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ELife Dec 2015Robust sleep/wake rhythms are important for health and cognitive function. Unfortunately, many people are living in an environment where their circadian system is...
Robust sleep/wake rhythms are important for health and cognitive function. Unfortunately, many people are living in an environment where their circadian system is challenged by inappropriate meal- or work-times. Here we scheduled food access to the sleep time and examined the impact on learning and memory in mice. Under these conditions, we demonstrate that the molecular clock in the master pacemaker, the suprachiasmatic nucleus (SCN), is unaltered while the molecular clock in the hippocampus is synchronized by the timing of food availability. This chronic circadian misalignment causes reduced hippocampal long term potentiation and total CREB expression. Importantly this mis-timed feeding resulted in dramatic deficits in hippocampal-dependent learning and memory. Our findings suggest that the timing of meals have far-reaching effects on hippocampal physiology and learned behaviour.
Topics: Animals; Circadian Rhythm; Feeding Behavior; Feeding Methods; Hippocampus; Memory; Mice; Suprachiasmatic Nucleus
PubMed: 26652002
DOI: 10.7554/eLife.09460 -
Annual Review of Pharmacology and... 2014Most facets of mammalian physiology and behavior vary according to time of day, thanks to endogenous circadian clocks. Therefore, it is not surprising that many aspects... (Review)
Review
Most facets of mammalian physiology and behavior vary according to time of day, thanks to endogenous circadian clocks. Therefore, it is not surprising that many aspects of pharmacology and toxicology also oscillate according to the same 24-h clocks. Daily oscillations in abundance of proteins necessary for either drug absorption or metabolism result in circadian pharmacokinetics, and oscillations in the physiological systems targeted by these drugs result in circadian pharmacodynamics. These clocks are present in most cells of the body, organized in a hierarchical fashion. Interestingly, some aspects of physiology and behavior are controlled directly via a "master clock" in the suprachiasmatic nuclei of the hypothalamus, whereas others are controlled by "slave" oscillators in separate brain regions or body tissues. Recent research shows that these clocks can respond to different cues and thereby show different phase relationships. Therefore, full prediction of chronopharmacology in pathological contexts will likely require a systems biology approach that considers chronointeractions among different clock-regulated systems.
Topics: Animals; Circadian Clocks; Disease Models, Animal; Drug Chronotherapy; Humans; Hypothalamus; Pharmaceutical Preparations; Pharmacokinetics; Suprachiasmatic Nucleus
PubMed: 24160700
DOI: 10.1146/annurev-pharmtox-011613-135923 -
Proceedings of the National Academy of... Mar 2022SignificanceThe function of our biological clock is dependent on environmental light. Rodent studies have shown that there are multiple colors that affect the clock, but...
SignificanceThe function of our biological clock is dependent on environmental light. Rodent studies have shown that there are multiple colors that affect the clock, but indirect measures in humans suggest blue light is key. We performed functional MRI studies in human subjects with unprecedented spatial resolution to investigate color sensitivity of our clock. Here, we show that narrowband blue, green, and orange light were all effective in changing neuronal activity of the clock. While the clock of nocturnal rodents is excited by light, the human clock responds with a decrease in neuronal activity as indicated by a negative BOLD response. The sensitivity of the clock to multiple colors should be integrated in light therapy aimed to strengthen our 24-h rhythms.
Topics: Circadian Clocks; Circadian Rhythm; Humans; Light; Photobiology; Suprachiasmatic Nucleus
PubMed: 35312355
DOI: 10.1073/pnas.2118803119 -
Continuum (Minneapolis, Minn.) Feb 2013This article reviews the recent advances in understanding of the fundamental properties of circadian rhythms and discusses the clinical features, diagnosis, and... (Review)
Review
PURPOSE
This article reviews the recent advances in understanding of the fundamental properties of circadian rhythms and discusses the clinical features, diagnosis, and treatment of circadian rhythm sleep disorders (CRSDs).
RECENT FINDINGS
Recent evidence strongly points to the ubiquitous influence of circadian timing in nearly all physiologic functions. Thus, in addition to the prominent sleep and wake disturbances, circadian rhythm disorders are associated with cognitive impairment, mood disturbances, and increased risk of cardiometabolic disorders. The recent availability of biomarkers of circadian timing in clinical practice has improved our ability to identify and treat these CRSDs.
SUMMARY
Circadian rhythms are endogenous rhythms with a periodicity of approximately 24 hours. These rhythms are synchronized to the physical environment by social and work schedules by various photic and nonphotic stimuli. CRSDs result from a misalignment between the timing of the circadian rhythm and the external environment (eg, jet lag and shift work) or a dysfunction of the circadian clock or its afferent and efferent pathways (eg, delayed sleep-phase, advanced sleep-phase, non-24-hour, and irregular sleep-wake rhythm disorders). The most common symptoms of these disorders are difficulties with sleep onset and/or sleep maintenance and excessive sleepiness that are associated with impaired social and occupational functioning. Effective treatment for most of the CRSDs requires a multimodal approach to accelerate circadian realignment with timed exposure to light, avoidance of bright light at inappropriate times, and adherence to scheduled sleep and wake times. In addition, pharmacologic agents are recommended for some of the CRSDs. For delayed sleep-phase, non-24-hour, and shift work disorders, timed low-dose melatonin can help advance or entrain circadian rhythms; and for shift work disorder, wake-enhancing agents such as caffeine, modafinil, and armodafinil are options for the management of excessive sleepiness.
