Desipramine restores the alterations in circadian entrainment induced by prenatal exposure to glucocorticoids

Abstract Alterations in circadian rhythms are closely linked to depression, and we have shown earlier that progressive alterations in circadian entrainment precede the onset of depression in mice exposed in utero to excess glucocorticoids. The aim of this study was to investigate whether treatment with the noradrenaline reuptake inhibitor desipramine (DMI) could restore the alterations in circadian entrainment and prevent the onset of depression-like behavior. C57Bl/6 mice were exposed to dexamethasone (DEX—synthetic glucocorticoid analog, 0.05 mg/kg/day) between gestational day 14 and delivery. Male offspring aged 6 months (mo) were treated with DMI (10 mg/kg/day in drinking water) for at least 21 days before behavioral testing. We recorded spontaneous activity using the TraffiCage™ system and found that DEX mice re-entrained faster than controls after an abrupt advance in light-dark cycle by 6 h, while DMI treatment significantly delayed re-entrainment. Next we assessed the synchronization of peripheral oscillators with the central clock (located in the suprachiasmatic nucleus—SCN), as well as the mechanisms required for entrainment. We found that photic entrainment of the SCN was apparently preserved in DEX mice, but the expression of clock genes in the hippocampus was not synchronized with the light-dark cycle. This was associated with downregulated mRNA expression for arginine vasopressin (AVP; the main molecular output entraining peripheral clocks) in the SCN, and for glucocorticoid receptor (GR; required for the negative feedback loop regulating glucocorticoid secretion) in the hippocampus. DMI treatment restored the mRNA expression of AVP in the SCN and enhanced GR-mediated signaling by upregulating GR expression and nuclear translocation in the hippocampus. Furthermore, DMI treatment at 6 mo prevented the onset of depression-like behavior and the associated alterations in neurogenesis in 12-mo-old DEX mice. Taken together, our data indicate that DMI treatment enhances GR-mediated signaling and restores the synchronization of peripheral clocks with the SCN and support the hypothesis that altered circadian entrainment is a modifiable risk factor for depression.

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Minireview: The Circadian Clockwork of the Suprachiasmatic Nuclei—Analysis of a Cellular Oscillator that Drives Endocrine Rhythms

Endocrinology ◽

10.1210/en.2007-0660 ◽

2007 ◽

Vol 148 (12) ◽

pp. 5624-5634 ◽

Cited By ~ 85

Author(s):

Elizabeth S. Maywood ◽

John S. O’Neill ◽

Johanna E. Chesham ◽

Michael H. Hastings

Keyword(s):

Neural Circuits ◽

Clock Genes ◽

Time Base ◽

Suprachiasmatic Nuclei ◽

Dark Cycle ◽

Cellular Mechanisms ◽

Circadian Control ◽

Daily Cycles ◽

Central Clock ◽

Retinal Afferents

The secretion of hormones is temporally precise and periodic, oscillating over hours, days, and months. The circadian timekeeper within the suprachiasmatic nuclei (SCN) is central to this coordination, modulating the frequency of pulsatile release, maintaining daily cycles of secretion, and defining the time base for longer-term rhythms. This central clock is driven by cell-autonomous, transcriptional/posttranslational feedback loops incorporating Period (Per) and other clock genes. SCN neurons exist, however, within neural circuits, and an unresolved question is how SCN clock cells interact. By monitoring the SCN molecular clockwork using fluorescence and bioluminescence videomicroscopy of organotypic slices from mPer1::GFP and mPer1::luciferase transgenic mice, we show that interneuronal neuropeptidergic signaling via the vasoactive intestinal peptide (VIP)/PACAP2 (VPAC2) receptor for VIP (an abundant SCN neuropeptide) is necessary to maintain both the amplitude and the synchrony of clock cells in the SCN. Acute induction of mPer1 by light is, however, independent of VIP/VPAC2 signaling, demonstrating dissociation between cellular mechanisms mediating circadian control of the clockwork and those mediating its retinally dependent entrainment to the light/dark cycle. The latter likely involves the Ca2+/cAMP response elements of mPer genes, triggered by a MAPK cascade activated by retinal afferents to the SCN. In the absence of VPAC2 signaling, however, this cascade is inappropriately responsive to light during circadian daytime. Hence VPAC2-mediated signaling sustains the SCN cellular clockwork and is necessary both for interneuronal synchronization and appropriate entrainment to the light/dark cycle. In its absence, behavioral and endocrine rhythms are severely compromised.

