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ISSUE INFORMATION
CIRCADIAN RHYTHMS ‐ SPECIAL ISSUE
Metabolic rhythms: A framework for coordinating cellular function
- Pages: 1-12
- First Published: 13 December 2018
Yeast grown at high density under aerobic conditions undergo short period oscillations in oxygen consumption that coordinate a number of metabolic and cellular processes. Although yeast are not known to have a clock transcription‐translation feedback loop; these rhythms share a number of characteristics with 12 and 24 hr rhythms in other eukaryotes. This article reviews literature on the yeast respiratory oscillation and highlights features that are likely to underpin biological oscillations of multiple periods.
Principles of rhythmicity emerging from cyanobacteria
- Pages: 13-18
- First Published: 14 May 2019
Principles of the animal molecular clock learned from Neurospora
- Pages: 19-33
- First Published: 27 January 2019
Neurospora crassa, a genetically tractable model system, has informed the study of animal clocks. Within the oscillator core is a heterodimeric PAS‐domain transcription factor that activates expression of proteins that enter a negative element complex capable of blocking positive element activity. The heterodimer also activates clock‐controlled genes, leading to rhythmic cascades of gene expression within the cell. Light resets clock phase by changing the amount of the negative element complex.
Circadian rhythm of redox state regulates membrane excitability in hippocampal CA1 neurons
- Pages: 34-46
- First Published: 04 January 2019
The rat SCN and hippocampal CA1 layer have opposite membrane excitability and redox oscillations. During the day, when the SCN is more depolarized and reduced, the hippocampal CA1 region is more hyperpolarized and oxidized. During the night, while the SCN is more hyperpolarized and oxidized, the hippocampal CA1 is more depolarized and reduced.
Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators
- Pages: 47-70
- First Published: 30 September 2018
Copper (Cu) levels homeostatically modulate SCN circadian clock phase through complex cellular mechanisms that overlap, yet are distinct from, those underlying photic phase regulation. Given Cu's ability to modulate cell metabolism, redox state, membrane excitability and transcription, it could help to link multiple circadian oscillators within the SCN and thereby strengthen its rhythmic output.
Overexpression of striatal D2 receptors reduces motivation thereby decreasing food anticipatory activity
- Pages: 71-81
- First Published: 26 October 2018
When food availability is restricted to 8 hr during the mouse's inactive phase, control mice show food anticipatory activity (FAA) by running in their wheel prior to the appearance of the meal. In contrast, mice with overexpression of the dopamine D2 receptor (D2R‐OE) do not show FAA in these conditions. Treating the D2R‐OE mice with doxycycline to switch off overexpression of the transgenic D2Rs results in rescue of FAA.
Circuit development in the master clock network of mammals
- Pages: 82-108
- First Published: 06 November 2018
Daily rhythms are generated by the circadian timekeeping system, which is orchestrated by the master circadian clock in the suprachiasmatic nucleus (SCN) of mammals. The SCN is a neural network of cellular clocks that interact with one another to determine the emergent properties of the system. Like other important neural circuits, the development of the SCN network is a gradual process that spans both embryonic and postnatal ages. This review discusses SCN development at the cellular and circuit levels, with a focus on work performed in model rodent species (i.e., mouse, rat, and hamster). Particular emphasis is placed on the spatial and temporal patterns of SCN development that may contribute to clock function in adulthood.
Circadian regulation of membrane physiology in neural oscillators throughout the brain
- Pages: 109-138
- First Published: 11 January 2019
In this review, we consolidate the existing evidence for molecular and neurophysiological circadian rhythms throughout the brain, discuss the challenges in investigating these extra‐SCN clocks, and describe the importance of circadian regulation of excitability for neuronal function and diseases of the nervous system. In addition, we highlight the brain regions that are ripe for future investigation into the critical role of circadian rhythmicity for local oscillators.
Periodicity, repression, and the molecular architecture of the mammalian circadian clock
- Pages: 139-165
- First Published: 06 November 2018
Structural and biochemical analyses have uncovered a number of key features of the proteins that form the basis of circadian timing in vertebrates. In particular, a repeating motif in protein–protein interactions within the clockwork is shared, competitive interfaces. Here, we review major findings and make the case that competition at these sites between coactivators and repressors drives oscillatory gene expression and represents a key node for the regulation of periodicity within the clock.
Flies as models for circadian clock adaptation to environmental challenges
- Pages: 166-181
- First Published: 30 September 2018
Development of the mammalian circadian clock
- Pages: 182-193
- First Published: 27 December 2018
How and when the central and peripheral clocks start to tick during the pre‐ and post‐natal development are not well‐understood. The review summarizes the current knowledge on the development of mammalian circadian system especially that of the control of peripheral clocks by the central clock in the SCN and of the SCN network consists of multiple clusters of cellular circadian rhythms. The clusters are differentially integrated by peptidergic signals during postnatal development.
