Development and Entrainment of the Fetal Clock in the Suprachiasmatic Nuclei: The Role of Glucocorticoids

2019 ◽  
Vol 34 (3) ◽  
pp. 307-322 ◽  
Author(s):  
Vendula Čečmanová ◽  
Pavel Houdek ◽  
Karolína Šuchmanová ◽  
Martin Sládek ◽  
Alena Sumová
Keyword(s):  
Circadian Clock ◽  
Response Curve ◽  
Phase Response Curve ◽  
Placental Barrier ◽  
Suprachiasmatic Nuclei ◽  
Pregnant Rats ◽  
Peripheral Tissues ◽  
Pass Through

The adult circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is resilient to glucocorticoids (GCs). The fetal rodent SCN resembles that of the adult in its organization of GC-sensitive peripheral tissues. We tested the hypothesis that the fetal SCN clock is sensitive to changes in GC levels. Maternal GCs must pass through the placenta to reach the fetal SCN. We show that the maternal but not the fetal part of the placenta harbors the autonomous circadian clock, which is reset by dexamethasone (DEX) and rhythmically expresses Hsd11b2. The results suggest the presence of a mechanism for rhythmic GC passage through the placental barrier, which is adjusted according to actual GC levels. GC receptors are expressed rhythmically in the laser-dissected fetal SCN samples. We demonstrate that hypothalamic explants containing the SCN of the mPer2 Luc mouse prepared at embryonic day (E)15 spontaneously develop rhythmicity within several days of culture, with dynamics varying among fetuses from the same litter. Culturing these explants in media enriched with DEX accelerates the development. At E17, treatment of the explants with DEX induces phase advances and phase delays of the rhythms depending on the timing of treatments, and the shifts are completely blocked by the GC receptor antagonist, mifepristone. The DEX-induced phase-response curve differs from that induced by the vehicle. The fetal SCN is sensitive to GCs in vivo because DEX administration to pregnant rats acutely downregulates c-fos expression specifically in the laser-dissected fetal SCN. Our results provide evidence that the rodent fetal SCN clock may respond to changes in GC levels.

On the nature of the circadian clock in mammals

1993 ◽  
Vol 264 (5) ◽  
pp. R821-R832 ◽  
Author(s):  
J. D. Miller
Keyword(s):  
Cell Culture ◽  
Functional Analysis ◽  
Circadian Clock ◽  
Suprachiasmatic Nucleus ◽  
Response Curve ◽  
Essential Role ◽  
Phase Response Curve ◽  
Coupling Model ◽  
Clock Mechanism

The evidence for the essential role of the suprachiasmatic nucleus (SCN) for the generation and maintenance of circadian rhythms in mammals is briefly reviewed. The pharmacology of the phase-response curve is considered and a new circadian measure, the phase-dose-response surface (PDRS), is introduced. The role of neurotransmission, ion fluxes, and non-neuronal cellular elements in the generation and maintenance of circadian rhythmicity is considered. Cell culture of the SCN is proposed as a tool for the functional analysis of clock mechanism. The critical contribution of coupling and synchronization of clock elements is reviewed in the context of the explicit predictions generated by a strong coupling model of the circadian clock. Finally, the nature of the circadian output signal is analyzed from a phylogenetic viewpoint.

scholarly journals Circadian clock protein Rev-erbα regulates neuroinflammation

2019 ◽  
Vol 116 (11) ◽  
pp. 5102-5107 ◽  
Author(s):  
Percy Griffin ◽  
Julie M. Dimitry ◽  
Patrick W. Sheehan ◽  
Brian V. Lananna ◽  
Chun Guo ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Microglial Activation ◽  
Time Of Day ◽  
Resting State Functional Connectivity ◽  
Promoter Regions ◽  
Clock Component ◽  
Glial Cultures ◽  
Inflammatory Phenotype

Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα−/− mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα−/− mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα−/− microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB–related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα−/− mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα–deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα−/− mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

scholarly journals In Vivo Role of Phosphorylation of Cryptochrome 2 in the Mouse Circadian Clock

