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Molecular and Cellular Mechanisms of Synchronization within the Mammalian Circadian System

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 23729

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Special Issue Editors

Dr. Giles E. Duffield

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Guest Editor

Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
Interests: circadian rhythms; entomology; metabolism; molecular clocks; neurobiology; photobiology

Prof. Dr. Charlotte von Gall

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Guest Editor

Institute of Anatomy II, Medical Faculty, Heinrich-Heine-Universität, Duesseldorf, Germany
Interests: circadian rhythms; neuroanatomy; suprachiasmatic nucleus; molecular clockwork; cicadian clock; photoentrainment

Special Issue Information

Dear Colleagues,

In mammals, many brain and body rhythms are driven by a circadian system. The circadian system comprises three key components, the circadian rhythm generator located in the suprachiasmatic nucleus (SCN); the input pathways entraining the SCN to rhythmic events in the environment, the so-called “zeitgeber”; and output pathways mediating rhythmic signals from the SCN to subordinate oscillators within the brain and the periphery. The most prominent zeitgeber adjusting SCN timing is the environmental light/dark cycle. Light is received by the retinal photoreceptors and transmitted to the SCN. However, food, reward and social interaction can also act as strong zeitgebers. Rhythmic cell function in the SCN, retina and subordinate oscillators is driven by a molecular clock, which is composed of transcriptional/translational feedback loops of clock genes acting as transcriptional regulators. The light-resetting mechanism of the SCN molecular clock involves the activation of kinases and transcription factors and the expression of clock genes such as the periods (Per). In addition to the zeitgeber effect, the external environment also exerts a direct effect upon brain and body rhythms, the so-called “masking effect”. This Special Issue is devoted to the various mechanisms of the synchronization of rhythmic behaviour and physiology.

Dr. Giles E. Duffield
Prof. Dr. Charlotte von Gall
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

circadian ryhthm
zeitgeber
masking
clock genes
suprachiasmatic nucleus
retina
oscillator
entrainment
molecular clockwork

Published Papers (6 papers)

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Research

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20 pages, 9511 KiB

Open AccessArticle

Sex-Dependent Effects of Piromelatine Treatment on Sleep-Wake Cycle and Sleep Structure of Prenatally Stressed Rats

by Jana Tchekalarova, Lidia Kortenska, Pencho Marinov and Natasha Ivanova

Int. J. Mol. Sci. 2022, 23(18), 10349; https://doi.org/10.3390/ijms231810349 - 8 Sep 2022

Cited by 2 | Viewed by 1714

Abstract

Prenatal stress (PNS) impairs the circadian rhythm of the sleep/wake cycle. The melatonin (MT) analogue Piromelatine (Pir) was designed for the treatment of insomnia. The present study aimed to explore effects of Pir on circadian rhythmicity, motor activity, and sleep structure in male and female rats with a history of prenatal stress (PNS). In addition, we elucidated the role of MT receptors and brain-derived neurotrophic factor (BDNF) to ascertain the underlying mechanism of the drug. Pregnant rats were exposed to different stressors from day seven until birth. Piromelatine (20 mg/kg/day/14 days) was administered to young adult offspring. Home-cage locomotion, electroencephalographic (EEG) and electromyographic (EMG) recordings were conducted for 24 h. Offspring treated with vehicle showed sex-and phase-dependent disturbed circadian rhythm of motor activity and sleep/wake cycle accompanied by elevated rapid eye movement (REM) pattern and theta power and diminished non-rapid eye movement (NREM) sleep and delta power. While Pir corrected the PNS-induced impaired sleep patterns, the MT receptor antagonist luzindol suppressed its effects in male and female offspring. In addition, Pir increased the BDNF expression in the hippocampus in male and female offspring with PNS. Our findings suggest that the beneficial effect of Pir on PNS-induced impairment of sleep/wake cycle circadian rhythm and sleep structure is exerted via activation of MT receptors and enhanced BDNF expression in the hippocampus in male and female offspring. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Synchronization within the Mammalian Circadian System)