Topics: Adult; Animals; Circadian Rhythm; Female; Humans; Male; Period Circadian Proteins; Sleep Disorders, Circadian Rhythm; Suprachiasmatic Nucleus; Young Adult
PubMed: 23385698
DOI: 10.1212/01.CON.0000427209.21177.aa -
Protein & Cell Jul 2017Circadian rhythms orchestrate biochemical and physiological processes in living organisms to respond the day/night cycle. In mammals, nearly all cells hold... (Review)
Review
Circadian rhythms orchestrate biochemical and physiological processes in living organisms to respond the day/night cycle. In mammals, nearly all cells hold self-sustained circadian clocks meanwhile couple the intrinsic rhythms to systemic changes in a hierarchical manner. The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master pacemaker to initiate daily synchronization according to the photoperiod, in turn determines the phase of peripheral cellular clocks through a variety of signaling relays, including endocrine rhythms and metabolic cycles. With aging, circadian desynchrony occurs at the expense of peripheral metabolic pathologies and central neurodegenerative disorders with sleep symptoms, and genetic ablation of circadian genes in model organisms resembled the aging-related features. Notably, a number of studies have linked longevity nutrient sensing pathways in modulating circadian clocks. Therapeutic strategies that bridge the nutrient sensing pathways and circadian clock might be rational designs to defy aging.
Topics: Aging; Animals; Circadian Clocks; Humans; Suprachiasmatic Nucleus
PubMed: 28108951
DOI: 10.1007/s13238-016-0366-2 -
Seminars in Cell & Developmental Biology Jun 2022Nearly all mammals display robust daily rhythms of physiology and behavior. These approximately 24-h cycles, known as circadian rhythms, are driven by a master clock in... (Review)
Review
Nearly all mammals display robust daily rhythms of physiology and behavior. These approximately 24-h cycles, known as circadian rhythms, are driven by a master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus and affect biological processes ranging from metabolism to immune function. Perhaps the most overt output of the circadian clock is the sleep-wake cycle, the integrity of which is critical for health and homeostasis of the organism. In this review, we summarize our current understanding of the circadian regulation of sleep. We discuss the neural circuitry and molecular mechanisms underlying daily sleep timing, and the trajectory of circadian regulation of sleep across development. We conclude by proposing future research priorities for the field that will significantly advance our mechanistic understanding of the circadian regulation of sleep.
Topics: Animals; Circadian Clocks; Circadian Rhythm; Mammals; Sleep; Suprachiasmatic Nucleus
PubMed: 34092510
DOI: 10.1016/j.semcdb.2021.05.034 -
Journal of Neurophysiology Dec 2017GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian...
GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian oscillators within the SCN network and the stability and precision of the circadian rhythms. GABA transporters (GAT) regulate the extracellular GABA concentration and modulate GABA receptor (GABAR)-mediated currents. GABA transport inhibitors were applied to study how GABAR-mediated currents depend on the expression and function of GAT. Nipecotic acid inhibits GABA transport and induced an inward tonic current in concentration-dependent manner during whole cell patch-clamp recordings from SCN neurons. Application of either the selective GABA transporter 1 (GAT1) inhibitors NNC-711 or SKF-89976A, or the GABA transporter 3 (GAT3) inhibitor SNAP-5114, produced only small changes of the baseline current. Coapplication of GAT1 and GAT3 inhibitors induced a significant GABAR-mediated tonic current that was blocked by gabazine. GAT inhibitors decreased the amplitude and decay time constant and increased the rise time of spontaneous GABAR-mediated postsynaptic currents. However, inhibition of GAT did not alter the expression of either GAT1 or GAT3 in the hypothalamus. Thus GAT1 and GAT3 functionally complement each other to regulate the extracellular GABA concentration and GABAR-mediated synaptic and tonic currents in the SCN. Coapplication of SKF-89976A and SNAP-5114 (50 µM each) significantly reduced the circadian period of expression in the SCN by 1.4 h. Our studies demonstrate that GAT are important regulators of GABAR-mediated currents and the circadian clock in the SCN. In the suprachiasmatic nucleus (SCN), the GABA transporters GAT1 and GAT3 are expressed in astrocytes. Inhibition of these GABA transporters increased a tonic GABA current and reduced the circadian period of expression in SCN neurons. GAT1 and GAT3 showed functional cooperativity: inhibition of one GAT increased the activity but not the expression of the other. Our data demonstrate that GABA transporters are important regulators of GABA receptor-mediated currents and the circadian clock.