2014 ◽  
Vol 34 (24) ◽  
pp. 4464-4473 ◽  
Author(s):  
A. Hirano ◽  
N. Kurabayashi ◽  
T. Nakagawa ◽  
G. Shioi ◽  
T. Todo ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Cryptochrome 2

scholarly journals Molecular and Cellular Networks in The Suprachiasmatic Nuclei

2019 ◽  
Vol 20 (8) ◽  
pp. 2052 ◽  
Author(s):  
El Cheikh Hussein ◽  
Mollard ◽  
Bonnefont
Keyword(s):  
Circadian Clock ◽  
Functional Organization ◽  
Imaging Techniques ◽  
Internal Clock ◽  
Suprachiasmatic Nuclei ◽  
Daily Behavior ◽  
Freely Moving ◽  
Cell Networks ◽  
Night Shifts

Why do we experience the ailments of jetlag when we travel across time zones? Why is working night-shifts so detrimental to our health? In other words, why can’t we readily choose and stick to non-24 h rhythms? Actually, our daily behavior and physiology do not simply result from the passive reaction of our organism to the external cycle of days and nights. Instead, an internal clock drives the variations in our bodily functions with a period close to 24 h, which is supposed to enhance fitness to regular and predictable changes of our natural environment. This so-called circadian clock relies on a molecular mechanism that generates rhythmicity in virtually all of our cells. However, the robustness of the circadian clock and its resilience to phase shifts emerge from the interaction between cell-autonomous oscillators within the suprachiasmatic nuclei (SCN) of the hypothalamus. Thus, managing jetlag and other circadian disorders will undoubtedly require extensive knowledge of the functional organization of SCN cell networks. Here, we review the molecular and cellular principles of circadian timekeeping, and their integration in the multi-cellular complexity of the SCN. We propose that new, in vivo imaging techniques now enable to address these questions directly in freely moving animals.

scholarly journals Regulation of dendritic cell migration and adaptive immune response by leukotriene B4 receptors: a role for LTB4 in up-regulation of CCR7 expression and function

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 626-631 ◽  
Author(s):  
Annalisa Del Prete ◽  
Wen-Hai Shao ◽  
Stefania Mitola ◽  
Giuseppe Santoro ◽  
Silvano Sozzani ◽  
...  
Keyword(s):  
Gene Array ◽  
Adaptive Immune Response ◽  
Leukotriene B4 ◽  
Contact Hypersensitivity ◽  
Mrna Levels ◽  
Peripheral Tissues ◽  
Ccr7 Expression ◽  
Adaptive Immune

Abstract Trafficking of dendritic cells (DCs) to peripheral tissues and to secondary lymphoid organs depends on chemokines and lipid mediators. Here, we show that bone marrow–derived DCs (BM-DCs) express functional leukotriene B4 (LTB4) receptors as observed in dose-dependent chemotaxis and calcium mobilization responses. LTB4, at low concentrations, promoted the migration of immature and mature DCs to CCL19 and CCL21, which was associated with a rapid (30-minute) increase of CCR7 expression at the membrane level. At longer incubation times (6 hours), gene array analysis revealed a promoting role of LTB4, showing a significant increase of CCR7 and CCL19 mRNA levels. BM-DCs cultured from BLT1−/− or BLT1/2−/− mice showed a normal phenotype, but in vivo BLT1/2−/−DCs showed dramatic decrease in migration to the draining lymph nodes relative to wild-type (WT) DCs. Consistent with these observations, BLT1/2−/− mice showed a reduced response in a model of 2,4-dinitro-fluorobenzene (DNFB)–induced contact hypersensitivity. Adoptive transfer of 2,4-dinitrobenzene sulfonic acid (DNBS)–pulsed DCs directly implicated the defect in DC migration to lymph node with the defect in contact hypersensitivity. These results provide strong evidence for a role of LTB4 in regulating DC migration and the induction of adaptive immune responses.

