Light sets the brain’s daily clock by regional quickening and slowing of the molecular clockworks at dawn and dusk

How daily clocks in the brain are set by light to local environmental time and encode the seasons is not fully understood. The suprachiasmatic nucleus (SCN) is a central circadian clock in mammals that orchestrates physiology and behavior in tune with daily and seasonal light cycles. Here, we have found that optogenetically simulated light input to explanted mouse SCN changes the waveform of the molecular clockworks from sinusoids in free-running conditions to highly asymmetrical shapes with accelerated synthetic (rising) phases and extended degradative (falling) phases marking clock advances and delays at simulated dawn and dusk. Daily waveform changes arise under ex vivo entrainment to simulated winter and summer photoperiods, and to non-24 hr periods. Ex vivo SCN imaging further suggests that acute waveform shifts are greatest in the ventrolateral SCN, while period effects are greatest in the dorsomedial SCN. Thus, circadian entrainment is encoded by SCN clock gene waveform changes that arise from spatiotemporally distinct intrinsic responses within the SCN neural network.

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Central and Peripheral Clock Control of Circadian Feeding Rhythms

Journal of Biological Rhythms ◽

10.1177/07487304211045835 ◽

2021 ◽

pp. 074873042110458

Author(s):

Carson V. Fulgham ◽

Austin P. Dreyer ◽

Anita Nasseri ◽

Asia N. Miller ◽

Jacob Love ◽

...

Keyword(s):

Locomotor Activity ◽

Circadian Clock ◽

Feeding Behavior ◽

Molecular Clock ◽

Fat Body ◽

Molecular Clocks ◽

Central Brain ◽

Feeding Rhythms ◽

Free Running ◽

The Brain

Many behaviors exhibit ~24-h oscillations under control of an endogenous circadian timing system that tracks time of day via a molecular circadian clock. In the fruit fly, Drosophila melanogaster, most circadian research has focused on the generation of locomotor activity rhythms, but a fundamental question is how the circadian clock orchestrates multiple distinct behavioral outputs. Here, we have investigated the cells and circuits mediating circadian control of feeding behavior. Using an array of genetic tools, we show that, as is the case for locomotor activity rhythms, the presence of feeding rhythms requires molecular clock function in the ventrolateral clock neurons of the central brain. We further demonstrate that the speed of molecular clock oscillations in these neurons dictates the free-running period length of feeding rhythms. In contrast to the effects observed with central clock cell manipulations, we show that genetic abrogation of the molecular clock in the fat body, a peripheral metabolic tissue, is without effect on feeding behavior. Interestingly, we find that molecular clocks in the brain and fat body of control flies gradually grow out of phase with one another under free-running conditions, likely due to a long endogenous period of the fat body clock. Under these conditions, the period of feeding rhythms tracks with molecular oscillations in central brain clock cells, consistent with a primary role of the brain clock in dictating the timing of feeding behavior. Finally, despite a lack of effect of fat body selective manipulations, we find that flies with simultaneous disruption of molecular clocks in multiple peripheral tissues (but with intact central clocks) exhibit decreased feeding rhythm strength and reduced overall food intake. We conclude that both central and peripheral clocks contribute to the regulation of feeding rhythms, with a particularly dominant, pacemaker role for specific populations of central brain clock cells.

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Clock gene expressions in the suprachiasmatic nucleus and other areas of the brain during rhythm splitting in CS mice

Molecular Brain Research ◽

10.1016/s0169-328x(00)00295-3 ◽

2001 ◽

Vol 87 (1) ◽

pp. 92-99 ◽

Cited By ~ 45

Author(s):

Hiroshi Abe ◽

Sato Honma ◽

Masakazu Namihira ◽

Satoru Masubuchi ◽

Masaaki Ikeda ◽

...

Keyword(s):

Suprachiasmatic Nucleus ◽

Clock Gene ◽

Gene Expressions ◽

The Brain

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Weekend light shifts evoke persistent Drosophila circadian neural network desynchrony

10.1101/2019.12.31.891507 ◽

2020 ◽

Author(s):

Ceazar Nave ◽

Logan Roberts ◽

Patrick Hwu ◽

Jerson D. Estrella ◽

Thanh C Vo ◽

...

