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Korf HW. Photoneuroendocrine, circadian and seasonal systems: from photoneuroendocrinology to circadian biology and medicine. Cell Tissue Res 2025; 400:217-240. [PMID: 39264444 PMCID: PMC12089256 DOI: 10.1007/s00441-024-03913-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 07/30/2024] [Indexed: 09/13/2024]
Abstract
This contribution highlights the scientific development of two intertwined disciplines, photoneuroendocrinology and circadian biology. Photoneuroendocrinology has focused on nonvisual photoreceptors that translate light stimuli into neuroendocrine signals and serve rhythm entrainment. Nonvisual photoreceptors first described in the pineal complex and brain of nonmammalian species are luminance detectors. In the pineal, they control the formation of melatonin, the highly conserved hormone of darkness which is synthesized night by night. Pinealocytes endowed with both photoreceptive and neuroendocrine capacities function as "photoneuroendocrine cells." In adult mammals, nonvisual photoreceptors controlling pineal melatonin biosynthesis and pupillary reflexes are absent from the pineal and brain and occur only in the inner layer of the retina. Encephalic photoreceptors regulate seasonal rhythms, such as the reproductive cycle. They are concentrated in circumventricular organs, the lateral septal organ and the paraventricular organ, and represent cerebrospinal fluid contacting neurons. Nonvisual photoreceptors employ different photopigments such as melanopsin, pinopsin, parapinopsin, neuropsin, and vertebrate ancient opsin. After identification of clock genes and molecular clockwork, circadian biology became cutting-edge research with a focus on rhythm generation. Molecular clockworks tick in every nucleated cell and, as shown in mammals, they drive the expression of more than 3000 genes and are of overall importance for regulation of cell proliferation and metabolism. The mammalian circadian system is hierarchically organized; the central rhythm generator is located in the suprachiasmatic nuclei which entrain peripheral circadian oscillators via multiple neuronal and neuroendocrine pathways. Disrupted molecular clockworks may cause various diseases, and investigations of this interplay will establish a new discipline: circadian medicine.
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Affiliation(s)
- Horst-Werner Korf
- Institute Anatomy I, Medical Faculty, Heinrich Heine University, Duesseldorf, Federal Republic of Germany.
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2
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Nakazawa K, Matsuo M, Nakao K, Nonaka S, Numano R. Visible Exocytosis of the Non-Photic Signal Neuropeptide Y to the Suprachiasmatic Nucleus in Fasted Transgenic Mice Throughout Their Circadian Rhythms. Bioengineering (Basel) 2025; 12:192. [PMID: 40001711 PMCID: PMC11851631 DOI: 10.3390/bioengineering12020192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 02/02/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
Organisms maintain circadian rhythms corresponding to approximately 24 h in the absence of external environmental cues, and they synchronize the phases of their autonomous circadian clocks to light-dark cycles, feeding timing, and other factors. The suprachiasmatic nucleus (SCN) occupies the top position of the hierarchy in the mammalian circadian system and functions as a photic-dependent oscillator, while the food-entrainable circadian oscillator (FEO) entrains the clocks of the digestive peripheral tissues and behaviors according to feeding timing. In mammals, neuropeptide Y (NPY) from the intergeniculate leaflet (IGL) neurons projected onto the SCN plays an important role in entraining circadian rhythms to feeding conditions. However, the relationship between the FEO and SCN has been unclear under various feeding conditions. In this study, novel NPY::Venus transgenic (Tg) mice, which expressed the NPY fused to Venus fluorescent protein, were generated to investigate the secretion of NPY on the SCN from the IGL. NPY-containing secretory granules with Venus signals in the SCN slices of the Tg mice could be observed using confocal and super-resolution microscopy. We observed that the number of NPY secretory granules released on the SCNs increased during fasting, and these mice were valuable tools for further investigating the role of NPY secretion from the IGL to the SCN in mediating interactions between the FEO and the SCN.
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Affiliation(s)
- Kazuo Nakazawa
- Department of Applied Chemistry and Life Science, Toyohashi University of Technology, Toyohashi 441-8580, Japan;
| | - Minako Matsuo
- Institute for Research on Next-generation Semiconductor and Sensing Science, Toyohashi University of Technology, Toyohashi 441-8580, Japan
| | - Kazuki Nakao
- Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The Osaka University, Suita 565-0871, Japan
| | - Shigenori Nonaka
- Spatiotemporal Regulations Group, Exploratory Research Center for Life and Living Systems (ExCELLS), Okazaki 444-8585, Japan
- Laboratory for Spatiotemporal Regulations, National Institute for Basic Biology, Okazaki 444-8585, Japan
| | - Rika Numano
- Department of Applied Chemistry and Life Science, Toyohashi University of Technology, Toyohashi 441-8580, Japan;
- Institute for Research on Next-generation Semiconductor and Sensing Science, Toyohashi University of Technology, Toyohashi 441-8580, Japan
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Korf HW, von Gall C. Mouse Models in Circadian Rhythm and Melatonin Research. J Pineal Res 2024; 76:e12986. [PMID: 38965880 DOI: 10.1111/jpi.12986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/14/2024] [Accepted: 06/22/2024] [Indexed: 07/06/2024]
Abstract
This contribution reviews the role of inbred and transgenic mouse strains for deciphering the mammalian melatoninergic and circadian system. It focusses on the pineal organ as melatonin factory and two major targets of the melatoninergic system, the suprachiasmatic nuclei (SCN) and the hypophysial pars tuberalis (PT). Mammalian pinealocytes sharing molecular characteristics with true pineal and retinal photoreceptors synthesize and secrete melatonin into the blood and cerebrospinal fluid night by night. Notably, neuron-like connections exist between the deep pinealocytes and the habenular/pretectal region suggesting direct pineal-brain communication. Control of melatonin biosynthesis in rodents involves transcriptional regulation including phosphorylation of CREB and upregulation of mPer1. In the SCN, melatonin acts upon MT1 and MT2 receptors. Melatonin is not necessary to maintain the rhythm of the SCN molecular clockwork, but it has distinct effects on the synchronization of the circadian rhythm by light, facilitates re-entrainment of the circadian system to phase advances in the level of the SCN molecular clockwork by acting upon MT2 receptors and plays a stabilizing role in the circadian system as evidenced from locomotor activity recordings. While the effects in the SCN are subtle, melatonin is essential for PT functions. Via the MT1 receptor it drives the PT-intrinsic molecular clockwork and the retrograde and anterograde output pathways controlling seasonal rhythmicity. Although inbred and transgenic mice do not show seasonal reproduction, the pathways from the PT are fully intact if the animals are melatonin proficient. Thus, only melatonin-proficient strains are suited to investigate the circadian and melatoninergic systems.
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Affiliation(s)
- Horst-Werner Korf
- Institute of Anatomy I, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Charlotte von Gall
- Institute of Anatomy II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
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Savvidis C, Kallistrou E, Kouroglou E, Dionysopoulou S, Gavriiloglou G, Ragia D, Tsiama V, Proikaki S, Belis K, Ilias I. Circadian rhythm disruption and endocrine-related tumors. World J Clin Oncol 2024; 15:818-834. [PMID: 39071458 PMCID: PMC11271730 DOI: 10.5306/wjco.v15.i7.818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 06/20/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
This review delved into the intricate relationship between circadian clocks and physiological processes, emphasizing their critical role in maintaining homeostasis. Orchestrated by interlocked clock genes, the circadian timekeeping system regulates fundamental processes like the sleep-wake cycle, energy metabolism, immune function, and cell proliferation. The central oscillator in the hypothalamic suprachiasmatic nucleus synchronizes with light-dark cycles, while peripheral tissue clocks are influenced by cues such as feeding times. Circadian disruption, linked to modern lifestyle factors like night shift work, correlates with adverse health outcomes, including metabolic syndrome, cardiovascular diseases, infections, and cancer. We explored the molecular mechanisms of circadian clock genes and their impact on metabolic disorders and cancer pathogenesis. Specific associations between circadian disruption and endocrine tumors, spanning breast, ovarian, testicular, prostate, thyroid, pituitary, and adrenal gland cancers, are highlighted. Shift work is associated with increased breast cancer risk, with PER genes influencing tumor progression and drug resistance. CLOCK gene expression correlates with cisplatin resistance in ovarian cancer, while factors like aging and intermittent fasting affect prostate cancer. Our review underscored the intricate interplay between circadian rhythms and cancer, involving the regulation of the cell cycle, DNA repair, metabolism, immune function, and the tumor microenvironment. We advocated for integrating biological timing into clinical considerations for personalized healthcare, proposing that understanding these connections could lead to novel therapeutic approaches. Evidence supports circadian rhythm-focused therapies, particularly chronotherapy, for treating endocrine tumors. Our review called for further research to uncover detailed connections between circadian clocks and cancer, providing essential insights for targeted treatments. We emphasized the importance of public health interventions to mitigate lifestyle-related circadian disruptions and underscored the critical role of circadian rhythms in disease mechanisms and therapeutic interventions.
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Affiliation(s)
- Christos Savvidis
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Efthymia Kallistrou
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Eleni Kouroglou
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Sofia Dionysopoulou
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | | | - Dimitra Ragia
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Vasiliki Tsiama
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Stella Proikaki
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Konstantinos Belis
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Ioannis Ilias
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
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Touitou Y, Cermakian N, Touitou C. The environment and the internal clocks: The study of their relationships from prehistoric to modern times. Chronobiol Int 2024; 41:859-887. [PMID: 38757600 DOI: 10.1080/07420528.2024.2353857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/17/2024] [Accepted: 05/03/2024] [Indexed: 05/18/2024]
Abstract
The origin of biological rhythms goes back to the very beginning of life. They are observed in the animal and plant world at all levels of organization, from cells to ecosystems. As early as the 18th century, plant scientists were the first to explain the relationship between flowering cycles and environmental cycles, emphasizing the importance of daily light-dark cycles and the seasons. Our temporal structure is controlled by external and internal rhythmic signals. Light is the main synchronizer of the circadian system, as daily exposure to light entrains our clock over 24 hours, the endogenous period of the circadian system being close to, but not exactly, 24 hours. In 1960, a seminal scientific meeting, the Cold Spring Harbor Symposium on Biological Rhythms, brought together all the biological rhythms scientists of the time, a number of whom are considered the founders of modern chronobiology. All aspects of biological rhythms were addressed, from the properties of circadian rhythms to their practical and ecological aspects. Birth of chronobiology dates from this period, with the definition of its vocabulary and specificities in metabolism, photoperiodism, animal physiology, etc. At around the same time, and right up to the present day, research has focused on melatonin, the circadian neurohormone of the pineal gland, with data on its pattern, metabolism, control by light and clinical applications. However, light has a double face, as it has positive effects as a circadian clock entraining agent, but also deleterious effects, as it can lead to chronodisruption when exposed chronically at night, which can increase the risk of cancer and other diseases. Finally, research over the past few decades has unraveled the anatomical location of circadian clocks and their cellular and molecular mechanisms. This recent research has in turn allowed us to explain how circadian rhythms control physiology and health.
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Affiliation(s)
- Yvan Touitou
- Unité de Chronobiologie, Fondation A. de Rothschild, Paris, France
| | - Nicolas Cermakian
- Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
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Nakazawa K, Matsuo M, Kikuchi Y, Nakajima Y, Numano R. Melanopsin DNA aptamers can regulate input signals of mammalian circadian rhythms by altering the phase of the molecular clock. Front Neurosci 2024; 18:1186677. [PMID: 38694901 PMCID: PMC11062245 DOI: 10.3389/fnins.2024.1186677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 03/18/2024] [Indexed: 05/04/2024] Open
Abstract
DNA aptamers can bind specifically to biomolecules to modify their function, potentially making them ideal oligonucleotide therapeutics. Herein, we screened for DNA aptamer of melanopsin (OPN4), a blue-light photopigment in the retina, which plays a key role using light signals to reset the phase of circadian rhythms in the central clock. Firstly, 15 DNA aptamers of melanopsin (Melapts) were identified following eight rounds of Cell-SELEX using cells expressing melanopsin on the cell membrane. Subsequent functional analysis of each Melapt was performed in a fibroblast cell line stably expressing both Period2:ELuc and melanopsin by determining the degree to which they reset the phase of mammalian circadian rhythms in response to blue-light stimulation. Period2 rhythmic expression over a 24-h period was monitored in Period2:ELuc stable cell line fibroblasts expressing melanopsin. At subjective dawn, four Melapts were observed to advance phase by >1.5 h, while seven Melapts delayed phase by >2 h. Some Melapts caused a phase shift of approximately 2 h, even in the absence of photostimulation, presumably because Melapts can only partially affect input signaling for phase shift. Additionally, some Melaps were able to induce phase shifts in Per1::luc transgenic (Tg) mice, suggesting that these DNA aptamers may have the capacity to affect melanopsin in vivo. In summary, Melapts can successfully regulate the input signal and shifting phase (both phase advance and phase delay) of mammalian circadian rhythms in vitro and in vivo.