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23 pages, 4634 KiB

Open AccessArticle

Targeted Disruption of the Inhibitor of DNA Binding 4 (Id4) Gene Alters Photic Entrainment of the Circadian Clock

by Giles E. Duffield, Maricela Robles-Murguia, Tim Y. Hou and Kathleen A. McDonald

Int. J. Mol. Sci. 2021, 22(17), 9632; https://doi.org/10.3390/ijms22179632 - 6 Sep 2021

Cited by 2 | Viewed by 1969

Abstract

Inhibitor of DNA binding (Id) genes comprise a family of four helix–loop–helix (HLH) transcriptional inhibitors. Our earlier studies revealed a role for ID2 within the circadian system, contributing to input, output, and core clock function through its interaction with CLOCK and BMAL1. Here, we explore the contribution of ID4 to the circadian system using a targeted disruption of the Id4 gene. Attributes of the circadian clock were assessed by monitoring the locomotor activity of Id4−/− mice, and they revealed disturbances in its operation. Id4-mutant mice expressed a shorter circadian period length, attenuated phase shifts in responses to continuous and discrete photic cues, and an advanced phase angle of entrainment under a 12:12 light:dark cycle and under short and long photoperiods. To understand the basis for these properties, suprachiasmatic nucleus (SCN) and retinal structures were examined. Anatomical analysis reveals a smaller Id4−/− SCN in the width dimension, which is a finding consistent with its smaller brain. As a result of this feature, anterograde tracing in Id4−/− mice revealed retinal afferents innovate a disproportionally larger SCN area. The Id4−/− photic entrainment responses are unlikely to be due to an impaired function of the retinal pathways since Id4−/− retinal anatomy and function tested by pupillometry were similar to wild-type mice. Furthermore, these circadian characteristics are opposite to those exhibited by the Id2−/− mouse, suggesting an opposing influence of the ID4 protein within the circadian system; or, the absence of ID4 results in changes in the expression or activity of other members of the Id gene family. Expression analysis of the Id genes within the Id4−/− SCN revealed a time-of-day specific elevated Id1. It is plausible that the increased Id1 and/or absence of ID4 result in changes in interactions with bHLH canonical clock components or with targets upstream and/or downstream of the clock, thereby resulting in abnormal properties of the circadian clock and its entrainment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Synchronization within the Mammalian Circadian System)

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11 pages, 1426 KiB

Open AccessArticle

Does a Red House Affect Rhythms in Mice with a Corrupted Circadian System?

by Menekse Öztürk, Marc Ingenwerth, Martin Sager, Charlotte von Gall and Amira A. H. Ali

Int. J. Mol. Sci. 2021, 22(5), 2288; https://doi.org/10.3390/ijms22052288 - 25 Feb 2021

Cited by 3 | Viewed by 2459

Abstract

The circadian rhythms of body functions in mammals are controlled by the circadian system. The suprachiasmatic nucleus (SCN) in the hypothalamus orchestrates subordinate oscillators. Time information is conveyed from the retina to the SCN to coordinate an organism’s physiology and behavior with the light/dark cycle. At the cellular level, molecular clockwork composed of interlocked transcriptional/translational feedback loops of clock genes drives rhythmic gene expression. Mice with targeted deletion of the essential clock gene Bmal1 (Bmal1−/−) have an impaired light input pathway into the circadian system and show a loss of circadian rhythms. The red house (RH) is an animal welfare measure widely used for rodents as a hiding place. Red plastic provides light at a low irradiance and long wavelength—conditions which affect the circadian system. It is not known yet whether the RH affects rhythmic behavior in mice with a corrupted circadian system. Here, we analyzed whether the RH affects spontaneous locomotor activity in Bmal1−/− mice under standard laboratory light conditions. In addition, mPER1- and p-ERK-immunoreactions, as markers for rhythmic SCN neuronal activity, and day/night plasma corticosterone levels were evaluated. Our findings indicate that application of the RH to Bmal1−/− abolishes rhythmic locomotor behavior and dampens rhythmic SCN neuronal activity. However, RH had no effect on the day/night difference in corticosterone levels. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Synchronization within the Mammalian Circadian System)