Keyword(s):

Single Cell ◽

Real Time ◽

Learning And Memory ◽

Suprachiasmatic Nucleus ◽

Ex Vivo ◽

Phase Shifting ◽

Light Signals ◽

Light Shifts ◽

Behavior Shift ◽

And Behavior

AbstractBillions of people subject themselves to phase-shifting light signals on a weekly basis by remaining active later at night and sleeping in later on weekends relative to weekday for up to a 3hr weekend light shift (WLS). Unnatural light signals disrupt circadian rhythms and physiology and behavior. Real-time light responses of mammalian suprachiasmatic nucleus are unmeasurable at single cell resolution. We compared Drosophila whole-circadian circuit responses between unshifted daytime/nighttime schedule and a 3hr WLS schedule at the single-cell resolution in cultured adult Drosophila brains using real-time bioluminescence imaging of the PERIOD protein for 11 days to determine how light shifts alter biological clock entrainment and stability. We find that circadian circuits show highly synchronous oscillations across all major circadian neuronal subgroups in unshifted light schedules. In contrast, circadian circuits exposed to a WLS schedule show significantly dampened oscillator synchrony and rhythmicity in most circadian neurons during, and after exposure. The WLS schedule first desynchronizes lateral ventral neuron (LNv) oscillations and the LNv are the last to resynchronize upon returning to a simulated weekday schedule. Surprisingly, one circadian subgroup, the dorsal neuron group-3 (DN3s), robustly increase their within-group synchrony in response to WLS exposure. Intact adult flies exposed to the WLS schedule show post-WLS transient defects in sleep stability, learning, and memory. Our findings suggest that WLS schedules disrupt circuit-wide circadian neuronal oscillator synchrony for much of the week, thus leading to observed behavioral defects in sleep, learning, and memory.Significance StatementThe circadian clock controls numerous aspects of daily animal physiology, metabolism and behavior. Shift work in humans is harmful. Our understanding of circadian circuit-level oscillations stem from ex vivo imaging of mammalian suprachiasmatic nucleus (SCN) brain slices. However, our knowledge is limited to investigations without direct interrogation of phase-shifting light signals. We measured circuit-level circadian responses to a WLS protocol in light sensitive ex vivo Drosophila whole-brain preparation and find robust sub-circuit-specific oscillator desynchrony/resynchrony responses to light. These circuit-level behaviors correspond to our observed functional defects in learning and memory, and sleep pattern disruption in vivo. Our results reflect that WLS cause circadian-circuit desynchronization and correlate with disrupted cognitive and sleep performance.

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In Vivo Monitoring of Circadian Clock Gene Expression in the Mouse Suprachiasmatic Nucleus Using Fluorescence Reporters

Journal of Visualized Experiments ◽

10.3791/56765 ◽

2018 ◽

Author(s):

Long Mei ◽

Cheng Zhan ◽

Eric Erquan Zhang

Keyword(s):

Gene Expression ◽

Circadian Clock ◽

Suprachiasmatic Nucleus ◽

Clock Gene ◽

Circadian Clock Gene ◽

Clock Gene Expression

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Minireview: The Neuroendocrinology of the Suprachiasmatic Nucleus as a Conductor of Body Time in Mammals

Endocrinology ◽

10.1210/en.2007-1083 ◽

2007 ◽

Vol 148 (12) ◽

pp. 5640-5647 ◽

Cited By ~ 61

Author(s):

Ilia N. Karatsoreos ◽

Rae Silver

Keyword(s):

Circadian Rhythms ◽

Suprachiasmatic Nucleus ◽

Hormone Secretion ◽

Gonadal Hormone ◽

Multiple Levels ◽

And Behavior ◽

Circadian Behavior ◽

The Brain ◽

Indirect Route ◽

Photic Input

Circadian rhythms in physiology and behavior are regulated by a master clock resident in the suprachiasmatic nucleus (SCN) of the hypothalamus, and dysfunctions in the circadian system can lead to serious health effects. This paper reviews the organization of the SCN as the brain clock, how it regulates gonadal hormone secretion, and how androgens modulate aspects of circadian behavior known to be regulated by the SCN. We show that androgen receptors are restricted to a core SCN region that receives photic input as well as afferents from arousal systems in the brain. We suggest that androgens modulate circadian behavior directly via actions on the SCN and that both androgens and estrogens modulate circadian rhythms through an indirect route, by affecting overall activity and arousal levels. Thus, this system has multiple levels of regulation; the SCN regulates circadian rhythms in gonadal hormone secretion, and hormones feed back to influence SCN functions.