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Affiliation(s)
- Kazuo Nakazawa
- Department of Applied Chemistry and Life Science, Toyohashi University of Technology, Toyohashi, Aichi, Japan
- TechnoPro, Inc., Tokyo, Japan
| | - Minako Matsuo
- Institute for Research on Next-Generation Semiconductor and Sensing Science, Toyohashi University of Technology, Toyohashi, Aichi, Japan
| | - Yo Kikuchi
- Department of Applied Chemistry and Life Science, Toyohashi University of Technology, Toyohashi, Aichi, Japan
- Institute for Research on Next-Generation Semiconductor and Sensing Science, Toyohashi University of Technology, Toyohashi, Aichi, Japan
| | - Yoshihiro Nakajima
- Health and Medical Research, National Institute of Advanced Industrial Science and Technology (AIST), Takamatsu, Kagawa, Japan
| | - Rika Numano
- Department of Applied Chemistry and Life Science, Toyohashi University of Technology, Toyohashi, Aichi, Japan
- Institute for Research on Next-Generation Semiconductor and Sensing Science, Toyohashi University of Technology, Toyohashi, Aichi, Japan
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Chawla S, Oster H, Duffield GE, Maronde E, Guido ME, Chabot C, Dkhissi-Benyahya O, Provencio I, Goel N, Youngstedt SD, Zi-Ching Mak N, Caba M, Nikhat A, Chakrabarti S, Wang L, Davis SJ. Reflections on Several Landmark Advances in Circadian Biology. J Circadian Rhythms 2024; 22:1. [PMID: 38617711 PMCID: PMC11011952 DOI: 10.5334/jcr.236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 01/17/2024] [Indexed: 04/16/2024] Open
Abstract
Circadian Biology intersects with diverse scientific domains, intricately woven into the fabric of organismal physiology and behavior. The rhythmic orchestration of life by the circadian clock serves as a focal point for researchers across disciplines. This retrospective examination delves into several of the scientific milestones that have fundamentally shaped our contemporary understanding of circadian rhythms. From deciphering the complexities of clock genes at a cellular level to exploring the nuances of coupled oscillators in whole organism responses to stimuli. The field has undergone significant evolution lately guided by genetics approaches. Our exploration here considers key moments in the circadian-research landscape, elucidating the trajectory of this discipline with a keen eye on scientific advancements and paradigm shifts.
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Affiliation(s)
| | - Henrik Oster
- Institute of Neurobiology, Center for Brain, Behavior & Metabolism (CBBM), University of Luebeck, 23562 Luebeck, DE
| | - Giles E. Duffield
- Department of Biological Sciences and Eck Institute for Global Health, Galvin Life Science Center, University of Notre Dame, Notre Dame, IN 46556, US
| | - Erik Maronde
- Institut für Anatomie II, Dr. Senckenbergische Anatomie, Goethe-Universität Frankfurt, Theodor-Stern-Kai-7, 60590 Frankfurt, DE
| | - Mario E. Guido
- CIQUIBIC-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, AR
- Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, AR
| | - Christopher Chabot
- Department of Biological Sciences, Plymouth State University, Plymouth, NH 03264, US
| | - Ouria Dkhissi-Benyahya
- Inserm, Stem Cell and Brain Research Institute U1208, Univ Lyon, UniversitéClaude Bernard Lyon 1, 18 Avenue du Doyen Lépine, 69500, Bron, FR
| | - Ignacio Provencio
- Department of Biology and Department of Ophthalmology, University of Virginia, Charlottesville, VA, US
| | - Namni Goel
- Biological Rhythms Research Laboratory, Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL, US
| | - Shawn D. Youngstedt
- Edson College of Nursing and Health Innovation, Arizona State University, Phoenix, AZ, US
- Department of Medicine, University of Arizona, Tucson, AZ, US
| | | | - Mario Caba
- Centro de Investigaciones Biomédicas, Universidad Veracruzana, Xalapa, Ver., MX
| | - Anjoom Nikhat
- Simons Centre for the Study of Living Machines, National Centre for Biological Sciences, Bangalore, Karnataka 560065, IN
| | - Shaon Chakrabarti
- Simons Centre for the Study of Living Machines, National Centre for Biological Sciences, Bangalore, Karnataka 560065, IN
| | - Lei Wang
- Key Laboratory of Plant Molecular Physiology, CAS Center for Excellence in Molecular Plant Sciences, China National Botanical Garden, Beijing 100093, CN
| | - Seth J. Davis
- Department of Biology, University of York, York YO105DD, UK
- State Key Laboratory of Crop Stress Biology, School of Life Sciences, Henan University, Kaifeng 475004, CN
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Ono D, Weaver DR, Hastings MH, Honma KI, Honma S, Silver R. The Suprachiasmatic Nucleus at 50: Looking Back, Then Looking Forward. J Biol Rhythms 2024; 39:135-165. [PMID: 38366616 PMCID: PMC7615910 DOI: 10.1177/07487304231225706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2024]
Abstract
It has been 50 years since the suprachiasmatic nucleus (SCN) was first identified as the central circadian clock and 25 years since the last overview of developments in the field was published in the Journal of Biological Rhythms. Here, we explore new mechanisms and concepts that have emerged in the subsequent 25 years. Since 1997, methodological developments, such as luminescent and fluorescent reporter techniques, have revealed intricate relationships between cellular and network-level mechanisms. In particular, specific neuropeptides such as arginine vasopressin, vasoactive intestinal peptide, and gastrin-releasing peptide have been identified as key players in the synchronization of cellular circadian rhythms within the SCN. The discovery of multiple oscillators governing behavioral and physiological rhythms has significantly advanced our understanding of the circadian clock. The interaction between neurons and glial cells has been found to play a crucial role in regulating these circadian rhythms within the SCN. Furthermore, the properties of the SCN network vary across ontogenetic stages. The application of cell type-specific genetic manipulations has revealed components of the functional input-output system of the SCN and their correlation with physiological functions. This review concludes with the high-risk effort of identifying open questions and challenges that lie ahead.
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Affiliation(s)
- Daisuke Ono
- Stress Recognition and Response, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - David R Weaver
- Department of Neurobiology and NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Michael H Hastings
- Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge, UK
| | - Ken-Ichi Honma
- Research and Education Center for Brain Science, Hokkaido University, Sapporo, Japan
- Center for Sleep and Circadian Rhythm Disorders, Sapporo Hanazono Hospital, Sapporo, Japan
| | - Sato Honma
- Research and Education Center for Brain Science, Hokkaido University, Sapporo, Japan
- Center for Sleep and Circadian Rhythm Disorders, Sapporo Hanazono Hospital, Sapporo, Japan
| | - Rae Silver
- Stress Recognition and Response, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
- Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Neuroscience & Behavior, Barnard College and Department of Psychology, Columbia University, New York City, New York, USA
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Eckle T, Bertazzo J, Khatua TN, Tabatabaei SRF, Bakhtiari NM, Walker LA, Martino TA. Circadian Influences on Myocardial Ischemia-Reperfusion Injury and Heart Failure. Circ Res 2024; 134:675-694. [PMID: 38484024 PMCID: PMC10947118 DOI: 10.1161/circresaha.123.323522] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 02/02/2024] [Accepted: 02/08/2024] [Indexed: 03/19/2024]
Abstract
The impact of circadian rhythms on cardiovascular function and disease development is well established, with numerous studies in genetically modified animals emphasizing the circadian molecular clock's significance in the pathogenesis and pathophysiology of myocardial ischemia and heart failure progression. However, translational preclinical studies targeting the heart's circadian biology are just now emerging and are leading to the development of a novel field of medicine termed circadian medicine. In this review, we explore circadian molecular mechanisms and novel therapies, including (1) intense light, (2) small molecules modulating the circadian mechanism, and (3) chronotherapies such as cardiovascular drugs and meal timings. These promise significant clinical translation in circadian medicine for cardiovascular disease. (4) Additionally, we address the differential functioning of the circadian mechanism in males versus females, emphasizing the consideration of biological sex, gender, and aging in circadian therapies for cardiovascular disease.
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Affiliation(s)
- Tobias Eckle
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Júlia Bertazzo
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Tarak Nath Khatua
- Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Seyed Reza Fatemi Tabatabaei
- Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Naghmeh Moori Bakhtiari
- Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Lori A Walker
- Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Tami A. Martino
- Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
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10
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Xu W, Li X. Regulation of Pol II Pausing during Daily Gene Transcription in Mouse Liver. BIOLOGY 2023; 12:1107. [PMID: 37626993 PMCID: PMC10452108 DOI: 10.3390/biology12081107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/20/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023]
Abstract
Cell autonomous circadian oscillation is present in central and various peripheral tissues. The intrinsic tissue clock and various extrinsic cues drive gene expression rhythms. Transcription regulation is thought to be the main driving force for gene rhythms. However, how transcription rhythms arise remains to be fully characterized due to the fact that transcription is regulated at multiple steps. In particular, Pol II recruitment, pause release, and premature transcription termination are critical regulatory steps that determine the status of Pol II pausing and transcription output near the transcription start site (TSS) of the promoter. Recently, we showed that Pol II pausing exhibits genome-wide changes during daily transcription in mouse liver. In this article, we review historical as well as recent findings on the regulation of transcription rhythms by the circadian clock and other transcription factors, and the potential limitations of those results in explaining rhythmic transcription at the TSS. We then discuss our results on the genome-wide characteristics of daily changes in Pol II pausing, the possible regulatory mechanisms involved, and their relevance to future research on circadian transcription regulation.
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Affiliation(s)
| | - Xiaodong Li
- College of Life Sciences, Wuhan University, Wuhan 430072, China;
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11
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Zhuang Y, Li Z, Xiong S, Sun C, Li B, Wu SA, Lyu J, Shi X, Yang L, Chen Y, Bao Z, Li X, Sun C, Chen Y, Deng H, Li T, Wu Q, Qi L, Huang Y, Yang X, Lin Y. Circadian clocks are modulated by compartmentalized oscillating translation. Cell 2023; 186:3245-3260.e23. [PMID: 37369203 DOI: 10.1016/j.cell.2023.05.045] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/12/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023]
Abstract
Terrestrial organisms developed circadian rhythms for adaptation to Earth's quasi-24-h rotation. Achieving precise rhythms requires diurnal oscillation of fundamental biological processes, such as rhythmic shifts in the cellular translational landscape; however, regulatory mechanisms underlying rhythmic translation remain elusive. Here, we identified mammalian ATXN2 and ATXN2L as cooperating master regulators of rhythmic translation, through oscillating phase separation in the suprachiasmatic nucleus along circadian cycles. The spatiotemporal oscillating condensates facilitate sequential initiation of multiple cycling processes, from mRNA processing to protein translation, for selective genes including core clock genes. Depleting ATXN2 or 2L induces opposite alterations to the circadian period, whereas the absence of both disrupts translational activation cycles and weakens circadian rhythmicity in mice. Such cellular defect can be rescued by wild type, but not phase-separation-defective ATXN2. Together, we revealed that oscillating translation is regulated by spatiotemporal condensation of two master regulators to achieve precise circadian rhythm in mammals.