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Review

Jump to: Research

22 pages, 5167 KiB

Open AccessReview

Cosmeceutical Therapy: Engaging the Repercussions of UVR Photoaging on the Skin’s Circadian Rhythm

by Camille Keisha Mahendra, Hooi-Leng Ser, Priyia Pusparajah, Thet Thet Htar, Lay-Hong Chuah, Wei Hsum Yap, Yin-Quan Tang, Gokhan Zengin, Siah Ying Tang, Wai Leng Lee, Kai Bin Liew, Long Chiau Ming and Bey Hing Goh

Int. J. Mol. Sci. 2022, 23(5), 2884; https://doi.org/10.3390/ijms23052884 - 7 Mar 2022

Cited by 7 | Viewed by 4220

Abstract

Sunlight is an important factor in regulating the central circadian rhythm, including the modulation of our sleep/wake cycles. Sunlight had also been discovered to have a prominent influence on our skin’s circadian rhythm. Overexposure or prolonged exposure to the sun can cause skin photodamage, such as the formation of irregular pigmentation, collagen degradation, DNA damage, and even skin cancer. Hence, this review will be looking into the detrimental effects of sunlight on our skin, not only at the aspect of photoaging but also at its impact on the skin’s circadian rhythm. The growing market trend of natural-product-based cosmeceuticals as also caused us to question their potential to modulate the skin’s circadian rhythm. Questions about how the skin’s circadian rhythm could counteract photodamage and how best to maximize its biopotential will be discussed in this article. These discoveries regarding the skin’s circadian rhythm have opened up a completely new level of understanding of our skin’s molecular mechanism and may very well aid cosmeceutical companies, in the near future, to develop better products that not only suppress photoaging but remain effective and relevant throughout the day. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Synchronization within the Mammalian Circadian System)

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21 pages, 919 KiB

Open AccessReview

The Effects of Light and the Circadian System on Rhythmic Brain Function

by Charlotte von Gall

Int. J. Mol. Sci. 2022, 23(5), 2778; https://doi.org/10.3390/ijms23052778 - 3 Mar 2022

Cited by 23 | Viewed by 7246

Abstract

Life on earth has evolved under the influence of regularly recurring changes in the environment, such as the 24 h light/dark cycle. Consequently, organisms have developed endogenous clocks, generating 24 h (circadian) rhythms that serve to anticipate these rhythmic changes. In addition to these circadian rhythms, which persist in constant conditions and can be entrained to environmental rhythms, light drives rhythmic behavior and brain function, especially in nocturnal laboratory rodents. In recent decades, research has made great advances in the elucidation of the molecular circadian clockwork and circadian light perception. This review summarizes the role of light and the circadian clock in rhythmic brain function, with a focus on the complex interaction between the different components of the mammalian circadian system. Furthermore, chronodisruption as a consequence of light at night, genetic manipulation, and neurodegenerative diseases is briefly discussed. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Synchronization within the Mammalian Circadian System)

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12 pages, 778 KiB

Open AccessReview

Photic Entrainment of the Circadian System

by Anna Ashton, Russell G. Foster and Aarti Jagannath

Int. J. Mol. Sci. 2022, 23(2), 729; https://doi.org/10.3390/ijms23020729 - 10 Jan 2022

Cited by 35 | Viewed by 4937

Abstract

Circadian rhythms are essential for the survival of all organisms, enabling them to predict daily changes in the environment and time their behaviour appropriately. The molecular basis of such rhythms is the circadian clock, a self-sustaining molecular oscillator comprising a transcriptional–translational feedback loop. This must be continually readjusted to remain in alignment with the external world through a process termed entrainment, in which the phase of the master circadian clock in the suprachiasmatic nuclei (SCN) is adjusted in response to external time cues. In mammals, the primary time cue, or “zeitgeber”, is light, which inputs directly to the SCN where it is integrated with additional non-photic zeitgebers. The molecular mechanisms underlying photic entrainment are complex, comprising a number of regulatory factors. This review will outline the photoreception pathways mediating photic entrainment, and our current understanding of the molecular pathways that drive it in the SCN. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Synchronization within the Mammalian Circadian System)

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