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Circadian influences on dopamine circuits of the brain: regulation of striatal rhythms of clock gene expression and implications for psychopathology and disease

F1000Research ◽

10.12688/f1000research.9180.1 ◽

2016 ◽

Vol 5 ◽

pp. 2062 ◽

Cited By ~ 23

Author(s):

Michael Verwey ◽

Sabine Dhir ◽

Shimon Amir

Keyword(s):

Gene Expression ◽

Circadian Rhythms ◽

Circadian Clock ◽

Clock Gene ◽

Dorsal Striatum ◽

Brain Regions ◽

Physiological Importance ◽

Clock Gene Expression ◽

Dopamine Circuits ◽

The Brain

Circadian clock proteins form an autoregulatory feedback loop that is central to the endogenous generation and transmission of daily rhythms in behavior and physiology. Increasingly, circadian rhythms in clock gene expression are being reported in diverse tissues and brain regions that lie outside of the suprachiasmatic nucleus (SCN), the master circadian clock in mammals. For many of these extra-SCN rhythms, however, the region-specific implications are still emerging. In order to gain important insights into the potential behavioral, physiological, and psychological relevance of these daily oscillations, researchers have begun to focus on describing the neurochemical, hormonal, metabolic, and epigenetic contributions to the regulation of these rhythms. This review will highlight important sites and sources of circadian control within dopaminergic and striatal circuitries of the brain and will discuss potential implications for psychopathology and disease. For example, rhythms in clock gene expression in the dorsal striatum are sensitive to changes in dopamine release, which has potential implications for Parkinson’s disease and drug addiction. Rhythms in the ventral striatum and limbic forebrain are sensitive to psychological and physical stressors, which may have implications for major depressive disorder. Collectively, a rich circadian tapestry has emerged that forces us to expand traditional views and to reconsider the psychopathological, behavioral, and physiological importance of these region-specific rhythms in brain areas that are not immediately linked with the regulation of circadian rhythms.

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Development of dilated cardiomyopathy in Bmal1-deficient mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00238.2012 ◽

2012 ◽

Vol 303 (4) ◽

pp. H475-H485 ◽

Cited By ~ 64

Author(s):

Mellani Lefta ◽

Kenneth S. Campbell ◽

Han-Zhong Feng ◽

Jian-Ping Jin ◽

Karyn A. Esser

Keyword(s):

Circadian Clock ◽

Dilated Cardiomyopathy ◽

Myosin Heavy Chain ◽

Heavy Chain ◽

Clock Gene ◽

Ex Vivo ◽

Chain Gene ◽

Circadian Clock Gene ◽

Myosin Heavy Chain Isoform ◽

Wide Range

Circadian rhythms are approximate 24-h oscillations in physiology and behavior. Circadian rhythm disruption has been associated with increased incidence of hypertension, coronary artery disease, dyslipidemia, and other cardiovascular pathologies in both humans and animal models. Mice lacking the core circadian clock gene, brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein ( Bmal1), are behaviorally arrhythmic, die prematurely, and display a wide range of organ pathologies. However, data are lacking on the role of Bmal1 on the structural and functional integrity of cardiac muscle. In the present study, we demonstrate that Bmal1 −/− mice develop dilated cardiomyopathy with age, characterized by thinning of the myocardial walls, dilation of the left ventricle, and decreased cardiac performance. Shortly after birth the Bmal1 −/− mice exhibit a transient increase in myocardial weight, followed by regression and later onset of dilation and failure. Ex vivo working heart preparations revealed systolic ventricular dysfunction at the onset of dilation and failure, preceded by downregulation of both myosin heavy chain isoform mRNAs. We observed structural disorganization at the level of the sarcomere with a shift in titin isoform composition toward the stiffer N2B isoform. However, passive tension generation in single cardiomyocytes was not increased. Collectively, these findings suggest that the loss of the circadian clock gene, Bmal1, gives rise to the development of an age-associated dilated cardiomyopathy, which is associated with shifts in titin isoform composition, altered myosin heavy chain gene expression, and disruption of sarcomere structure.