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Peripheral clocks and their role in circadian timing: insights from insects

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2001.0960 ◽

2001 ◽

Vol 356 (1415) ◽

pp. 1791-1799 ◽

Cited By ~ 70

Author(s):

Jadwiga M. Giebultowicz

Keyword(s):

Feedback Loop ◽

Clock Genes ◽

Expression Patterns ◽

Isolated Organs ◽

Peripheral Organs ◽

Peripheral Clocks ◽

Molecular Components ◽

The Brain

Impressive advances have been made recently in our understanding of the molecular basis of the cell–autonomous circadian feedback loop; however, much less is known about the overall organization of the circadian systems. How many clocks tick in a multicellular animal, such as an insect, and what are their roles and the relationships between them? Most attempts to locate clock–containing tissues were based on the analysis of behavioural rhythms and identified brain–located timing centres in a variety of animals. Characterization of several essential clock genes and analysis of their expression patterns revealed that molecular components of the clock are active not only in the brain, but also in many peripheral organs of Drosophila and other insects as well as in vertebrates. Subsequent experiments have shown that isolated peripheral organs can maintain self–sustained and light sensitive cycling of clock genes in vitro . This, together with earlier demonstrations that physiological output rhythms persist in isolated organs and tissues, provide strong evidence for the existence of functionally autonomous local circadian clocks in insects and other animals. Circadian systems in complex animals may include many peripheral clocks with tissue–specific functions and a varying degree of autonomy, which seems to be correlated with their sensitivity to external entraining signals.

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Resetting Process of Peripheral Circadian Gene Expression after the Combined Reversal of Feeding Schedule and Light/Dark Cycle Via a 24-h Light Period Transition in Rats

Physiological Research ◽

10.33549/physiolres.931818 ◽

2010 ◽

pp. 581-590

Author(s):

T Wu ◽

Y Ni ◽

F Zhuge ◽

Z Fu

Keyword(s):

Time Course ◽

Clock Genes ◽

Dark Period ◽

Light Period ◽

Feeding Schedule ◽

Circadian Gene ◽

Dark Cycle ◽

Peripheral Clocks ◽

Effect Of Light

To investigate the effect of light cue on the resetting of the peripheral clocks, we examined the resetting processes of clock genes (Per1, Per2, Bmal1, Cry1, Dec1, and Rev-erbα) in the liver and heart of rats after the feeding and light-dark (LD) reversal via a 24-h light period transition. The liver clock was reset quickly within 3 days, while the heart clock needed a longer time course of 5-7 days to be completely re-entrained. Moreover, the reentrainment of Per1 and Per2 in the liver clock was more rapid than that of the other four clock genes, suggesting the important role of these two clock genes in initiating the circadian resetting of the hepatic clock. However, the resetting rates of these two clock genes were as similar as the others in the heart clock. Therefore, the resetting mechanisms underlining these two peripheral clocks may be totally distinct. Furthermore, the reentrainment of the liver and heart clocks were relatively lengthened after the feeding and LD reversal via a light period transition compared to a dark period transition, suggesting a simultaneous shift of feeding schedule and the LD cycle may facilitate the circadian resetting in rats.

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Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident macrophages

Blood ◽

10.1182/blood-2010-12-327353 ◽

2011 ◽

Vol 118 (2) ◽

pp. 330-338 ◽

Cited By ~ 363

Author(s):

Hosoon Choi ◽

Ryang Hwa Lee ◽

Nikolay Bazhanov ◽

Joo Youn Oh ◽

Darwin J. Prockop

Keyword(s):

Negative Feedback ◽

Feedback Loop ◽

Nuclear Translocation ◽

Negative Feedback Loop ◽

Beneficial Effects ◽

Inflammatory Protein ◽

Tnf Α ◽

Anti Inflammatory ◽

Pathologic Processes ◽

First Time

AbstractHuman mesenchymal stem/progenitor cells (hMSCs) repair tissues and modulate immune systems but the mechanisms are not fully understood. We demonstrated that hMSCs are activated by inflammatory signals to secrete the anti-inflammatory protein, TNF-α–stimulated gene 6 protein (TSG-6) and thereby create a negative feedback loop that reduces inflammation in zymosan-induced peritonitis. The results demonstrate for the first time that TSG-6 interacts through the CD44 receptor on resident macrophages to decrease zymosan/TLR2-mediated nuclear translocation of the NF-κB. The negative feedback loop created by MSCs through TSG-6 attenuates the inflammatory cascade that is initiated by resident macrophages and then amplified by mesothelial cells and probably other cells of the peritoneum. Because inflammation underlies many pathologic processes, including immune responses, the results may explain the beneficial effects of MSCs and TSG-6 in several disease models.

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Oxyntomodulin regulates resetting of the liver circadian clock by food

eLife ◽

10.7554/elife.06253 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 43

Author(s):

Dominic Landgraf ◽

Anthony H Tsang ◽

Alexei Leliavski ◽

Christiane E Koch ◽

Johanna L Barclay ◽

...