Involvement of protein synthesis in circadian clock of Aplysia eye

1986 ◽  
Vol 250 (1) ◽  
pp. R5-R17
Author(s):  
D. P. Lotshaw ◽  
J. W. Jacklet
Keyword(s):  
Protein Synthesis ◽  
Circadian Clock ◽  
Response Curve ◽  
Phase Response Curve ◽  
Phase Shifting ◽  
Protein Synthesis Inhibition ◽  
Protein Synthesis Inhibitors ◽  
Synthesis Inhibition ◽  
Subjective Night ◽  
Induce Phase

The effects of the protein synthesis inhibitors anisomycin and puromycin were measured on protein synthesis and phase shifting of the circadian rhythm in the isolated Aplysia eye. Anisomycin pulses induce phase delays proportional in magnitude to the duration and percentage of protein synthesis inhibition. The phase-response curve to anisomycin pulses consisted of delays induced throughout the subjective night. Delays were maximal between circadian times (CT) 18 and CT 2; pulses initiated between CT 2 and CT 12 did not phase shift. Puromycin induced phase delays and advances. Delays were proportional to the duration and percentage of protein synthesis inhibition, occurring with increasing magnitude throughout the subjective night (CT 12-2). Peptidyl-puromycin formation may contribute to the magnitude of the delay. Advances, occurring between CT 2 and CT 8, required a greater drug concentration and pulse duration than delays and appeared to result from an effect other than protein synthesis inhibition. Our results support the hypothesis of a phase-dependent requirement for protein synthesis during the subjective night in this circadian clock.

scholarly journals Emerging role of circadian clock disruption in alcohol-induced liver disease

2018 ◽  
Vol 315 (3) ◽  
pp. G364-G373 ◽  
Author(s):  
Shannon M. Bailey
Keyword(s):  
Liver Disease ◽  
Circadian Clock ◽  
Therapeutic Approaches ◽  
Excessive Alcohol Consumption ◽  
Peripheral Tissues ◽  
New Therapeutic Approaches ◽  
Timing System ◽  
Excessive Alcohol ◽  
The Impact

The detrimental health effects of excessive alcohol consumption are well documented. Alcohol-induced liver disease (ALD) is the leading cause of death from chronic alcohol use. As with many diseases, the etiology of ALD is influenced by how the liver responds to other secondary insults. The molecular circadian clock is an intrinsic cellular timing system that helps organisms adapt and synchronize metabolism to changes in their environment. The clock also influences how tissues respond to toxic, environmental, and metabolic stressors, like alcohol. Consistent with the essential role for clocks in maintaining health, genetic and environmental disruption of the circadian clock contributes to disease. While a large amount of rich literature is available showing that alcohol disrupts circadian-driven behaviors and that circadian clock disruption increases alcohol drinking and preference, very little is known about the role circadian clocks play in alcohol-induced tissue injuries. In this review, recent studies examining the effect alcohol has on the circadian clock in peripheral tissues (liver and intestine) and the impact circadian clock disruption has on development of ALD are presented. This review also highlights some of the rhythmic metabolic processes in the liver that are disrupted by alcohol and potential mechanisms through which alcohol disrupts the liver clock. Improved understanding of the mechanistic links between the circadian clock and alcohol will hopefully lead to the development of new therapeutic approaches for treating ALD and other alcohol-related organ pathologies.

Conjugated dopamine: peripheral origin, distribution, and response to acute stress in the dog

1980 ◽  
Vol 58 (1) ◽  
pp. 22-27 ◽  
Author(s):  
Thomas Unger ◽  
Nguyen T. Buu ◽  
Otto Kuchel ◽  
Walter Schürch
Keyword(s):  
Acute Stress ◽  
Surgical Stress ◽  
Direct Conversion ◽  
Peripheral Tissues ◽  
Liver And Kidney ◽  
Arterial Plasma ◽  
Peripheral Origin

Conjugated catecholamines in the circulation and in peripheral tissues were measured together with free catecholamines in an attempt to investigate whether there are in vivo correlates to a possible biological role of dopamine sulfate suggested by an in vitro finding of direct conversion of dopamine sulfate to free norepinephrine by dopamine β-hydroxylase.Following the strong sympathoadrenergic stimulus of surgical stress accompanied by an increase in blood pressure and heart rate, conjugated dopamine showed a twofold rise in arterial plasma (p < 0.005) together with increases of all free catecholamines (0.005 < p < 0.02), while conjugates of noreprinephrine and epinephrine decreased in the circulation (0.01 < p < 0.05). Measurements of arteriovenous differences have shown that release of conjugated dopamine occurred from the adrenal gland during operation along with free catecholamines. However, the venous outflow of conjugated dopamine from liver and kidney did not exceed its arterial influx. Conjugated dopamine, in contrast with other conjugates, is present in adrenals, liver, small intestine, and kidney with higher concentrations than free dopamine in the adrenals (p < 0.01). After ultracentrifugation, the chromaffin granule fraction of the adrenal medulla (site of dopamine β-hydroxylase) contains large amounts of conjugated dopamine (apparently sulfate) suggesting a selective accumulation of dopamine sulfate as a readily available free norepinephrine precursor during stress.These findings establish major in vivo differences between peripheral conjugated dopamine and conjugates of norepinephrine and epinephrine. They suggest that there may be biological roles for conjugated dopamine beyond that of a dopamine metabolite.