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Affiliation(s)
- Yanrong Zhuang
- State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Zhiyuan Li
- School of Life Sciences, MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, Tsinghua University, Beijing 100084, China
| | - Shiyue Xiong
- State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Chujie Sun
- School of Life Sciences, MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, Tsinghua University, Beijing 100084, China
| | - Boya Li
- State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Shuangcheng Alivia Wu
- Department of Molecular & Integrative Physiology, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA
| | - Jiali Lyu
- State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xiang Shi
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Liang Yang
- Department of Medical Bioinformatics, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education, National Health Commission of China, Peking University, Beijing 100191, China
| | - Yutong Chen
- State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Zhangbin Bao
- State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xi Li
- State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Chuhanwen Sun
- State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yuling Chen
- School of Life Sciences, MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, Tsinghua University, Beijing 100084, China
| | - Haiteng Deng
- School of Life Sciences, MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, Tsinghua University, Beijing 100084, China
| | - Tingting Li
- Department of Medical Bioinformatics, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education, National Health Commission of China, Peking University, Beijing 100191, China
| | - Qingfeng Wu
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Ling Qi
- Department of Molecular & Integrative Physiology, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA
| | - Yue Huang
- China National Clinical Research Center for Neurological Diseases and Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Phamalology Department, School of Biomedical Sciences, Faculty of Medicine, UNSW Sydney, Sydney, Australia
| | - Xuerui Yang
- School of Life Sciences, MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, Tsinghua University, Beijing 100084, China.
| | - Yi Lin
- State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
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12
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Nakazawa K, Matsuo M, Kimura N, Numano R. Restricted Feeding Resets the Peripheral Clocks of the Digestive System. Biomedicines 2023; 11:biomedicines11051463. [PMID: 37239134 DOI: 10.3390/biomedicines11051463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/08/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
All organisms maintain an internal clock that matches the Earth's rotation over a period of 24 h, known as the circadian rhythm. Previously, we established Period1 luciferase (Per1::luc) transgenic (Tg) mice in order to monitor the expression rhythms of the Per1 clock gene in each tissue in real time using a bioluminescent reporter. The Per1 gene is a known key molecular regulator of the mammalian clock system in the autonomous central clock in the suprachiasmatic nucleus (SCN), and the peripheral tissues. Per1::luc Tg mice were used as a biosensing system of circadian rhythms. They were maintained by being fed ad lib (FF) and subsequently subjected to 4 hour (4 h) restricted feeding (RF) during the rest period under light conditions in order to examine whether the peripheral clocks of different parts in the digestive tract could be entrained. The peak points of the bioluminescent rhythms in the Per1::luc Tg mouse tissue samples were analyzed via cosine fitting. The bioluminescent rhythms of the cultured peripheral tissues of the esophagus and the jejunum exhibited phase shift from 5 to 11 h during RF, whereas those of the SCN tissue remained unchanged for 7 days during RF. We examined whether RF for 4 h during the rest period in light conditions could reset the activity rhythms, the central clock in the SCN, and the peripheral clock in the different points in the gastrointestinal tract. The fasting signals during RF did not entrain the SCN, but they did entrain each peripheral clock of the digestive system, the esophagus, and the jejunum. During RF for 7 days, the peak time of the esophagus tended to return to that of the FF control, unlike that of the jejunum; hence, the esophagus was regulated more strongly under the control of the cultured SCN compared to the jejunum. Thus, the peripheral clocks of the digestive system can entrain their molecular clock rhythms via RF-induced fasting signals in each degree, independently from the SCN.
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Affiliation(s)
- Kazuo Nakazawa
- Department of Applied Chemistry and Life Science, Toyohashi University of Technology, Toyohashi 441-8580, Japan
| | - Minako Matsuo
- Institute for Research on Next-Generation Semiconductor and Sensing Science, Toyohashi University of Technology, Toyohashi 441-8580, Japan
| | - Naobumi Kimura
- Institute for Research on Next-Generation Semiconductor and Sensing Science, Toyohashi University of Technology, Toyohashi 441-8580, Japan
| | - Rika Numano
- Department of Applied Chemistry and Life Science, Toyohashi University of Technology, Toyohashi 441-8580, Japan
- Institute for Research on Next-Generation Semiconductor and Sensing Science, Toyohashi University of Technology, Toyohashi 441-8580, Japan
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13
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Bhoi JD, Goel M, Ribelayga CP, Mangel SC. Circadian clock organization in the retina: From clock components to rod and cone pathways and visual function. Prog Retin Eye Res 2023; 94:101119. [PMID: 36503722 PMCID: PMC10164718 DOI: 10.1016/j.preteyeres.2022.101119] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 08/22/2022] [Accepted: 08/25/2022] [Indexed: 12/13/2022]
Abstract
Circadian (24-h) clocks are cell-autonomous biological oscillators that orchestrate many aspects of our physiology on a daily basis. Numerous circadian rhythms in mammalian and non-mammalian retinas have been observed and the presence of an endogenous circadian clock has been demonstrated. However, how the clock and associated rhythms assemble into pathways that support and control retina function remains largely unknown. Our goal here is to review the current status of our knowledge and evaluate recent advances. We describe many previously-observed retinal rhythms, including circadian rhythms of morphology, biochemistry, physiology, and gene expression. We evaluate evidence concerning the location and molecular machinery of the retinal circadian clock, as well as consider findings that suggest the presence of multiple clocks. Our primary focus though is to describe in depth circadian rhythms in the light responses of retinal neurons with an emphasis on clock control of rod and cone pathways. We examine evidence that specific biochemical mechanisms produce these daily light response changes. We also discuss evidence for the presence of multiple circadian retinal pathways involving rhythms in neurotransmitter activity, transmitter receptors, metabolism, and pH. We focus on distinct actions of two dopamine receptor systems in the outer retina, a dopamine D4 receptor system that mediates circadian control of rod/cone gap junction coupling and a dopamine D1 receptor system that mediates non-circadian, light/dark adaptive regulation of gap junction coupling between horizontal cells. Finally, we evaluate the role of circadian rhythmicity in retinal degeneration and suggest future directions for the field of retinal circadian biology.
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Affiliation(s)
- Jacob D Bhoi
- Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School, UTHEALTH-The University of Texas Health Science Center at Houston, Houston, TX, USA; Neuroscience Honors Research Program, William Marsh Rice University, Houston, TX, USA
| | - Manvi Goel
- Department of Neuroscience, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Christophe P Ribelayga
- Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School, UTHEALTH-The University of Texas Health Science Center at Houston, Houston, TX, USA; Neuroscience Honors Research Program, William Marsh Rice University, Houston, TX, USA.
| | - Stuart C Mangel
- Department of Neuroscience, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH, USA.
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14
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Chu Y, He H, Liu Q, Jia S, Fan W, Huang F. The Circadian Clocks, Oscillations of Pain-Related Mediators, and Pain. Cell Mol Neurobiol 2023; 43:511-523. [PMID: 35179680 PMCID: PMC11415172 DOI: 10.1007/s10571-022-01205-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 02/06/2022] [Indexed: 01/07/2023]
Abstract
The circadian clock is a biochemical oscillator that is synchronized with solar time. Normal circadian rhythms are necessary for many physiological functions. Circadian rhythms have also been linked with many physiological functions, several clinical symptoms, and diseases. Accumulating evidence suggests that the circadian clock appears to modulate the processing of nociceptive information. Many pain conditions display a circadian fluctuation pattern clinically. Thus, the aim of this review is to summarize the existing knowledge about the circadian clocks involved in diurnal rhythms of pain. Possible cellular and molecular mechanisms regarding the connection between the circadian clocks and pain are discussed.
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Affiliation(s)
- Yanhao Chu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen Uni-versity, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Hongwen He
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Qing Liu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen Uni-versity, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Shilin Jia
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen Uni-versity, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Wenguo Fan
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.
| | - Fang Huang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen Uni-versity, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.
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15
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Mood phenotypes in rodent models with circadian disturbances. Neurobiol Sleep Circadian Rhythms 2022; 13:100083. [PMID: 36345502 PMCID: PMC9636574 DOI: 10.1016/j.nbscr.2022.100083] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022] Open
Abstract
Many physiological functions with approximately 24-h rhythmicity (circadian rhythms) are generated by an internal time-measuring system of the circadian clock. While sleep/wake cycles, feeding patterns, and body temperature are the most widely known physiological functions under the regulation of the circadian clock, physiological regulation by the circadian clock extends to higher brain functions. Accumulating evidence suggests strong associations between the circadian clock and mood disorders such as depression, but the underlying mechanisms of the functional relationship between them are obscure. This review overviews rodent models with disrupted circadian rhythms on depression-related responses. The animal models with circadian disturbances (by clock gene mutations and artifactual interventions) will help understand the causal link between the circadian clock and depression.
The molecular mechanisms of the mammalian circadian rhythm are systematically overviewed. We overview how genetic and pharmacological manipulations of clock (related) genes are linked to mood phenotypes. We overview how artificial perturbations, such as SCN lesions and aberrant light, affect circadian rhythm and mood.
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16
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Smies CW, Bodinayake KK, Kwapis JL. Time to learn: The role of the molecular circadian clock in learning and memory. Neurobiol Learn Mem 2022; 193:107651. [PMID: 35697314 PMCID: PMC9903177 DOI: 10.1016/j.nlm.2022.107651] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/18/2022] [Accepted: 06/07/2022] [Indexed: 12/27/2022]
Abstract
The circadian system plays an important role in aligning biological processes with the external time of day. A range of physiological functions are governed by the circadian cycle, including memory processes, yet little is understood about how the clock interfaces with memory at a molecular level. The molecular circadian clock consists of four key genes/gene families, Period, Clock, Cryptochrome, and Bmal1, that rhythmically cycle in an ongoing transcription-translation negative feedback loop that maintains an approximately 24-hour cycle within cells of the brain and body. In addition to their roles in generating the circadian rhythm within the brain's master pacemaker (the suprachiasmatic nucleus), recent research has suggested that these clock genes may function locally within memory-relevant brain regions to modulate memory across the day/night cycle. This review will discuss how these clock genes function both within the brain's central clock and within memory-relevant brain regions to exert circadian control over memory processes. For each core clock gene, we describe the current research that demonstrates a potential role in memory and outline how these clock genes might interface with cascades known to support long-term memory formation. Together, the research suggests that clock genes function locally within satellite clocks across the brain to exert circadian control over long-term memory formation and possibly other biological processes. Understanding how clock genes might interface with local molecular cascades in the hippocampus and other brain regions is a critical step toward developing treatments for the myriad disorders marked by dysfunction of both the circadian system and cognitive processes.
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Affiliation(s)
- Chad W Smies
- Department of Biology, Pennsylvania State University, University Park, PA 16802, USA
| | - Kasuni K Bodinayake
- Department of Biology, Pennsylvania State University, University Park, PA 16802, USA
| | - Janine L Kwapis
- Department of Biology, Pennsylvania State University, University Park, PA 16802, USA.
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17
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Ardiel EL, Lauziere A, Xu S, Harvey BJ, Christensen RP, Nurrish S, Kaplan JM, Shroff H. Stereotyped behavioral maturation and rhythmic quiescence in C.elegans embryos. eLife 2022; 11:76836. [PMID: 35929725 PMCID: PMC9448323 DOI: 10.7554/elife.76836] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 08/01/2022] [Indexed: 11/18/2022] Open
Abstract
Systematic analysis of rich behavioral recordings is being used to uncover how circuits encode complex behaviors. Here, we apply this approach to embryos. What are the first embryonic behaviors and how do they evolve as early neurodevelopment ensues? To address these questions, we present a systematic description of behavioral maturation for Caenorhabditis elegans embryos. Posture libraries were built using a genetically encoded motion capture suit imaged with light-sheet microscopy and annotated using custom tracking software. Analysis of cell trajectories, postures, and behavioral motifs revealed a stereotyped developmental progression. Early movement is dominated by flipping between dorsal and ventral coiling, which gradually slows into a period of reduced motility. Late-stage embryos exhibit sinusoidal waves of dorsoventral bends, prolonged bouts of directed motion, and a rhythmic pattern of pausing, which we designate slow wave twitch (SWT). Synaptic transmission is required for late-stage motion but not for early flipping nor the intervening inactive phase. A high-throughput behavioral assay and calcium imaging revealed that SWT is elicited by the rhythmic activity of a quiescence-promoting neuron (RIS). Similar periodic quiescent states are seen prenatally in diverse animals and may play an important role in promoting normal developmental outcomes.