Topics: Animals; Anisoles; GABA Antagonists; GABA Plasma Membrane Transport Proteins; GABA Uptake Inhibitors; Male; Neurons; Nipecotic Acids; Oximes; Period Circadian Proteins; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Suprachiasmatic Nucleus; Synaptic Potentials
PubMed: 28855287
DOI: 10.1152/jn.00194.2017 -
The Journal of Physiological Sciences :... May 2018The circadian nature of physiology and behavior is regulated by a circadian clock that generates intrinsic rhythms with a periodicity of approximately 24 h. The... (Review)
Review
The circadian nature of physiology and behavior is regulated by a circadian clock that generates intrinsic rhythms with a periodicity of approximately 24 h. The mammalian circadian system is composed of a hierarchical multi-oscillator structure, with the central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus regulating the peripheral clocks found throughout the body. In the past two decades, key clock genes have been discovered in mammals and shown to be interlocked in transcriptional and translational feedback loops. At the cellular level, each cell is governed by its own independent clock; and yet, these cellular circadian clocks in the SCN form regional oscillators that are further coupled to one another to generate a single rhythm for the tissue. The oscillatory coupling within and between the regional oscillators appears to be critical for the extraordinary stability and the wide range of adaptability of the circadian clock, the mechanism of which is now being elucidated with newly advanced molecular tools.
Topics: Animals; Circadian Clocks; Circadian Rhythm; Humans; Hypothalamus; Mammals; Suprachiasmatic Nucleus
PubMed: 29460036
DOI: 10.1007/s12576-018-0597-5 -
Journal of Biological Rhythms Oct 2009How the cellular elements of the SCN are synchronized to each other is not well understood. We explore circadian oscillations manifest at the level of the cell, the... (Review)
Review
How the cellular elements of the SCN are synchronized to each other is not well understood. We explore circadian oscillations manifest at the level of the cell, the tissue, and the whole animal to better understand intra-SCN synchrony and master clock function of the nucleus. At each level of analysis, responses to variations in operating environment (robustness), and following damage to components of the system (resilience), provide insight into the mechanisms whereby the SCN orchestrates circadian timing. Tissue level rhythmicity reveals circuits associated with an orderly spatiotemporal daily pattern of activity that is not predictable from their cellular elements. Specifically, in stable state, some SCN regions express low amplitude or undetectable rhythms in clock gene expression while others produce high amplitude oscillations. Within the SCN, clock gene expression follows a spatially ordered, repeated pattern of activation and inactivation. This pattern of activation is plastic and subserves responses to changes in external and internal conditions. Just as daily rhythms at the cellular level depend on sequential expression and interaction of clock genes, so too do rhythms at the SCN tissue level depend on sequential activation of local nodes. We hypothesize that individual neurons are organized into nodes that are themselves sequentially activated across the volume of the SCN in a cycle that repeats on a daily basis. We further propose that robustness is expressed in the ability of the SCN to sustain rhythmicity over a wide range of internal and external conditions, and that this reflects plasticity of the underlying nodes and circuits. Resilience is expressed in the ability of SCN cells to oscillate and to sustain activity-related rhythms at the behavioral level. Importantly, other aspects of pacemaker function remain to be examined.
Topics: Animals; Biological Clocks; Circadian Rhythm; Nerve Net; Neural Pathways; Neurons; Neuropeptides; Neurotransmitter Agents; Photoperiod; Suprachiasmatic Nucleus
PubMed: 19755580
DOI: 10.1177/0748730409344800 -
FEBS Letters Sep 2020The circadian system is composed of coupled endogenous oscillators that allow living beings, including humans, to anticipate and adapt to daily changes in their... (Review)
Review
The circadian system is composed of coupled endogenous oscillators that allow living beings, including humans, to anticipate and adapt to daily changes in their environment. In mammals, circadian clocks form a hierarchically organized network with a 'master clock' located in the suprachiasmatic nucleus of the hypothalamus, which ensures entrainment of subsidiary oscillators to environmental cycles. Robust rhythmicity of body clocks is indispensable for temporally coordinating organ functions, and the disruption or misalignment of circadian rhythms caused for instance by modern lifestyle is strongly associated with various widespread diseases. This review aims to provide a comprehensive overview of our current knowledge about the molecular architecture and system-level organization of mammalian circadian oscillators. Furthermore, we discuss the regulatory roles of peripheral clocks for cell and organ physiology and their implication in the temporal coordination of metabolism in human health and disease. Finally, we summarize methods for assessing circadian rhythmicity in humans.
Topics: Animals; CLOCK Proteins; Circadian Clocks; Circadian Rhythm; Feedback, Physiological; Gene Expression Regulation; Humans; Mammals; Metabolic Diseases; Photoperiod; Signal Transduction; Suprachiasmatic Nucleus
PubMed: 32750151
DOI: 10.1002/1873-3468.13898