scholarly journals Control of Dendritic Cell Migration, T Cell-Dependent Immunity, and Autoimmunity by Protein Tyrosine Phosphatase PTPN12 Expressed in Dendritic Cells

2013 ◽  
Vol 34 (5) ◽  
pp. 888-899 ◽  
Author(s):  
Inmoo Rhee ◽  
Ming-Chao Zhong ◽  
Boris Reizis ◽  
Cheolho Cheong ◽  
André Veillette
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Genetically Engineered ◽  
Lymphoid Tissues ◽  
Peripheral Tissues ◽  
Protein Tyrosine

Dendritic cells (DCs) capture and process antigens in peripheral tissues, migrate to lymphoid tissues, and present the antigens to T cells. PTPN12, also known as PTP-PEST, is an intracellular protein tyrosine phosphatase (PTP) involved in cell-cell and cell-substratum interactions. Herein, we examined the role of PTPN12 in DCs, using a genetically engineered mouse lacking PTPN12 in DCs. Our data indicated that PTPN12 was not necessary for DC differentiation, DC maturation, or cytokine production in response to inflammatory stimuli. However, it was needed for full induction of T cell-dependent immune responsesin vivo. This function largely correlated with the need of PTPN12 for DC migration from peripheral sites to secondary lymphoid tissues. Loss of PTPN12 in DCs resulted in hyperphosphorylation of the protein tyrosine kinase Pyk2 and its substrate, the adaptor paxillin. Pharmacological inhibition of Pyk2 or downregulation of Pyk2 expression also compromised DC migration, suggesting that Pyk2 deregulation played a pivotal role in the migration defect caused by PTPN12 deficiency. Together, these findings identified PTPN12 as a key regulator in the ability of DCs to induce antigen-induced T cell responses. This is due primarily to the role of PTPN12 in DC migration from peripheral sites to secondary lymphoid organs through regulation of Pyk2.

scholarly journals IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo

Blood ◽  
2006 ◽  
Vol 109 (5) ◽  
pp. 2023-2031 ◽  
Author(s):  
Anja Fröhlich ◽  
Benjamin J. Marsland ◽  
Ivo Sonderegger ◽  
Michael Kurrer ◽  
Martin R. Hodge ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Allergic Airway Inflammation ◽  
Nippostrongylus Brasiliensis ◽  
Autoimmune Myocarditis ◽  
Heligmosomoides Polygyrus ◽  
Peripheral Tissues ◽  
Th2 Cell ◽  
Th2 Responses

Abstract Interleukin 21 (IL-21) is a member of the common γ-chain family of cytokines, which influence a broad spectrum of immunologic responses. A number of studies have examined the function of IL-21, but its specific role in Th1/Th2-cell differentiation and related effector responses remains to be clarified. Thus, we generated IL-21R–deficient mice and have investigated the role of IL-21R signaling using a series of in vivo experimentally induced disease models. We first addressed the role of IL-21R signaling in Th2 immune responses by examining allergic airway inflammation, and Nippostrongylus brasiliensis and Heligmosomoides polygyrus antihelminth responses. In each of these systems, IL-21R signaling played a clear role in the development of Th2 responses. Comparatively, IL-21R signaling was not required for the containment of Leishmania major infection or the development of experimental autoimmune myocarditis, indicative of competent Th1 and Th17 responses, respectively. Adoptive transfer of T cells and analysis of IL-21R+/+/IL-21R−/− chimera mice revealed that IL-21R–signaling was central to Th2-cell survival or migration to peripheral tissues. Overall, our data show IL-21 plays a crucial role in supporting polarized Th2 responses in vivo, while appearing superfluous for Th1 and Th17 responses.

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