Keyword(s):

Circadian Rhythm ◽

Food Intake ◽

Metabolic Disorders ◽

Clock Genes ◽

Circadian Clocks ◽

Direct Link ◽

Dark Cycle ◽

The Core ◽

Peripheral Clocks ◽

Master Clock

Circadian clocks coordinate 24-hr rhythms of behavior and physiology. In mammals, a master clock residing in the suprachiasmatic nucleus (SCN) is reset by the light–dark cycle, while timed food intake is a potent synchronizer of peripheral clocks such as the liver. Alterations in food intake rhythms can uncouple peripheral clocks from the SCN, resulting in internal desynchrony, which promotes obesity and metabolic disorders. Pancreas-derived hormones such as insulin and glucagon have been implicated in signaling mealtime to peripheral clocks. In this study, we identify a novel, more direct pathway of food-driven liver clock resetting involving oxyntomodulin (OXM). In mice, food intake stimulates OXM secretion from the gut, which resets liver transcription rhythms via induction of the core clock genes Per1 and 2. Inhibition of OXM signaling blocks food-mediated resetting of hepatocyte clocks. These data reveal a direct link between gastric filling with food and circadian rhythm phasing in metabolic tissues.

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A robust and self-sustained peripheral circadian oscillator reveals differences in temperature compensation properties with central brain clocks

10.1101/2020.06.24.168450 ◽

2020 ◽

Author(s):

Marijke Versteven ◽

Karla-Marlen Ernst ◽

Ralf Stanewsky

Keyword(s):

Temperature Compensation ◽

Biological Rhythms ◽

The Body ◽

Circadian Clocks ◽

Luciferase Reporter ◽

Pigment Dispersing Factor ◽

Peripheral Oscillators ◽

Peripheral Clocks ◽

Central Clock ◽

Fitness And Health

AbstractCircadian clocks temporally organize physiology and behavior of organisms exposed to the daily changes of light and temperature on our planet, thereby contributing to fitness and health. Circadian clocks and the biological rhythms they control are characterized by three properties. (1) The rhythms are self-sustained in constant conditions with a period of ~ 24 hr, (2), they can be synchronized to the environmental cycles of light and temperature, and (3), they are temperature compensated, meaning they run with the same speed at different temperatures within the physiological range of the organism. Apart from the central clocks located in or near the brain, which regulate the daily activity rhythms of animals, the so-called peripheral clocks are dispersed throughout the body of insects and vertebrates. Based on the three defining properties, it has been difficult to determine if these peripheral clocks are true circadian clocks. We used a set of clock gene – luciferase reporter genes to address this question in Drosophila circadian clocks. We show that self-sustained fly peripheral oscillators over compensate temperature changes, i.e., they slow down with increasing temperature. This over-compensation is not observed in central clock neurons in the fly brain, both in intact flies and in cultured brains, suggesting that neural network properties contribute to temperature compensation. However, an important neuropeptide for synchronizing the circadian neuronal network, the Pigment Dispersing Factor (PDF), is not required for self-sustained and temperature-compensated oscillations in subsets of the central clock neurons. Our findings reveal a fundamental difference between central and peripheral clocks, which likely also applies for vertebrate clocks.

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Circadian Rhythm Variations and Nutrition in Children

Journal of Child Science ◽

10.1055/s-0038-1670667 ◽

2018 ◽

Vol 08 (01) ◽

pp. e60-e66 ◽

Cited By ~ 1

Author(s):

Marie Gombert ◽

Joaquín Carrasco-Luna ◽

Gonzalo Pin-Arboledas ◽

Pilar Codoñer-Franch

Keyword(s):

Circadian Rhythms ◽

Metabolic Diseases ◽

Clock Genes ◽

Light Exposure ◽

Daily Basis ◽

Biological Processes ◽

Life Habits ◽

Peripheral Clocks ◽

Opposite Situation ◽

Central Clock

AbstractCircadian rhythms are the changes in biological processes that occur on a daily basis. Among these processes are reactions involved in metabolic homeostasis. Circadian rhythms are structured by the central clock in the suprachiasmatic nucleus of the hypothalamus via the control of melatonin expression. Circadian rhythms are also controlled by the peripheral clocks, which are intracellular mechanisms composed of the clock genes, whose expression follows a circadian pattern. Circadian rhythms are impacted by signals from the environment called zeitgebers, or time givers, which include light exposure, feeding schedule and composition, sleeping schedule and pattern, temperature, and physical exercise. When the signals from the environment are synchronized with the internal clocks, metabolism is optimized. The term chronodisruption is used to describe the opposite situation. The latest research has demonstrated that life habits coherent with the internal clocks should be adopted, especially during childhood, to prevent metabolic diseases. Nevertheless, a few studies have investigated this link in children, and key information remains unknown.

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