Circadian regulation in the retina: From molecules to network
- Pages: 194-216
- First Published: 30 September 2018
The vertebrate retina is the most unique tissue among those that display robust circadian rhythms, because it is a light sensing tissue that can “know” time through detecting the ambient illumination, but its own “circadian system” prepares the retina ready to anticipate the upcoming down or dusk. This review provides an overview on how circadian oscillations in various retinal cells are integrated, and how retinal diseases might affect daily rhythms.
Modulation of circadian rhythms through estrogen receptor signaling
- Pages: 217-228
- First Published: 30 September 2018
A review of the organizational and activational modulation of circadian locomotor rhythms via estrogen signaling. Here, we highlight the impact of genetic manipulation of estrogen receptors and exogenous manipulation of circulating estrogens on locomotor activity, photic responsiveness, and gene expression. Current body of literature suggests that estrogens modulate circadian rhythms by acting on multiple levels of the circadian timekeeping network, including the suprachiasmatic nucleus and its afferents and efferents. Acronyms: Estrogen receptors (ESR), estrogen receptor 1 (ESR1), estrogen receptor 2 (ESR2), retinohypothalamic tract (RHT), third ventricle (3V), intergeniculate leaflet (IGL), serotonergic raphe nuclei (5‐HT), suprachiasmatic nucleus (SCN).
Synchronization and maintenance of circadian timing in the mammalian clockwork
- Pages: 229-240
- First Published: 21 November 2018
The suprachiasmatic nucleus (SCN) is the master circadian pacemaker in mammals. Intercellular coupling of cell‐autonomous oscillators confers robustness, stability and amplitude to the circadian pacemaker. The SCN can be delineated into distinct subdivisions with a retino‐recipient core and dorsomedial shell regions. Recent advances in mouse intersectional genetics are enabling the understanding of the contribution of these heterogeneous neuronal populations in controlling SCN network properties.
Transcriptional control of synaptic components by the clock machinery
- Pages: 241-267
- First Published: 02 December 2018
Transcription factors from the molecular circadian clock regulate the expression of genes of multiple components of the synapse, the functional communication unit of the nervous system. Direct and indirect transcriptional regulation by the clock machinery of selected components such as neuropeptides, neurotransmitter regulators, vesicle proteins, receptors, transporters, channels, and adhesion and scaffolding molecules is reviewed for different brain areas.
Molecular and circuit mechanisms mediating circadian clock output in the Drosophila brain
- Pages: 268-281
- First Published: 30 July 2018
Circadian pacemaker neurons of the Madeira cockroach are inhibited and activated by GABAA and GABAB receptors
- Pages: 282-299
- First Published: 17 November 2018
Combining Ca2+ imaging of primary cell cultures of the cockroach circadian clock with pharmacology showed that GABA‐dependent decreases in calcium baseline levels could be accounted for by different combinations of inhibitory/excitatory GABAA or GABAB receptors. In contrast, excitatory actions of GABA required excitatory GABAB receptors, combined with excitatory or inhibitory GABAA receptors. This is the first report of excitatory GABAB receptors in circadian clock cells.
Mystery of rhythmic signal emergence within the suprachiasmatic nuclei
- Pages: 300-309
- First Published: 06 September 2018
Interacting influences of aging and Alzheimer's disease on circadian rhythms
- Pages: 310-325
- First Published: 28 January 2019
Aging and low levels of daytime light exposure lead to gradual attenuation and disruption of circadian rhythms. Both aging and circadian rhythm disruption increase the risk of Alzheimer's disease (AD), further disrupting of circadian rhythms. Disruption of circadian rhythms, notably the circadian sleep–wake rhythm, increases AD neuropathological changes such as brain amyloid‐beta accumulation. The mechanisms underlying the viscous cycle of disrupted circadian rhythms and progression of AD, as well as the normal age‐related circadian rhythm alterations, and are described in this article.
Mood‐related central and peripheral clocks
- Pages: 326-345
- First Published: 06 November 2018
Circadian clocks exist throughout the central nervous system and periphery, where they regulate a variety of physiological processes implicated in mood regulation. These processes include monoamine and glutamatergic signaling, HPA axis function, immune response, metabolism, and microbiome. This review will highlight the interactions between the circadian system and each of these processes and discuss their potential role in the development of mood disorders.
Perspectives in affective disorders: Clocks and sleep
- Pages: 346-365
- First Published: 31 January 2019
Effect of acute total sleep deprivation on plasma melatonin, cortisol and metabolite rhythms in females
- Pages: 366-378
- First Published: 30 March 2019
Young females were kept in controlled laboratory conditions comprising baseline sleep, sleep deprivation and recovery sleep and 1–2 hr blood sampling for 70 hr. Night‐time melatonin increased during sleep deprivation, returning to baseline levels during recovery sleep, whilst no significant changes were observed in cortisol. Of 130 plasma metabolites quantified by targeted metabolomics, 41 were altered across the nights (00:00–06:00 hr) and 58 maintained their rhythmicity across the three study days.