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Affiliation(s)
- Evan L Ardiel
- Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
| | - Andrew Lauziere
- National Institute of Biomedical Imaging and Bioengineering, Bethesda, United States
| | - Stephen Xu
- National Institute of Biomedical Imaging and Bioengineering, Bethesda, United States
| | - Brandon J Harvey
- National Institute of Biomedical Imaging and Bioengineering, Bethesda, United States
| | | | - Stephen Nurrish
- Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
| | - Joshua M Kaplan
- Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
| | - Hari Shroff
- National Institute of Biomedical Imaging and Bioengineering, Bethesda, United States
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18
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Gao L, Gao D, Zhang J, Li C, Wu M, Xiao Y, Yang L, Ma T, Wang X, Zhang M, Yang D, Pan T, Zhang H, Wang A, Jin Y, Chen H. Age-related endoplasmic reticulum stress represses testosterone synthesis via attenuation of the circadian clock in Leydig cells. Theriogenology 2022; 189:137-149. [PMID: 35753227 DOI: 10.1016/j.theriogenology.2022.06.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 06/10/2022] [Accepted: 06/10/2022] [Indexed: 11/18/2022]
Abstract
Senile animals exhibit a high risk of elevated endoplasmic reticulum (ER) stress, attenuated circadian clock, and impaired steroidogenesis in testes. However, how these three processes are intertwined in mouse Leydig cells remains unclear. In this study, a mouse model of aging and hydrogen peroxide (H2O2)-induced senescent TM3 Leydig cells were used to dissect the connections among ER stress, circadian oscillators, and steroidogenesis in Leydig cells. Additionally, thapsigargin (Tg, 60 nM)/tunicamycin (Tm, 60 ng/mL)-induced ER stress were established to investigate the underlying mechanisms by which ER stress regulated testosterone synthesis via circadian clock-related signaling pathways in TM3 cells and primary Leydig cells. Elevated ER stress, attenuated circadian clock, and diminished steroidogenesis were detected in the testes of aged mice (24-month-old) and H2O2-induced (200 μM) senescent TM3 cells in comparison with their control groups. Tg/Tm-induced ER stress reduced the transcription of the circadian clock and steroidogenic genes in TM3 cells and LH-treated (100 ng/mL) primary Leydig cells. Furthermore, 4-phenylbutyric acid (4-PBA, 1 μM), an inhibitor of ER stress, alleviated the inhibitory effect of Tg-mediated ER stress on Per2:Luc oscillations in primary Leydig cells isolated from mPer2Luc knock-in mice, and attenuated the repressive effect of H2O2-induced or Tg-mediated ER stress on the transcription of circadian clock and steroidogenic genes expression and testosterone synthesis in TM3 cells. Collectively, these data indicate that age-related ER stress represses testosterone synthesis via attenuation of the circadian clock in Leydig cells.
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Affiliation(s)
- Lei Gao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; College of Agriculture and Animal Husbandry, Qing Hai University, Xining, 810006, Qinghai, China
| | - Dengke Gao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Jing Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Cuimei Li
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Meina Wu
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Yaoyao Xiao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Luda Yang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Tiantian Ma
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Xiaoyu Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Manhui Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Dan Yang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Tao Pan
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Haisen Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Aihua Wang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Yaping Jin
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Huatao Chen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
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19
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Yao Y, Silver R. Mutual Shaping of Circadian Body-Wide Synchronization by the Suprachiasmatic Nucleus and Circulating Steroids. Front Behav Neurosci 2022; 16:877256. [PMID: 35722187 PMCID: PMC9200072 DOI: 10.3389/fnbeh.2022.877256] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/11/2022] [Indexed: 11/18/2022] Open
Abstract
Background Steroids are lipid hormones that reach bodily tissues through the systemic circulation, and play a major role in reproduction, metabolism, and homeostasis. All of these functions and steroids themselves are under the regulation of the circadian timing system (CTS) and its cellular/molecular underpinnings. In health, cells throughout the body coordinate their daily activities to optimize responses to signals from the CTS and steroids. Misalignment of responses to these signals produces dysfunction and underlies many pathologies. Questions Addressed To explore relationships between the CTS and circulating steroids, we examine the brain clock located in the suprachiasmatic nucleus (SCN), the daily fluctuations in plasma steroids, the mechanisms producing regularly recurring fluctuations, and the actions of steroids on their receptors within the SCN. The goal is to understand the relationship between temporal control of steroid secretion and how rhythmic changes in steroids impact the SCN, which in turn modulate behavior and physiology. Evidence Surveyed The CTS is a multi-level organization producing recurrent feedback loops that operate on several time scales. We review the evidence showing that the CTS modulates the timing of secretions from the level of the hypothalamus to the steroidogenic gonadal and adrenal glands, and at specific sites within steroidogenic pathways. The SCN determines the timing of steroid hormones that then act on their cognate receptors within the brain clock. In addition, some compartments of the body-wide CTS are impacted by signals derived from food, stress, exercise etc. These in turn act on steroidogenesis to either align or misalign CTS oscillators. Finally this review provides a comprehensive exploration of the broad contribution of steroid receptors in the SCN and how these receptors in turn impact peripheral responses. Conclusion The hypothesis emerging from the recognition of steroid receptors in the SCN is that mutual shaping of responses occurs between the brain clock and fluctuating plasma steroid levels.
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Affiliation(s)
- Yifan Yao
- Department of Psychology, Columbia University, New York City, NY, United States
- *Correspondence: Yifan Yao,
| | - Rae Silver
- Department of Psychology, Columbia University, New York City, NY, United States
- Department of Neuroscience, Barnard College, New York City, NY, United States
- Department of Psychology, Barnard College, New York City, NY, United States
- Department of Pathology and Cell Biology, Graduate School, Columbia University Irving Medical Center, New York City, NY, United States
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20
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Dardente H, Simonneaux V. GnRH and the photoperiodic control of seasonal reproduction: Delegating the task to kisspeptin and RFRP-3. J Neuroendocrinol 2022; 34:e13124. [PMID: 35384117 DOI: 10.1111/jne.13124] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 02/22/2022] [Accepted: 03/03/2022] [Indexed: 10/18/2022]
Abstract
Synchronization of mammalian breeding activity to the annual change of photoperiod and environmental conditions is of the utmost importance for individual survival and species perpetuation. Subsequent to the early 1960s, when the central role of melatonin in this adaptive process was demonstrated, our comprehension of the mechanisms through which light regulates gonadal activity has increased considerably. The current model for the photoperiodic neuroendocrine system points to pivotal roles for the melatonin-sensitive pars tuberalis (PT) and its seasonally-regulated production of thyroid-stimulating hormone (TSH), as well as for TSH-sensitive hypothalamic tanycytes, radial glia-like cells located in the basal part of the third ventricle. Tanycytes respond to TSH through increased expression of thyroid hormone (TH) deiodinase 2 (Dio2), which leads to heightened production of intrahypothalamic triiodothyronine (T3) during longer days of spring and summer. There is strong evidence that this local, long-day driven, increase in T3 links melatonin input at the PT to gonadotropin-releasing hormone (GnRH) output, to align breeding with the seasons. The mechanism(s) through which T3 impinges upon GnRH remain(s) unclear. However, two distinct neuronal populations of the medio-basal hypothalamus, which express the (Arg)(Phe)-amide peptides kisspeptin and RFamide-related peptide-3, appear to be well-positioned to relay this seasonal T3 message towards GnRH neurons. Here, we summarize our current understanding of the cellular, molecular and neuroendocrine players, which keep track of photoperiod and ultimately govern GnRH output and seasonal breeding.
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Affiliation(s)
- Hugues Dardente
- CNRS, IFCE, INRAE, Université de Tours, PRC, Nouzilly, France
| | - Valérie Simonneaux
- Institute for Cellular and Integrative Neuroscience, University of Strasbourg, Strasbourg, France
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21
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Numano R, Goryu A, Kubota Y, Sawahata H, Yamagiwa S, Matsuo M, Iimura T, Tei H, Ishida M, Kawano T. Nanoscale-tipped wire array injections transfer DNA directly into brain cells ex vivo and in vivo. FEBS Open Bio 2022; 12:835-851. [PMID: 35293154 PMCID: PMC8972050 DOI: 10.1002/2211-5463.13377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 12/24/2021] [Accepted: 02/04/2022] [Indexed: 11/26/2022] Open
Abstract
Genetic modification to restore cell functions in the brain can be performed through the delivery of biomolecules in a minimally invasive manner into live neuronal cells within brain tissues. However, conventional nanoscale needles are too short (lengths of ~10 µm) to target neuronal cells in ~1‐mm‐thick brain tissues because the neuronal cells are located deep within the tissue. Here, we report the use of nanoscale‐tipped wire (NTW) arrays with diameters < 100 nm and wire lengths of ~200 µm to address biomolecule delivery issues. The NTW arrays were manufactured by growth of silicon microwire arrays and nanotip formation. This technique uses pinpoint, multiple‐cell DNA injections in deep areas of brain tissues, enabling target cells to be marked by fluorescent protein (FP) expression vectors. This technique has potential for use for electrophysiological recordings and biological transfection into neuronal cells. Herein, simply pressing an NTW array delivers and expresses plasmid DNA in multiple‐cultured cells and multiple‐neuronal cells within a brain slice with reduced cell damage. Additionally, DNA transfection is demonstrated using brain cells ex vivo and in vivo. Moreover, knockdown of a critical clock gene after injecting a short hairpin RNA (shRNA) and a genome‐editing vector demonstrates the potential to genetically alter the function of living brain cells, for example, pacemaker cells of the mammalian circadian rhythms. Overall, our NTW array injection technique enables genetic and functional modification of living cells in deep brain tissue areas, both ex vivo and in vivo.
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Affiliation(s)
- Rika Numano
- Department of Applied Chemistry and Life Science, Toyohashi University of Technology, Japan.,Electronics-Inspired Interdisciplinary Research Institute (EIIRIS), Toyohashi University of Technology, Japan
| | - Akihiro Goryu
- Department of Electrical and Electronic Information Engineering, Toyohashi University of Technology, Japan
| | - Yoshihiro Kubota
- Department of Electrical and Electronic Information Engineering, Toyohashi University of Technology, Japan
| | - Hirohito Sawahata
- Department of Electrical and Electronic Information Engineering, Toyohashi University of Technology, Japan.,National Institute of Technology, Ibaraki College, Japan
| | - Shota Yamagiwa
- Department of Electrical and Electronic Information Engineering, Toyohashi University of Technology, Japan
| | - Minako Matsuo
- Department of Applied Chemistry and Life Science, Toyohashi University of Technology, Japan.,Electronics-Inspired Interdisciplinary Research Institute (EIIRIS), Toyohashi University of Technology, Japan
| | - Tadahiro Iimura
- Department of Pharmacology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Hajime Tei
- Graduate School of Natural Science and Technology, Kanazawa University, Japan
| | - Makoto Ishida
- Electronics-Inspired Interdisciplinary Research Institute (EIIRIS), Toyohashi University of Technology, Japan.,Department of Electrical and Electronic Information Engineering, Toyohashi University of Technology, Japan
| | - Takeshi Kawano
- Department of Electrical and Electronic Information Engineering, Toyohashi University of Technology, Japan
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22
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Tir S, Steel LCE, Tam SKE, Semo M, Pothecary CA, Vyazovskiy VV, Foster RG, Peirson SN. Rodent models in translational circadian photobiology. PROGRESS IN BRAIN RESEARCH 2022; 273:97-116. [PMID: 35940726 DOI: 10.1016/bs.pbr.2022.02.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Over the last decades remarkable advances have been made in the understanding of the photobiology of circadian rhythms. The identification of a third photoreceptive system in the mammalian eye, in addition to the rods and cones that mediate vision, has transformed our appreciation of the role of light in regulating physiology and behavior. These photosensitive retinal ganglion cells (pRGCs) express the blue-light sensitive photopigment melanopsin and project to the suprachiasmatic nuclei (SCN)-the master circadian pacemaker-as well as many other brain regions. Much of our understanding of the fundamental mechanisms of the pRGCs, and the processes that they regulate, comes from mouse and other rodent models. Here we describe the contribution of rodent models to circadian photobiology, including both their strengths and limitations. In addition, we discuss how an appreciation of both rodent and human data is important for translational circadian photobiology. Such an approach enables a bi-directional flow of information whereby an understanding of basic mechanisms derived from mice can be integrated with studies from humans. Progress in this field is being driven forward at several levels of analysis, not least by the use of personalized light measurements and photoreceptor specific stimuli in human studies, and by studying the impact of environmental, rather than laboratory, lighting on different rodent models.