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Dissociation of Per1 and Bmal1 circadian rhythms in the suprachiasmatic nucleus in parallel with behavioral outputs

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1613374114 ◽

2017 ◽

Vol 114 (18) ◽

pp. E3699-E3708 ◽

Cited By ~ 34

Author(s):

Daisuke Ono ◽

Sato Honma ◽

Yoshihiro Nakajima ◽

Shigeru Kuroda ◽

Ryosuke Enoki ◽

...

Keyword(s):

Circadian Rhythms ◽

Suprachiasmatic Nucleus ◽

Clock Genes ◽

Behavioral Rhythm ◽

Calcium Indicator ◽

Intracellular Ca ◽

Regional Specificity ◽

Free Running ◽

Activity Onset ◽

And Behavior

The temporal order of physiology and behavior in mammals is primarily regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). Taking advantage of bioluminescence reporters, we monitored the circadian rhythms of the expression of clock genes Per1 and Bmal1 in the SCN of freely moving mice and found that the rate of phase shifts induced by a single light pulse was different in the two rhythms. The Per1-luc rhythm was phase-delayed instantaneously by the light presented at the subjective evening in parallel with the activity onset of behavioral rhythm, whereas the Bmal1-ELuc rhythm was phase-delayed gradually, similar to the activity offset. The dissociation was confirmed in cultured SCN slices of mice carrying both Per1-luc and Bmal1-ELuc reporters. The two rhythms in a single SCN slice showed significantly different periods in a long-term (3 wk) culture and were internally desynchronized. Regional specificity in the SCN was not detected for the period of Per1-luc and Bmal1-ELuc rhythms. Furthermore, neither is synchronized with circadian intracellular Ca2+ rhythms monitored by a calcium indicator, GCaMP6s, or with firing rhythms monitored on a multielectrode array dish, although the coupling between the circadian firing and Ca2+ rhythms persisted during culture. These findings indicate that the expressions of two key clock genes, Per1 and Bmal1, in the SCN are regulated in such a way that they may adopt different phases and free-running periods relative to each other and are respectively associated with the expression of activity onset and offset.

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Impact of Targeted Deletion of the Circadian Clock Gene Bmal1 in Excitatory Forebrain Neurons on Adult Neurogenesis and Olfactory Function

International Journal of Molecular Sciences ◽

10.3390/ijms21041394 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1394

Author(s):

Amira A. H. Ali ◽

Federica Tundo-Lavalle ◽

Soha A. Hassan ◽

Martina Pfeffer ◽

Anna Stahr ◽

...

Keyword(s):

Oxidative Stress ◽

Olfactory Bulb ◽

Circadian Clock ◽

Adult Neurogenesis ◽

Clock Gene ◽

Olfactory Function ◽

Circadian Clock Gene ◽

Targeted Deletion ◽

Forebrain Neurons ◽

And Behavior

The circadian system is an endogenous timekeeping system that synchronizes physiology and behavior with the 24 h solar day. Mice with total deletion of the core circadian clock gene Bmal1 show circadian arrhythmicity, cognitive deficits, and accelerated age-dependent decline in adult neurogenesis as a consequence of increased oxidative stress. However, it is not yet known if the impaired adult neurogenesis is due to circadian disruption or to loss of the Bmal1 gene function. Therefore, we investigated oxidative stress and adult neurogenesis of the two principle neurogenic niches, the hippocampal subgranular zone and the subventricular zone in mice with a forebrain specific deletion of Bmal1 (Bmal1 fKO), which show regular circadian rhythmicity. Moreover, we analyzed the morphology of the olfactory bulb, as well as olfactory function in Bmal1 fKO mice. In Bmal1 fKO mice, oxidative stress was increased in subregions of the hippocampus and the olfactory bulb but not in the neurogenic niches. Consistently, adult neurogenesis was not affected in Bmal1 fKO mice. Although Reelin expression in the olfactory bulb was higher in Bmal1 fKO mice as compared to wildtype mice (Bmal1 WT), the olfactory function was not affected. Taken together, the targeted deletion of Bmal1 in mouse forebrain neurons is associated with a regional increase in oxidative stress and increased Reelin expression in the olfactory bulb but does not affect adult neurogenesis or olfactory function.

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