey security.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2012-07-01 2012-07-01 false Election to convey... Election to convey security. (a) If the holder acquires the property that secured the guaranteed loan at... accept conveyance of the property if the holder fails to notify the Secretary of its election within...

  11. 38 CFR 36.4323 - Election to convey security.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2011-07-01 2011-07-01 false Election to convey... Election to convey security. (a) If the holder acquires the property that secured the guaranteed loan at... accept conveyance of the property if the holder fails to notify the Secretary of its election within...

  12. 14 CFR 49.21 - Return of original conveyance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Return of original conveyance. 49.21 Section 49.21 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT RECORDING OF AIRCRAFT TITLES AND SECURITY DOCUMENTS General § 49.21 Return of original conveyance. If a person submitting a conveyance for...

  13. 30 CFR 56.19065 - Lowering conveyances by the brakes.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Lowering conveyances by the brakes. 56.19065... Hoisting Hoisting Procedures § 56.19065 Lowering conveyances by the brakes. Conveyances shall not be lowered by the brakes alone except during emergencies....

  14. 30 CFR 56.19065 - Lowering conveyances by the brakes.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Lowering conveyances by the brakes. 56.19065... Hoisting Hoisting Procedures § 56.19065 Lowering conveyances by the brakes. Conveyances shall not be lowered by the brakes alone except during emergencies....

  15. 30 CFR 56.19065 - Lowering conveyances by the brakes.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Lowering conveyances by the brakes. 56.19065... Hoisting Hoisting Procedures § 56.19065 Lowering conveyances by the brakes. Conveyances shall not be lowered by the brakes alone except during emergencies....

  16. 30 CFR 57.19065 - Lowering conveyances by the brakes.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Lowering conveyances by the brakes. 57.19065... Hoisting Hoisting Procedures § 57.19065 Lowering conveyances by the brakes. Conveyances shall not be lowered by the brakes alone except during emergencies....

  17. 30 CFR 57.19065 - Lowering conveyances by the brakes.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Lowering conveyances by the brakes. 57.19065... Hoisting Hoisting Procedures § 57.19065 Lowering conveyances by the brakes. Conveyances shall not be lowered by the brakes alone except during emergencies....

  18. 30 CFR 57.19065 - Lowering conveyances by the brakes.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Lowering conveyances by the brakes. 57.19065... Hoisting Hoisting Procedures § 57.19065 Lowering conveyances by the brakes. Conveyances shall not be lowered by the brakes alone except during emergencies....

  19. 30 CFR 57.19065 - Lowering conveyances by the brakes.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Lowering conveyances by the brakes. 57.19065... Hoisting Hoisting Procedures § 57.19065 Lowering conveyances by the brakes. Conveyances shall not be lowered by the brakes alone except during emergencies....

  20. 30 CFR 56.19065 - Lowering conveyances by the brakes.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Lowering conveyances by the brakes. 56.19065... Hoisting Hoisting Procedures § 56.19065 Lowering conveyances by the brakes. Conveyances shall not be lowered by the brakes alone except during emergencies....

  1. 21 CFR 1250.51 - Railroad conveyances; discharge of wastes.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Railroad conveyances; discharge of wastes. 1250.51 Section 1250.51 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... CONVEYANCE SANITATION Equipment and Operation of Land and Air Conveyances § 1250.51 Railroad...

  2. A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability

    PubMed Central

    Flourakis, Matthieu; Kula-Eversole, Elzbieta; Hutchison, Alan L.; Han, Tae Hee; Aranda, Kimberly; Moose, Devon L.; White, Kevin P.; Dinner, Aaron R.; Lear, Bridget C.; Ren, Dejian; Diekman, Casey O.; Raman, Indira M.; Allada, Ravi

    2015-01-01

    Summary Circadian clocks regulate membrane excitability in master pacemaker neurons to control daily rhythms of sleep and wake. Here we find that two distinctly timed electrical drives collaborate to impose rhythmicity on Drosophila clock neurons. In the morning, a voltage-independent sodium conductance via the NA/NALCN ion channel depolarizes these neurons. This current is driven by the rhythmic expression of NCA localization factor-1, linking the molecular clock to ion channel function. In the evening, basal potassium currents peak to silence clock neurons. Remarkably, daily antiphase cycles of sodium and potassium currents also drive mouse clock neuron rhythms. Thus, we reveal an evolutionarily ancient strategy for the neural mechanisms that govern daily sleep and wake. PMID:26276633

  3. A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability.

    PubMed

    Flourakis, Matthieu; Kula-Eversole, Elzbieta; Hutchison, Alan L; Han, Tae Hee; Aranda, Kimberly; Moose, Devon L; White, Kevin P; Dinner, Aaron R; Lear, Bridget C; Ren, Dejian; Diekman, Casey O; Raman, Indira M; Allada, Ravi

    2015-08-13

    Circadian clocks regulate membrane excitability in master pacemaker neurons to control daily rhythms of sleep and wake. Here, we find that two distinctly timed electrical drives collaborate to impose rhythmicity on Drosophila clock neurons. In the morning, a voltage-independent sodium conductance via the NA/NALCN ion channel depolarizes these neurons. This current is driven by the rhythmic expression of NCA localization factor-1, linking the molecular clock to ion channel function. In the evening, basal potassium currents peak to silence clock neurons. Remarkably, daily antiphase cycles of sodium and potassium currents also drive mouse clock neuron rhythms. Thus, we reveal an evolutionarily ancient strategy for the neural mechanisms that govern daily sleep and wake. PMID:26276633