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Affiliation(s)
- Selma Tir
- Sir Jules Thorn Sleep and Circadian Neuroscience Institute (SCNi), Kavli Institute for NanoScience Discovery, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - Laura C E Steel
- Sir Jules Thorn Sleep and Circadian Neuroscience Institute (SCNi), Kavli Institute for NanoScience Discovery, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - S K E Tam
- Sir Jules Thorn Sleep and Circadian Neuroscience Institute (SCNi), Kavli Institute for NanoScience Discovery, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - Ma'ayan Semo
- Sir Jules Thorn Sleep and Circadian Neuroscience Institute (SCNi), Kavli Institute for NanoScience Discovery, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - Carina A Pothecary
- Sir Jules Thorn Sleep and Circadian Neuroscience Institute (SCNi), Kavli Institute for NanoScience Discovery, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - Vladyslav V Vyazovskiy
- Sir Jules Thorn Sleep and Circadian Neuroscience Institute (SCNi), Kavli Institute for NanoScience Discovery, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | - Russell G Foster
- Sir Jules Thorn Sleep and Circadian Neuroscience Institute (SCNi), Kavli Institute for NanoScience Discovery, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - Stuart N Peirson
- Sir Jules Thorn Sleep and Circadian Neuroscience Institute (SCNi), Kavli Institute for NanoScience Discovery, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
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23
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Vazquez-Rivera E, Rojas B, Parrott JC, Shen AL, Xing Y, Carney PR, Bradfield CA. The aryl hydrocarbon receptor as a model PAS sensor. Toxicol Rep 2021; 9:1-11. [PMID: 34950569 PMCID: PMC8671103 DOI: 10.1016/j.toxrep.2021.11.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 11/19/2021] [Accepted: 11/24/2021] [Indexed: 01/02/2023] Open
Abstract
Proteins containing PER-ARNT-SIM (PAS) domains are commonly associated with environmental adaptation in a variety of organisms. The PAS domain is found in proteins throughout Archaea, Bacteria, and Eukarya and often binds small-molecules, supports protein-protein interactions, and transduces input signals to mediate an adaptive physiological response. Signaling events mediated by PAS sensors can occur through induced phosphorelays or genomic events that are often dependent upon PAS domain interactions. In this perspective, we briefly discuss the diversity of PAS domain containing proteins, with particular emphasis on the prototype member, the aryl hydrocarbon receptor (AHR). This ligand-activated transcription factor acts as a sensor of the chemical environment in humans and many chordates. We conclude with the idea that since mammalian PAS proteins often act through PAS-PAS dimers, undocumented interactions of this type may link biological processes that we currently think of as independent. To support this idea, we present a framework to guide future experiments aimed at fully elucidating the spectrum of PAS-PAS interactions with an eye towards understanding how they might influence environmental sensing in human and wildlife populations.
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Affiliation(s)
- Emmanuel Vazquez-Rivera
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Brenda Rojas
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Jessica C. Parrott
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Anna L. Shen
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Yongna Xing
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Patrick R. Carney
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
| | - Christopher A. Bradfield
- Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
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24
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The habenula clock influences response to a stressor. Neurobiol Stress 2021; 15:100403. [PMID: 34632007 PMCID: PMC8488752 DOI: 10.1016/j.ynstr.2021.100403] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/17/2021] [Accepted: 09/19/2021] [Indexed: 12/12/2022] Open
Abstract
The response of an animal to a sensory stimulus depends on the nature of the stimulus and on expectations, which are mediated by spontaneous activity. Here, we ask how circadian variation in the expectation of danger, and thus the response to a potential threat, is controlled. We focus on the habenula, a mediator of threat response that functions by regulating neuromodulator release, and use zebrafish as the experimental system. Single cell transcriptomics indicates that multiple clock genes are expressed throughout the habenula, while quantitative in situ hybridization confirms that the clock oscillates. Two-photon calcium imaging indicates a circadian change in spontaneous activity of habenula neurons. To assess the role of this clock, a truncated clocka gene was specifically expressed in the habenula. This partially inhibited the clock, as shown by changes in per3 expression as well as altered day-night variation in dopamine, serotonin and acetylcholine levels. Behaviourally, anxiety-like responses evoked by an alarm pheromone were reduced. Circadian effects of the pheromone were disrupted, such that responses in the day resembled those at night. Behaviours that are regulated by the pineal clock and not triggered by stressors were unaffected. We suggest that the habenula clock regulates the expectation of danger, thus providing one mechanism for circadian change in the response to a stressor.
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25
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Zhao L, Zhang J, Yang L, Zhang H, Zhang Y, Gao D, Jiang H, Li Y, Dong H, Ma T, Wang X, Wu M, Wang A, Jin Y, Yuan Y, Chen H. Glyphosate exposure attenuates testosterone synthesis via NR1D1 inhibition of StAR expression in mouse Leydig cells. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 785:147323. [PMID: 33957581 DOI: 10.1016/j.scitotenv.2021.147323] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/17/2021] [Accepted: 04/20/2021] [Indexed: 06/12/2023]
Abstract
Glyphosate is a broad-spectrum herbicide that impairs testosterone synthesis in mammals. Leydig cells (LCs), the primary producers of testosterone, demonstrate rhythmic expression of circadian clock genes both in vivo and in vitro. The nuclear receptor NR1D1 is an important clock component that constitutes the subsidiary transcriptional/translational loop in the circadian clock system. Nr1d1 deficiency resulted in diminished fertility in both male and female mice. However, whether NR1D1 is involved in the glyphosate-mediated inhibition of testosterone synthesis in LCs remains unclear. Here, the involvement of NR1D1 in glyphosate-mediated inhibition of testosterone synthesis was investigated both in vitro and in vivo. Glyphosate exposure of TM3 cells significantly increased Nr1d1 mRNA levels, but decreased Bmal1, Per2, StAR, Cyp11a1, and Cyp17a1 mRNA levels. Western blotting confirmed elevated NR1D1 and reduced StAR protein levels following glyphosate exposure. Glyphosate exposure also reduced testosterone production in TM3 cells. In primary LCs, glyphosate exposure also upregulated Nr1d1 mRNA levels and downregulated the mRNA levels of other clock genes (Bmal1 and Per2) and steroidogenic genes (StAR, Cyp17a1, Cyp11a1, and Hsd3b2), and inhibited testosterone synthesis. Moreover, glyphosate exposure significantly reduced the amplitude and shortened the period of PER2::LUCIFERASE oscillations in primary LCs isolated from mPer2Luciferase knock-in mice. Four weeks of oral glyphosate upregulated NR1D1 at both the mRNA and protein levels in mouse testes, and this was accompanied by a reduction in StAR expression. Notably, serum testosterone levels were also drastically reduced in mice treated with glyphosate. Moreover, dual-luciferase reporter and EMSA assays revealed that in TM3 cells NR1D1 inhibits the expression of StAR by binding to a canonical RORE element present within its promoter. Together, these data demonstrate that glyphosate perturbs testosterone synthesis via NR1D1 mediated inhibition of StAR expression in mouse LCs. These findings extend our understanding of how glyphosate impairs male fertility.
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Affiliation(s)
- Lijia Zhao
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Jing Zhang
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Luda Yang
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Haisen Zhang
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Yu Zhang
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Dengke Gao
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Haizhen Jiang
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Yating Li
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Hao Dong
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Tiantian Ma
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Xiaoyu Wang
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Meina Wu
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Aihua Wang
- Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Yaping Jin
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China.
| | - Yalin Yuan
- Northwest A&F University, Yangling 712100, Shaanxi, China.
| | - Huatao Chen
- Northwest A&F University, Yangling 712100, Shaanxi, China; Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China.
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26
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D Lipshitz H. The Expression of the Emotions in Man and Fruit Flies. Genetics 2021; 219:iyab110. [PMID: 34849915 PMCID: PMC8633119 DOI: 10.1093/genetics/iyab110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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27
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Guan D, Lazar MA. Interconnections between circadian clocks and metabolism. J Clin Invest 2021; 131:e148278. [PMID: 34338232 DOI: 10.1172/jci148278] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Circadian rhythms evolved through adaptation to daily light/dark changes in the environment; they are believed to be regulated by the core circadian clock interlocking feedback loop. Recent studies indicate that each core component executes general and specific functions in metabolism. Here, we review the current understanding of the role of these core circadian clock genes in the regulation of metabolism using various genetically modified animal models. Additionally, emerging evidence shows that exposure to environmental stimuli, such as artificial light, unbalanced diet, mistimed eating, and exercise, remodels the circadian physiological processes and causes metabolic disorders. This Review summarizes the reciprocal regulation between the circadian clock and metabolism, highlights remaining gaps in knowledge about the regulation of circadian rhythms and metabolism, and examines potential applications to human health and disease.
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Affiliation(s)
- Dongyin Guan
- Institute for Diabetes, Obesity, and Metabolism.,Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and
| | - Mitchell A Lazar
- Institute for Diabetes, Obesity, and Metabolism.,Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and.,Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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28
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Mei Y, Teng H, Li Z, Zeng C, Li Y, Song W, Zhang K, Sun ZS, Wang Y. Restricted Feeding Resets Endogenous Circadian Rhythm in Female Mice Under Constant Darkness. Neurosci Bull 2021; 37:1005-1009. [PMID: 33779891 PMCID: PMC8275728 DOI: 10.1007/s12264-021-00669-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 10/10/2020] [Indexed: 10/21/2022] Open
Affiliation(s)
- Yue Mei
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China
- CAS Center for Excellence in Biotic Interactions, University of the Chinese Academy of Sciences, Beijing, 100049, China
- Center for Translational Medicine, Second Military Medical University, Shanghai, 200080, China
| | - Huajing Teng
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zhigang Li
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China
| | - Cheng Zeng
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China
- CAS Center for Excellence in Biotic Interactions, University of the Chinese Academy of Sciences, Beijing, 100049, China
| | - Yuanyuan Li
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China
- CAS Center for Excellence in Biotic Interactions, University of the Chinese Academy of Sciences, Beijing, 100049, China
| | - Wei Song
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China
- CAS Center for Excellence in Biotic Interactions, University of the Chinese Academy of Sciences, Beijing, 100049, China
| | - Kaifan Zhang
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhong Sheng Sun
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China.
- CAS Center for Excellence in Biotic Interactions, University of the Chinese Academy of Sciences, Beijing, 100049, China.
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, 325000, China.
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Yan Wang
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China.
- CAS Center for Excellence in Biotic Interactions, University of the Chinese Academy of Sciences, Beijing, 100049, China.
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29
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Rosbash M. Circadian Rhythms and the Transcriptional Feedback Loop (Nobel Lecture)**. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202015199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Michael Rosbash
- Department of Biology Howard Hughes Medical Institute Brandeis University Waltham MA USA
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30
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Yi JS, Díaz NM, D'Souza S, Buhr ED. The molecular clockwork of mammalian cells. Semin Cell Dev Biol 2021; 126:87-96. [PMID: 33810978 DOI: 10.1016/j.semcdb.2021.03.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/15/2021] [Accepted: 03/17/2021] [Indexed: 12/20/2022]
Abstract
Most organisms contain self-sustained circadian clocks. These clocks can be synchronized by environmental stimuli, but can also oscillate indefinitely in isolation. In mammals this is true at the molecular level for the majority of cell types that have been examined. A core set of "clock genes" form a transcriptional/translational feedback loop (TTFL) which repeats with a period of approximately 24 h. The exact mechanism of the TTFL differs slightly in various cell types, but all involve similar family members of the core cohort of clock genes. The clock has many outputs which are unique for different tissues. Cells in diverse tissues will convert the timing signals provided by the TTFL into uniquely orchestrated transcriptional oscillations of many clock-controlled genes and cellular processes.