Mechanisms of circadian clock interactions with aryl hydrocarbon receptor signalling
- Pages: 379-395
- First Published: 31 January 2019
Upon activation by various ligands, AhR can interact with BMAL1 through its PAS domain, decreasing BMAL1:CLK heterodimer formation. AhR:BMAL1 heterodimers bind to EBox elements in target genes to act as a transcriptional repressor. Thus, AhR, which is expressed in a circadian pattern, can act to suppress the amplitude of circadian oscillations, which may contribute to clock‐disrupted pathophysiology.
Metabolic and cardiovascular consequences of shift work: The role of circadian disruption and sleep disturbances
- Pages: 396-412
- First Published: 25 October 2018
Shift work inevitably leads to the displacement of rest‐activity, sleep–wake and fasting–feeding cycles. In turn, this may cause misalignment of the endogenous circadian timing system with the external environment as well as sleep disturbance. While accumulating evidence suggests that this has negative effects on cardiovascular and metabolic health, more research is required for the development and implementation of strategies that prevent or mitigate the adverse health effects of shift work.
Sleep and synaptic down‐selection
- Pages: 413-421
- First Published: 05 January 2019
The synaptic homeostasis hypothesis (SHY): due to ongoing learning synaptic strength increases during wake in many brain circuits, leading to the strengthening of a majority of synapses. This net increase in synaptic strength is followed by synaptic down‐selection during sleep, when the brain is disconnected from the environment, allowing the weakening of the majority of synapses. Learning during waking occurs because the brain adapts to an ever‐changing environment, whether or not the subject is trained in a specific “task.”
Behavioral, neuroendocrine and physiological indicators of the circadian biology of male and female rabbits
- Pages: 429-453
- First Published: 08 November 2018
The circadian biology of rabbits is discussed and illustrated within three areas: (A) The “classic” circadian system, regulated by light, mediated by the suprachiasmatic nucleus (SCN), and modulated by a food‐entrained oscillator (FEO); (B) Suckling stimulation is a non‐photic zeitgeber interacting with the circadian system to regulate the display of the single daily nursing bout characteristic of mother rabbits; (C) Sleep and the immune system are modulated by the circadian system and also by each other, thus determining the response to infection and recovery from it.
Aging and the clock: Perspective from flies to humans
- Pages: 454-481
- First Published: 30 September 2018
Increasing longevity necessitates understanding the factors that negatively impact healthy aging. The circadian clock weakens with age and circadian dysfunction exacerbates age‐related pathologies. In this review, we highlight Drosophila as a valuable model for studying circadian‐aging interactions, examine the interplay between the circadian system and aging with examples from Drosophila to humans, and review studies in which reinforcement of the circadian system promotes healthier aging.
From clock to functional pacemaker
- Pages: 482-493
- First Published: 21 February 2019
All our bodily functions show 24‐hr patters, in order to increase fitness in an everchanging environment. It is phenomenal that these global rhythms rely on a handful of tiny oscillating neurons in the suprachiasmatic nuclei (SCN) that synchronize to the environmental cycle via a primitive retinal pathway. The neurons of the SCN have the extraordinary capacity to function as a pacemaker, and by their responsiveness to internal cues, they form an integrated circadian system subserving health.
Tired and stressed: Examining the need for sleep
- Pages: 494-508
- First Published: 08 October 2018
A Kiss to drive rhythms in reproduction
- Pages: 509-530
- First Published: 25 November 2018
In mammals, reproductive activity displays regular daily and ovarian (in female) and seasonal (in both sexes) rhythms. This review discusses how kisspeptin expressing neurons of the hypothalamus, known as potent activator of GnRH neurons, integrate daily and seasonal time cues to synchronize reproductive activity to the geophysical cycles.
Circadian disruption: What do we actually mean?
- Pages: 531-550
- First Published: 07 November 2018
Circadian and photic modulation of daily rhythms in diurnal mammals
- Pages: 551-566
- First Published: 30 September 2018
Although behavioral rhythms of diurnal and nocturnal mammals are in an anti‐phase relationship, rhythms in the principal brain clock in the suprachiasmatic nucleus (SCN) oscillate in phase in the two chronotypes. Downstream mechanisms responsible for the reversal in behavioral rhythms remain to be elucidated. Moreover, the direct behavioral response to light is very different, that is, light increases activity in diurnal mammals but inhibits it in nocturnal ones.
Circadian disruption and human health: A bidirectional relationship
- Pages: 567-583
- First Published: 14 December 2018
The relationship between circadian disruption and human health is bidirectional. Circadian dysfunction can either result from abnormal timing or decreased amplitude of circadian signals. This dysfunction is associated with an increased risk for neurodegenerative disease, cardiometabolic disease and malignancy. These disorders can in turn feedback and cause further circadian dysfunction. Further research is needed into the use of strategies to improve circadian health, in turn improving disease outcomes. This review highlights the importance of time across multiple aspects of medicine, and discusses the concept of a new field focused on these interactions: circadian medicine.