  4. Age-Related Changes in Sleep and Circadian Rhythms: Impact on Cognitive Performance and Underlying Neuroanatomical Networks

    PubMed Central

    Schmidt, Christina; Peigneux, Philippe; Cajochen, Christian

    2012-01-01

    Circadian and homeostatic sleep-wake regulatory processes interact in a fine tuned manner to modulate human cognitive performance. Dampening of the circadian alertness signal and attenuated deterioration of psychomotor vigilance in response to elevated sleep pressure with aging change this interaction pattern. As evidenced by neuroimaging studies, both homeostatic sleep pressure and circadian sleep-wake promotion impact on cognition-related cortical and arousal-promoting subcortical brain regions including the thalamus, the anterior hypothalamus, and the brainstem locus coeruleus (LC). However, how age-related changes in circadian and homeostatic processes impact on the cerebral activity subtending waking performance remains largely unexplored. Post-mortem studies point to neuronal degeneration in the SCN and age-related modifications in the arousal-promoting LC. Alongside, cortical frontal brain areas are particularly susceptible both to aging and misalignment between circadian and homeostatic processes. In this perspective, we summarize and discuss here the potential neuroanatomical networks underlying age-related changes in circadian and homeostatic modulation of waking performance, ranging from basic arousal to higher order cognitive behaviors. PMID:22855682

  5. Circadian dysregulation disrupts bile acid homeostasis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bile acids are potentially toxic compounds and their levels of hepatic production, uptake, and export are tightly regulated by many inputs, including circadian rhythm. We tested the impact of disrupting the peripheral circadian clock on integral steps of bile acid homeostasis. Both restricted feedi...

  6. Circadian dysfunction induces leptin resistance in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Circadian disruption is associated with obesity, implicating the central clock in body weight control. Our comprehensive screen of wild-type and three circadian mutant mouse models, with or without chronic jet lag, shows that distinct genetic and physiologic interventions differentially disrupt over...

  7. A colorful model of the circadian clock.

    PubMed

    Reppert, Steven M

    2006-01-27

    The migration of the colorful monarch butterfly provides biologists with a unique model system with which to study the cellular and molecular mechanisms underlying a sophisticated circadian clock. The monarch circadian clock is involved in the induction of the migratory state and navigation over long distances, using the sun as a compass. PMID:16439193

  8. Identifying Novel Transcriptional Regulators with Circadian Expression

    PubMed Central

    Schick, Sandra; Thakurela, Sudhir; Fournier, David; Hampel, Mareike Hildegard

    2015-01-01

    Organisms adapt their physiology and behavior to the 24-h day-night cycle to which they are exposed. On a cellular level, this is regulated by intrinsic transcriptional-translational feedback loops that are important for maintaining the circadian rhythm. These loops are organized by members of the core clock network, which further regulate transcription of downstream genes, resulting in their circadian expression. Despite progress in understanding circadian gene expression, only a few players involved in circadian transcriptional regulation, including transcription factors, epigenetic regulators, and long noncoding RNAs, are known. Aiming to discover such genes, we performed a high-coverage transcriptome analysis of a circadian time course in murine fibroblast cells. In combination with a newly developed algorithm, we identified many transcription factors, epigenetic regulators, and long intergenic noncoding RNAs that are cyclically expressed. In addition, a number of these genes also showed circadian expression in mouse tissues. Furthermore, the knockdown of one such factor, Zfp28, influenced the core clock network. Mathematical modeling was able to predict putative regulator-effector interactions between the identified circadian genes and may help for investigations into the gene regulatory networks underlying circadian rhythms. PMID:26644408

  9. INTRINSIC CIRCADIAN RHYTHMS IN THE CARDIOMYOCYTE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The cardiomyocyte possesses a fully functional circadian clock. Circadian clocks are a set of proteins that generate self-sustained transcriptional positive and negative feedback loops with a free-running period of 24 hours. These intracellular molecular mechanisms confer the selective advantage of ...

  10. Circadian regulation of ATP release in astrocytes.

    PubMed

    Marpegan, Luciano; Swanstrom, Adrienne E; Chung, Kevin; Simon, Tatiana; Haydon, Philip G; Khan, Sanjoy K; Liu, Andrew C; Herzog, Erik D; Beaulé, Christian

    2011-06-01

    Circadian clocks sustain daily oscillations in gene expression, physiology, and behavior, relying on transcription-translation feedback loops of clock genes for rhythm generation. Cultured astrocytes display daily oscillations of extracellular ATP, suggesting that ATP release is a circadian output. We hypothesized that the circadian clock modulates ATP release via mechanisms that regulate acute ATP release from glia. To test the molecular basis for circadian ATP release, we developed methods to measure in real-time ATP release and Bmal1::dLuc circadian reporter expression in cortical astrocyte cultures from mice of different genotypes. Daily rhythms of gene expression required functional Clock and Bmal1, both Per1 and Per2, and both Cry1 and Cry2 genes. Similarly, high-level, circadian ATP release also required a functional clock mechanism. Whereas blocking IP(3) signaling significantly disrupted ATP rhythms with no effect on Bmal1::dLuc cycling, blocking vesicular release did not alter circadian ATP release or gene expression. We conclude that astrocytes depend on circadian clock genes and IP(3) signaling to express daily rhythms in ATP release. PMID:21653839