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Affiliation(s)
- Jonathan S Yi
- University of Washington, Dept. of Ophthalmology, 750 Republican St., Seattle, WA 98109, USA
| | - Nicolás M Díaz
- University of Washington, Dept. of Ophthalmology, 750 Republican St., Seattle, WA 98109, USA
| | - Shane D'Souza
- Center for Chronobiology, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA
| | - Ethan D Buhr
- University of Washington, Dept. of Ophthalmology, 750 Republican St., Seattle, WA 98109, USA.
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31
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Stehle JH, Zemmar A, Hausmann L. How to time the time - A preface to the special issue Circadian Rhythms in the Brain. J Neurochem 2021; 157:6-10. [PMID: 33724468 DOI: 10.1111/jnc.15311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 01/21/2021] [Indexed: 01/01/2023]
Abstract
In this Preface to the Journal of Neurochemistry special issue "Circadian Rhythms in the Brain", we summarize recent insights into connections between circadian rhythms and societal concerns related to aging and food intake, with consequences for healthy or aberrant metabolic homeostasis. The articles in this special issue were written by leading authors who presented their research at the 2019 Congress of the European Biological Rhythm Society, and are thus reflective of a broad variety of state-of-the-art research on all levels of chronobiology, from circadian rhythm generators in various tissues (including astrocytes) and the molecular mechanisms they base on, such as GABAergic regulation or ubiquitination, to the systems and behavioral level effects of chrono-nutrition and aging. Cover Image for this issue: https://doi.org/10.1111/jnc.15058.
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Affiliation(s)
- Jörg H Stehle
- Department of Neurosurgery, People's Hospital of Zhengzhou University, Henan Provincial People´s Hospital, Henan University People's Hospital, Henan University School of Medicine, Henan, China.,Institute of Cellular and Molecular Anatomy, Goethe-University, Frankfurt, Germany
| | - Ajmal Zemmar
- Department of Neurosurgery, People's Hospital of Zhengzhou University, Henan Provincial People´s Hospital, Henan University People's Hospital, Henan University School of Medicine, Henan, China.,Brain Research Institute, University of Zurich, Zurich, Switzerland.,Department of Biology and Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.,Department of Neurosurgery, University of Louisville, School of Medicine, Louisville, KY, USA
| | - Laura Hausmann
- Department of Neurology, University Hospital RWTH Aachen, Aachen, Germany
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32
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Rosbash M. Circadian Rhythms and the Transcriptional Feedback Loop (Nobel Lecture)**. Angew Chem Int Ed Engl 2021; 60:8650-8666. [DOI: 10.1002/anie.202015199] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Indexed: 11/10/2022]
Affiliation(s)
- Michael Rosbash
- Department of Biology Howard Hughes Medical Institute Brandeis University Waltham MA USA
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33
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Maejima T, Tsuno Y, Miyazaki S, Tsuneoka Y, Hasegawa E, Islam MT, Enoki R, Nakamura TJ, Mieda M. GABA from vasopressin neurons regulates the time at which suprachiasmatic nucleus molecular clocks enable circadian behavior. Proc Natl Acad Sci U S A 2021; 118:e2010168118. [PMID: 33526663 PMCID: PMC8017960 DOI: 10.1073/pnas.2010168118] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals, is a network structure composed of multiple types of γ-aminobutyric acid (GABA)-ergic neurons and glial cells. However, the roles of GABA-mediated signaling in the SCN network remain controversial. Here, we report noticeable impairment of the circadian rhythm in mice with a specific deletion of the vesicular GABA transporter in arginine vasopressin (AVP)-producing neurons. These mice showed disturbed diurnal rhythms of GABAA receptor-mediated synaptic transmission in SCN neurons and marked lengthening of the activity time in circadian behavioral rhythms due to the extended interval between morning and evening locomotor activities. Synchrony of molecular circadian oscillations among SCN neurons did not significantly change, whereas the phase relationships between SCN molecular clocks and circadian morning/evening locomotor activities were altered significantly, as revealed by PER2::LUC imaging of SCN explants and in vivo recording of intracellular Ca2+ in SCN AVP neurons. In contrast, daily neuronal activity in SCN neurons in vivo clearly showed a bimodal pattern that correlated with dissociated morning/evening locomotor activities. Therefore, GABAergic transmission from AVP neurons regulates the timing of SCN neuronal firing to temporally restrict circadian behavior to appropriate time windows in SCN molecular clocks.
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Affiliation(s)
- Takashi Maejima
- Department of Integrative Neurophysiology, Graduate School of Medical Sciences, Kanazawa University, 920-8640 Ishikawa, Japan
| | - Yusuke Tsuno
- Department of Integrative Neurophysiology, Graduate School of Medical Sciences, Kanazawa University, 920-8640 Ishikawa, Japan
| | - Shota Miyazaki
- Laboratory of Animal Physiology, School of Agriculture, Meiji University, 214-8571 Kanagawa, Japan
| | - Yousuke Tsuneoka
- Department of Anatomy, Faculty of Medicine, Toho University, 143-8540 Tokyo, Japan
| | - Emi Hasegawa
- Department of Integrative Neurophysiology, Graduate School of Medical Sciences, Kanazawa University, 920-8640 Ishikawa, Japan
| | - Md Tarikul Islam
- Department of Integrative Neurophysiology, Graduate School of Medical Sciences, Kanazawa University, 920-8640 Ishikawa, Japan
| | - Ryosuke Enoki
- Biophotonics Research Group, Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences, 444-8787 Okazaki, Japan
- Division of Biophotonics, National Institute for Physiological Sciences, National Institutes of Natural Sciences, 444-8787 Okazaki, Japan
| | - Takahiro J Nakamura
- Laboratory of Animal Physiology, School of Agriculture, Meiji University, 214-8571 Kanagawa, Japan
| | - Michihiro Mieda
- Department of Integrative Neurophysiology, Graduate School of Medical Sciences, Kanazawa University, 920-8640 Ishikawa, Japan;
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Jha PK, Bouâouda H, Kalsbeek A, Challet E. Distinct feedback actions of behavioural arousal to the master circadian clock in nocturnal and diurnal mammals. Neurosci Biobehav Rev 2021; 123:48-60. [PMID: 33440199 DOI: 10.1016/j.neubiorev.2020.12.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 09/16/2020] [Accepted: 12/10/2020] [Indexed: 12/20/2022]
Abstract
The master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus provides a temporal pattern of sleep and wake that - like many other behavioural and physiological rhythms - is oppositely phased in nocturnal and diurnal animals. The SCN primarily uses environmental light, perceived through the retina, to synchronize its endogenous circadian rhythms with the exact 24 h light/dark cycle of the outside world. The light responsiveness of the SCN is maximal during the night in both nocturnal and diurnal species. Behavioural arousal during the resting period not only perturbs sleep homeostasis, but also acts as a potent non-photic synchronizing cue. The feedback action of arousal on the SCN is mediated by processes involving several brain nuclei and neurotransmitters, which ultimately change the molecular functions of SCN pacemaker cells. Arousing stimuli during the sleeping period differentially affect the circadian system of nocturnal and diurnal species, as evidenced by the different circadian windows of sensitivity to behavioural arousal. In addition, arousing stimuli reduce and increase light resetting in nocturnal and diurnal species, respectively. It is important to address further question of circadian impairments associated with shift work and trans-meridian travel not only in the standard nocturnal laboratory animals but also in diurnal animal models.
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Affiliation(s)
- Pawan Kumar Jha
- Circadian Clocks and Metabolism Team, Institute of Cellular and Integrative Neurosciences, Centre National de la Recherche Scientifique (CNRS), University of Strasbourg, France; Department of Endocrinology and Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, the Netherlands; Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
| | - Hanan Bouâouda
- Circadian Clocks and Metabolism Team, Institute of Cellular and Integrative Neurosciences, Centre National de la Recherche Scientifique (CNRS), University of Strasbourg, France
| | - Andries Kalsbeek
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center (AUMC), University of Amsterdam, the Netherlands; Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands
| | - Etienne Challet
- Circadian Clocks and Metabolism Team, Institute of Cellular and Integrative Neurosciences, Centre National de la Recherche Scientifique (CNRS), University of Strasbourg, France
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Dannerfjord AA, Brown LA, Foster RG, Peirson SN. Light Input to the Mammalian Circadian Clock. Methods Mol Biol 2021; 2130:233-247. [PMID: 33284449 DOI: 10.1007/978-1-0716-0381-9_18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Circadian rhythms are 24-h cycles in physiology and behavior that occur in virtually all organisms. These processes are not simply driven by changes in the external environment as they persist under constant conditions, providing evidence for an internal biological clock. In mammals, this clock is located in the hypothalamic suprachiasmatic nuclei (SCN) and is based upon an intracellular mechanism composed of a transcriptional-translational feedback loop composed of a number of core clock genes. However, a clock is of no use unless it can be set to the correct time. The primary time cue for the molecular clock in the SCN is light detected by the eye. The photoreceptors involved in this process include the rods and cones that mediate vision, as well as the recently identified melanopsin-expressing photosensitive retinal ganglion cells (pRGCs). Light information is conveyed to the SCN via the retinohypothalamic tract, resulting in an intracellular signaling cascade which converges on cAMP-response elements in the promoters of several key clock genes. Over the last two decades a number of studies have investigated the transcriptional response of the SCN to light stimuli with the aim of further understanding these molecular signaling pathways. Here we provide an overview of these studies and provide protocols for studying the molecular responses to light in the SCN clock.
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Affiliation(s)
- Adam A Dannerfjord
- Sleep and Circadian Neuroscience Institute (SCNi), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.,Nuffield Department of Clinical Neurosciences, Sleep and Circadian Neuroscience Institute (SCNi), Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, Oxford, UK
| | - Laurence A Brown
- Sleep and Circadian Neuroscience Institute (SCNi), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Russell G Foster
- Sleep and Circadian Neuroscience Institute (SCNi), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.,Nuffield Department of Clinical Neurosciences, Sleep and Circadian Neuroscience Institute (SCNi), Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, Oxford, UK
| | - Stuart N Peirson
- Sleep and Circadian Neuroscience Institute (SCNi), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. .,Nuffield Department of Clinical Neurosciences, Sleep and Circadian Neuroscience Institute (SCNi), Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, Oxford, UK.
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Li C, Zhang L, Ma T, Gao L, Yang L, Wu M, Pang Z, Wang X, Yao Q, Xiao Y, Zhao L, Liu W, Zhao H, Wang C, Wang A, Jin Y, Chen H. Bisphenol A attenuates testosterone production in Leydig cells via the inhibition of NR1D1 signaling. CHEMOSPHERE 2021; 263:128020. [PMID: 33297044 DOI: 10.1016/j.chemosphere.2020.128020] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/09/2020] [Accepted: 08/13/2020] [Indexed: 06/12/2023]
Abstract
Bisphenol A (BPA) is an endocrine-disrupting compound that impairs testosterone synthesis in male mammals. A circadian clock gene deficiency leads to diminished fertility and even infertility in male mice. However, whether circadian clock signaling pathways mediate the suppressive effect of BPA on testosterone synthesis in Leydig cells (LCs) remains unknown. The present study aims to detect the effect of BPA on cellular circadian clock and testosterone synthesis in mouse LCs, and examine the mechanisms underlying NR1D1 signaling. BPA treatment significantly attenuated the transcription levels of Nr1d1 and steroidogenic genes (Hsd3b2 and Hsd17b3) in TM3 cells, but increased other circadian clock gene levels (Per2 and Dbp). BPA treatment also significantly downregulated NR1D1 and StAR protein expression, but upregulated BMAL1 protein expression in TM3 cells. Furthermore, there was a marked decline in testosterone production in BPA-treated TM3 cells. Intraperitoneal injection of BPA profoundly reduced NR1D1 and StAR protein levels and steroidogenic gene transcription levels (Cyp11a1, Hsd3b2, and Hsd17b3), while enhancing BMAL1 protein and other circadian clock gene (Per2 and Dbp) levels in mouse testes. Notably, serum testosterone levels were also drastically reduced in BPA-treated mice. Moreover, SR9009, an NR1D1 agonist, augmented testosterone production in TM3 cells via elevated expression of steroidogenic genes (StAR, Cyp11a1 and Hsd17b3). Conversely, Nr1d1 knockdown inhibited testosterone accumulation and attenuated steroidogenic gene expression. Moreover, treatment with SR9009 partially reversed the BPA effect on the circadian clock and testosterone production. Taken together, our study demonstrates that BPA perturbs testosterone production, at least partially, via inhibiting NR1D1 signaling in LCs.
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Affiliation(s)
- Cuimei Li
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Linlin Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Tiantian Ma
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Lei Gao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Luda Yang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Meina Wu
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Zhaoxia Pang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Xiaoyu Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Qiyang Yao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Yaoyao Xiao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Lijia Zhao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Wei Liu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Hongcong Zhao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Caixia Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Aihua Wang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China; Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Yaping Jin
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Huatao Chen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
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Cox KH, Takahashi JS. Introduction to the Clock System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1344:3-20. [PMID: 34773223 DOI: 10.1007/978-3-030-81147-1_1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Circadian (24-h) rhythms dictate almost everything we do, setting our clocks for specific times of sleeping and eating, as well as optimal times for many other basic functions. The physiological systems that coordinate circadian rhythms are intricate, but at their core, they all can be distilled down to cell-autonomous rhythms that are then synchronized within and among tissues. At first glance, these cell-autonomous rhythms may seem rather straight-forward, but years of research in the field has shown that they are strikingly complex, responding to many different external signals, often with remarkable tissue-specificity. To understand the cellular clock system, it is important to be familiar with the major players, which consist of pairs of proteins in a triad of transcriptional/translational feedback loops. In this chapter, we will go through each of the core protein pairs one-by-one, summarizing the literature as to their regulation and their broader impacts on circadian gene expression. We will conclude by briefly examining the human genetics literature, as well as providing perspectives on the future of the study of the molecular clock.
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Affiliation(s)
- Kimberly H Cox
- Department of Neuroscience and Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Joseph S Takahashi
- Department of Neuroscience and Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. .,Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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The circadian machinery links metabolic disorders and depression: A review of pathways, proteins and potential pharmacological interventions. Life Sci 2020; 265:118809. [PMID: 33249097 DOI: 10.1016/j.lfs.2020.118809] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/11/2020] [Accepted: 11/18/2020] [Indexed: 12/16/2022]
Abstract
Circadian rhythms are responsible for regulating a number of physiological processes. The central oscillator is located within the suprachiasmatic nucleus (SCN) of the hypothalamus and the SCN synchronises the circadian clocks that are found in our peripheral organs through neural and humoral signalling. At the molecular level, biological clocks consist of transcription-translation feedback loops (TTFLs) and these pathways are influenced by transcription factors, post-translational modifications, signalling pathways and epigenetic modifiers. When disruptions occur in the circadian machinery, the activities of the proteins implicated in this network and the expression of core clock or clock-controlled genes (CCGs) can be altered. Circadian misalignment can also arise when there is desychronisation between our internal clocks and environmental stimuli. There is evidence in the literature demonstrating that disturbances in the circadian rhythm contribute to the pathophysiology of several diseases and disorders. This includes the metabolic syndrome and recently, it has been suggested that the 'circadian syndrome' may be a more appropriate term to use to not only describe the cardio-metabolic risk factors but also the associated comorbidities. Here we overview the molecular architecture of circadian clocks in mammals and provide insight into the effects of shift work, exposure to artificial light, food intake and stress on the circadian rhythm. The relationship between circadian rhythms, metabolic disorders and depression is reviewed and this is a topic that requires further investigation. We also describe how particular proteins involved in the TTFLs can be potentially modulated by small molecules, including pharmacological interventions and dietary compounds.
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39
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Kim YH, Lazar MA. Transcriptional Control of Circadian Rhythms and Metabolism: A Matter of Time and Space. Endocr Rev 2020; 41:5835826. [PMID: 32392281 PMCID: PMC7334005 DOI: 10.1210/endrev/bnaa014] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/04/2020] [Indexed: 02/07/2023]
Abstract
All biological processes, living organisms, and ecosystems have evolved with the Sun that confers a 24-hour periodicity to life on Earth. Circadian rhythms arose from evolutionary needs to maximize daily organismal fitness by enabling organisms to mount anticipatory and adaptive responses to recurrent light-dark cycles and associated environmental changes. The clock is a conserved feature in nearly all forms of life, ranging from prokaryotes to virtually every cell of multicellular eukaryotes. The mammalian clock comprises transcription factors interlocked in negative feedback loops, which generate circadian expression of genes that coordinate rhythmic physiology. In this review, we highlight previous and recent studies that have advanced our understanding of the transcriptional architecture of the mammalian clock, with a specific focus on epigenetic mechanisms, transcriptomics, and 3-dimensional chromatin architecture. In addition, we discuss reciprocal ways in which the clock and metabolism regulate each other to generate metabolic rhythms. We also highlight implications of circadian biology in human health, ranging from genetic and environment disruptions of the clock to novel therapeutic opportunities for circadian medicine. Finally, we explore remaining fundamental questions and future challenges to advancing the field forward.
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Affiliation(s)
- Yong Hoon Kim
- Institute for Diabetes, Obesity, and Metabolism, and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Mitchell A Lazar
- Institute for Diabetes, Obesity, and Metabolism, and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
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40
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Duffield GE, Han S, Hou TY, de la Iglesia HO, McDonald KA, Mecklenburg KL, Robles-Murguia M. Inhibitor of DNA binding 2 (Id2) Regulates Photic Entrainment Responses in Mice: Differential Responses of the Id2-/- Mouse Circadian System Are Dependent on Circadian Phase and on Duration and Intensity of Light. J Biol Rhythms 2020; 35:555-575. [PMID: 32981454 DOI: 10.1177/0748730420957504] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
ID2 is a rhythmically expressed helix-loop-helix transcriptional repressor, and its deletion results in abnormal properties of photoentrainment. By examining parametric and nonparametric models of entrainment, we have started to explore the mechanism underlying this circadian phenotype. Id2-/- mice were exposed to differing photoperiods, and the phase angle of entrainment under short days was delayed 2 h as compared with controls. When exposed to long durations of continuous light, enhanced entrainment responses were observed after a delay of the clock but not with phase advances. However, the magnitude of phase shifts was not different in Id2-/- mice tested in constant darkness using a discrete pulse of saturating light. No differences were observed in the speed of clock resetting when challenged by a series of discrete pulses interspaced by varying time intervals. A photic phase-response curve was constructed, although no genotypic differences were observed. Although phase shifts produced by discrete saturating light pulses at CT16 were similar, treatment with a subsaturating pulse revealed a ~2-fold increase in the magnitude of the Id2-/- shift. A corresponding elevation of light-induced per1 expression was observed in the Id2-/- suprachiasmatic nucleus (SCN). To test whether the phenotype is based on a sensitivity change at the level of the retina, pupil constriction responses were measured. No differences were observed in responses or in retinal histology, suggesting that the phenotype occurs downstream of the retina and retinal hypothalamic tract. To test whether the phenotype is due to a reduced amplitude of state variables of the clock, the expression of clock genes per1 and per2 was assessed in vivo and in SCN tissue explants. Amplitude, phase, and period length were normal in Id2-/- mice. These findings suggest that ID2 contributes to a photoregulatory mechanism at the level of the SCN central pacemaker through control of the photic induction of negative elements of the clock.
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Affiliation(s)
- Giles E Duffield
- Department of Biological Sciences, Galvin Life Science Center, University of Notre Dame, Notre Dame, Indiana.,Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana
| | - Sung Han
- Department of Biology and Graduate Program in Neuroscience, University of Washington, Seattle, Washington
| | - Tim Y Hou
- Department of Biological Sciences, Galvin Life Science Center, University of Notre Dame, Notre Dame, Indiana
| | - Horacio O de la Iglesia
- Department of Biology and Graduate Program in Neuroscience, University of Washington, Seattle, Washington
| | - Kathleen A McDonald
- Department of Biological Sciences, Galvin Life Science Center, University of Notre Dame, Notre Dame, Indiana
| | - Kirk L Mecklenburg
- Department of Biology, Indiana University South Bend, South Bend, Indiana
| | - Maricela Robles-Murguia
- Department of Biological Sciences, Galvin Life Science Center, University of Notre Dame, Notre Dame, Indiana.,Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana
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Wu G, Ruben MD, Lee Y, Li J, Hughes ME, Hogenesch JB. Genome-wide studies of time of day in the brain: Design and analysis. BRAIN SCIENCE ADVANCES 2020. [DOI: 10.26599/bsa.2020.9050005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Transcriptome profiling at different times of day is powerful for studying circadian regulation in model organisms and humans. To date, 24 h profiles from many tissue types suggest that about half of all genes are circadian-expressed somewhere in the body. However, few of these studies focused on the brain. Thus, despite known links between circadian disruption and neurological disease, we have virtually no mechanistic understanding. In the coming decade, we expect more genome-wide studies of time of day in different brain diseases, regions, and cell types. We expect just as many different approaches to the design and analysis of these studies. This review considers key principles of circadian tran scriptomics, with the goal of maximizing utility and reproducibility of future studies in the nervous system.
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Affiliation(s)
- Gang Wu
- Divisions of Human Genetics and Immunobiology, Center for Chronobiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229, U.S.A
| | - Marc D. Ruben
- Divisions of Human Genetics and Immunobiology, Center for Chronobiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229, U.S.A
| | - Yinyeng Lee
- Divisions of Human Genetics and Immunobiology, Center for Chronobiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229, U.S.A
| | - Jiajia Li
- Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO 63310, U.S.A
| | - Michael E. Hughes
- Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO 63310, U.S.A
| | - John B. Hogenesch
- Divisions of Human Genetics and Immunobiology, Center for Chronobiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229, U.S.A
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Hastings MH, Smyllie NJ, Patton AP. Molecular-genetic Manipulation of the Suprachiasmatic Nucleus Circadian Clock. J Mol Biol 2020; 432:3639-3660. [PMID: 31996314 DOI: 10.1016/j.jmb.2020.01.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/10/2020] [Accepted: 01/15/2020] [Indexed: 01/08/2023]
Abstract
Circadian (approximately daily) rhythms of physiology and behaviour adapt organisms to the alternating environments of day and night. The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian timekeeper of mammals. The mammalian cell-autonomous circadian clock is built around a self-sustaining transcriptional-translational negative feedback loop (TTFL) in which the negative regulators Per and Cry suppress their own expression, which is driven by the positive regulators Clock and Bmal1. Importantly, such TTFL-based clocks are present in all major tissues across the organism, and the SCN is their central co-ordinator. First, we analyse SCN timekeeping at the cell-autonomous and the circuit-based levels of organisation. We consider how molecular-genetic manipulations have been used to probe cell-autonomous timing in the SCN, identifying the integral components of the clock. Second, we consider new approaches that enable real-time monitoring of the activity of these clock components and clock-driven cellular outputs. Finally, we review how intersectional genetic manipulations of the cell-autonomous clockwork can be used to determine how SCN cells interact to generate an ensemble circadian signal. Critically, it is these network-level interactions that confer on the SCN its emergent properties of robustness, light-entrained phase and precision- properties that are essential for its role as the central co-ordinator. Remaining gaps in knowledge include an understanding of how the TTFL proteins behave individually and in complexes: whether particular SCN neuronal populations act as pacemakers, and if so, by which signalling mechanisms, and finally the nature of the recently discovered role of astrocytes within the SCN network.
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Affiliation(s)
- Michael H Hastings
- Division of Neurobiology, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK.
| | - Nicola J Smyllie
- Division of Neurobiology, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK
| | - Andrew P Patton
- Division of Neurobiology, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK
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FUNATO H. Forward genetic approach for behavioral neuroscience using animal models. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2020; 96:10-31. [PMID: 31932526 PMCID: PMC6974404 DOI: 10.2183/pjab.96.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/18/2019] [Indexed: 06/10/2023]
Abstract
Forward genetics is a powerful approach to understand the molecular basis of animal behaviors. Fruit flies were the first animal to which this genetic approach was applied systematically and have provided major discoveries on behaviors including sexual, learning, circadian, and sleep-like behaviors. The development of different classes of model organism such as nematodes, zebrafish, and mice has enabled genetic research to be conducted using more-suitable organisms. The unprecedented success of forward genetic approaches was the identification of the transcription-translation negative feedback loop composed of clock genes as a fundamental and conserved mechanism of circadian rhythm. This approach has now expanded to sleep/wakefulness in mice. A conventional strategy such as dominant and recessive screenings can be modified with advances in DNA sequencing and genome editing technologies.
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Affiliation(s)
- Hiromasa FUNATO
- Department of Anatomy, Faculty of Medicine, Toho University, Tokyo, Japan
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki, Japan
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44
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Gamble KL, Silver R. Circadian rhythmicity and the community of clockworkers. Eur J Neurosci 2019; 51:2314-2328. [PMID: 31814204 DOI: 10.1111/ejn.14626] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/17/2019] [Accepted: 11/26/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Karen L Gamble
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rae Silver
- Department of Neuroscience, Barnard College, New York, NY, USA.,Department of Psychology, Columbia University, New York, NY, USA.,Department of Pathology and Cell Biology, Columbia University Health Sciences, New York, NY, USA
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45
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Li X, Shi L, Zhang K, Wei W, Liu Q, Mao F, Li J, Cai W, Chen H, Teng H, Li J, Sun Z. CirGRDB: a database for the genome-wide deciphering circadian genes and regulators. Nucleic Acids Res 2019; 46:D64-D70. [PMID: 29059379 PMCID: PMC5753205 DOI: 10.1093/nar/gkx944] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 10/03/2017] [Indexed: 01/16/2023] Open
Abstract
Circadian rhythms govern various kinds of physiological and behavioral functions of the living organisms, and disruptions of the rhythms are highly detrimental to health. Although several databases have been built for circadian genes, a resource for comprehensive post-transcriptional regulatory information of circadian RNAs and expression patterns of disease-related circadian RNAs is still lacking. Here, we developed CirGRDB (http://cirgrdb.biols.ac.cn) by integrating more than 4936 genome-wide assays, with the aim of fulfilling the growing need to understand the rhythms of life. CirGRDB presents a friendly web interface that allows users to search and browse temporal expression patterns of interested genes in 37 human/mouse tissues or cell lines, and three clinical disorders including sleep disorder, aging and tumor. More importantly, eight kinds of potential transcriptional and post-transcriptional regulators involved in the rhythmic expression of the specific genes, including transcription factors, histone modifications, chromatin accessibility, enhancer RNAs, miRNAs, RNA-binding proteins, RNA editing and RNA methylation, can also be retrieved. Furthermore, a regulatory network could be generated based on the regulatory information. In summary, CirGRDB offers a useful repository for exploring disease-related circadian RNAs, and deciphering the transcriptional and post-transcriptional regulation of circadian rhythms.
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Affiliation(s)
- Xianfeng Li
- State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
| | - Leisheng Shi
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.,Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Kun Zhang
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.,Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wenqing Wei
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - Qi Liu
- State Key Laboratory of Tree Genetics and Breeding, Research Institute of Forestry, Chinese Academy of Forestry, Beijing 100091, China
| | - Fengbiao Mao
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jinchen Li
- State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
| | - Wanshi Cai
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - Huiqian Chen
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Huajing Teng
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiada Li
- State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
| | - Zhongsheng Sun
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
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Abstract
In mammals, genetic influences of circadian rhythms occur at many levels. A set of core "clock genes" have been identified that form a feedback loop of gene transcription and translation. The core genetic clockwork generates circadian rhythms in cells throughout the body. Polymorphisms in both core clock genes and interacting genes contribute to individual differences in the expression and properties of circadian rhythms. The circadian clock profoundly influences the patterns of gene expression and cellular functions, providing a mechanistic basis for the impact of the genetic circadian system on normal physiological processes as well as the development of diseases.
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Affiliation(s)
- Martha Hotz Vitaterna
- Center for Sleep and Circadian Biology; Department of Neurobiology, Weinberg College of Arts and Sciences, Northwestern University, 2205 Tech Drive, Evanston, IL 60208, USA.
| | - Kazuhiro Shimomura
- Center for Sleep and Circadian Biology; Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, 420 East Superior Street, Chicago, IL 60611, USA
| | - Peng Jiang
- Center for Sleep and Circadian Biology; Department of Neurobiology, Weinberg College of Arts and Sciences, Northwestern University, 2205 Tech Drive, Evanston, IL 60208, USA
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47
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Wang C, Nanni L, Novakovic B, Megchelenbrink W, Kuznetsova T, Stunnenberg HG, Ceri S, Logie C. Extensive epigenomic integration of the glucocorticoid response in primary human monocytes and in vitro derived macrophages. Sci Rep 2019; 9:2772. [PMID: 30809020 PMCID: PMC6391480 DOI: 10.1038/s41598-019-39395-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/22/2019] [Indexed: 12/12/2022] Open
Abstract
Glucocorticoid receptor is a transcription factor that is ubiquitously expressed. Glucocorticoids are circadian steroids that regulate a wide range of bodily functions, including immunity. Here we report that synthetic glucocorticoids affect 1035 mRNAs in isolated healthy human blood monocytes but only 165 in the respective six day-old monocyte-derived macrophages. The majority of the glucocorticoid response in monocytes concerns genes that are dynamic upon monocyte to macrophage differentiation, whereby macrophage-like mRNA levels are often reached in monocytes within four hours of treatment. Concomitantly, over 5000 chromosomal H3K27ac regions undergo remodelling, of which 60% involve increased H3K27ac signal. We find that chromosomal glucocorticoid receptor binding sites correlate with positive but not with negative local epigenomic effects. To investigate further we assigned our data to topologically associating domains (TADs). This shows that about 10% of macrophage TADs harbour at least one GR binding site and that half of all the glucocorticoid-induced H3K27ac regions are confined to these TADs. Our analyses are therefore consistent with the notion that TADs naturally accommodate information from sets of distal glucocorticoid response elements.
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Affiliation(s)
- Cheng Wang
- Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Faculty of Science Radboud University, PO box 9101, 6500 HG, Nijmegen, The Netherlands
| | - Luca Nanni
- Department of Electronics, Information and Bioengineering (DEIB), Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133, Milano, Italy
| | - Boris Novakovic
- Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Faculty of Science Radboud University, PO box 9101, 6500 HG, Nijmegen, The Netherlands
- Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia
| | - Wout Megchelenbrink
- Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Faculty of Science Radboud University, PO box 9101, 6500 HG, Nijmegen, The Netherlands
| | - Tatyana Kuznetsova
- Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Faculty of Science Radboud University, PO box 9101, 6500 HG, Nijmegen, The Netherlands
- Department of Medical Biochemistry, Academic Medical Centre of the University of Amsterdam, Amsterdam, The Netherlands
| | - Hendrik G Stunnenberg
- Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Faculty of Science Radboud University, PO box 9101, 6500 HG, Nijmegen, The Netherlands
| | - Stefano Ceri
- Department of Electronics, Information and Bioengineering (DEIB), Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133, Milano, Italy
| | - Colin Logie
- Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Faculty of Science Radboud University, PO box 9101, 6500 HG, Nijmegen, The Netherlands.
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Kim P, Oster H, Lehnert H, Schmid SM, Salamat N, Barclay JL, Maronde E, Inder W, Rawashdeh O. Coupling the Circadian Clock to Homeostasis: The Role of Period in Timing Physiology. Endocr Rev 2019; 40:66-95. [PMID: 30169559 DOI: 10.1210/er.2018-00049] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 07/06/2018] [Indexed: 01/01/2023]
Abstract
A plethora of physiological processes show stable and synchronized daily oscillations that are either driven or modulated by biological clocks. A circadian pacemaker located in the suprachiasmatic nucleus of the ventral hypothalamus coordinates 24-hour oscillations of central and peripheral physiology with the environment. The circadian clockwork involved in driving rhythmic physiology is composed of various clock genes that are interlocked via a complex feedback loop to generate precise yet plastic oscillations of ∼24 hours. This review focuses on the specific role of the core clockwork gene Period1 and its paralogs on intra-oscillator and extra-oscillator functions, including, but not limited to, hippocampus-dependent processes, cardiovascular function, appetite control, as well as glucose and lipid homeostasis. Alterations in Period gene function have been implicated in a wide range of physical and mental disorders. At the same time, a variety of conditions including metabolic disorders also impact clock gene expression, resulting in circadian disruptions, which in turn often exacerbates the disease state.
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Affiliation(s)
- Pureum Kim
- School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia
| | - Henrik Oster
- Institute of Neurobiology, University of Lübeck, Lübeck, Germany
| | - Hendrik Lehnert
- Department of Internal Medicine 1, University of Lübeck, Lübeck, Germany
- German Center for Diabetes Research, Neuherberg, Germany
| | - Sebastian M Schmid
- Department of Internal Medicine 1, University of Lübeck, Lübeck, Germany
- German Center for Diabetes Research, Neuherberg, Germany
| | - Nicole Salamat
- School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia
| | - Johanna L Barclay
- Mater Research Institute, University of Queensland, Brisbane, Queensland, Australia
| | - Erik Maronde
- Department of Anatomy, Goethe University Frankfurt, Frankfurt, Germany
| | - Warrick Inder
- Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
- Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Oliver Rawashdeh
- School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia
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49
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Rosensweig C, Green CB. Periodicity, repression, and the molecular architecture of the mammalian circadian clock. Eur J Neurosci 2018; 51:139-165. [PMID: 30402960 DOI: 10.1111/ejn.14254] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 10/03/2018] [Accepted: 10/22/2018] [Indexed: 12/12/2022]
Abstract
Large molecular machines regulate daily cycles of transcriptional activity and help generate rhythmic behavior. In recent years, structural and biochemical analyses have elucidated a number of principles guiding the interactions of proteins that form the basis of circadian timing. In its simplest form, the circadian clock is composed of a transcription/translation feedback loop. However, this description elides a complicated process of activator recruitment, chromatin decompaction, recruitment of coactivators, expression of repressors, formation of a repressive complex, repression of the activators, and ultimately degradation of the repressors and reinitiation of the cycle. Understanding the core principles underlying the clock requires careful examination of molecular and even atomic level details of these processes. Here, we review major structural and biochemical findings in circadian biology and make the argument that shared protein interfaces within the clockwork are critical for both the generation of rhythmicity and timing of the clock.
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Affiliation(s)
- Clark Rosensweig
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Carla B Green
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas
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50
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Wang G, Peskin CS. Entrainment of a cellular circadian oscillator by light in the presence of molecular noise. Phys Rev E 2018; 97:062416. [PMID: 30011522 DOI: 10.1103/physreve.97.062416] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Indexed: 11/07/2022]
Abstract
In this paper, we consider a stochastic molecular circadian oscillator described by a sequence of biological reactions and its deterministic kinetics governed by a system of ordinary differential equations in the limit of large numbers of molecules. The oscillations in the model are generated by negative feedback regulation of a gene. The focus of this paper is the entrainment of the oscillator by a periodic light signal that affects the maximal transcription rate of the gene. We introduce two scalings of the model parameters that provide independent control over the natural frequency of the oscillator and the relative noise level. We study entrainment in two ways: by visualizing the stochastic limit cycle in various projections of the discrete phase space of the system and by evaluating the maximum of the normalized cross correlation of the light signal with the number of protein molecules in the cell. The visualization method ignores the phase of the oscillator, and we find in this way that entrainment has a subtle organizing effect on the limit cycle as a whole. The cross correlation results reveal an interval of natural frequencies of the oscillator surrounding the frequency of the light signal within which maximal entrainment occurs with rather sharp drops in entrainment at the edges of this interval. The width of the interval of maximal entrainment increases with the amplitude of the light signal. These statements are applicable both to the stochastic oscillator and to its deterministic limit, but the results are most clear-cut in the deterministic case and degrade from there as the relative noise level increases.
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Affiliation(s)
- Guanyu Wang
- Courant Institute of Mathematical Sciences, New York University, New York, New York 10012, USA
| | - Charles S Peskin
- Courant Institute of Mathematical Sciences, New York University, New York, New York 10012, USA
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