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Background: Circadian rhythm disorders are severe threats to human health. The negative impact of circadian rhythm disorders on tissues/organs has not been systematically analyzed. Therefore, there is an urgent need to evaluate the damage caused by circadian rhythm disorders and explore the possible mechanisms., Methods: Six-week-old male mice were divided into the control (Con) group (normal circadian rhythm), L24 group (constant light), D12L12 group (weekly shift light/dark cycle), and D24 group (constant dark). Body weight was recorded every 10 days. Ninety days after model construction, the serum lipid and cytokine level, liver function, fat accumulation, carotid artery stenosis, and cardiomyopathological changes were detected in mice. Macrophages in the liver, subscapular fat, and heart tissues were labeled with immunofluorescence staining. Mouse peritoneal macrophages were then isolated. Inflammatory cytokine levels were measured in the macrophage supernatant. The ability of macrophages to form foam cells was also tested. The supernatant from macrophages in different groups was added to AML12 (hepatocytes), 3T3-L1 (preadipocytes), or HL-1 (cardiomyocytes). Effects of conditioned media on recipient cells were determined., Results: Body weight, serum lipids and cytokines, subscapular fat accumulation, liver enzymes, carotid artery stenosis, and myocardial fibrosis levels of the L24, D12L12, and D24 groups mice were significantly higher than those in the Con group. Macrophages were significantly increased in the liver, heart, and subscapular fat of mice with circadian rhythmdisorders. Cytokine secretion by peritoneal macrophages was enhanced in the L24, D12L12, and D24 groups. Under oxidized low density lipoprotein (oxLDL) stimulation, macrophages with circadian rhythm disorders are more likely to form foam cells. Conditioned media from the L24, D12L12, and D24 groups significantly promoted AML12 apoptosis and lipid intake, accelerated the adipogenic differentiation of 3T3-L1, and up-regulated collagen I in HL-1., Conclusion: These findings reveal that macrophages are increased in the tissues/organs under circadian rhythm disorders, and these macrophages could aggravate obesity, promote liver disease, accelerate atherosclerosis, and increase myocardial fibrosis through the paracrine effect., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Adiponectin is an adipocyte-derived hormone, which is closely associated with the development of Alzheimer's disease (AD) and has potential preventive and therapeutic significance. In the present study, we explored the relationship between adiponectin and circadian rhythm disorder in AD, the effect of adiponectin on the abnormal expression of Bmal1 mRNA/protein induced by amyloid-β protein 31-35 (Aβ31-35), and the underlying mechanism of action. We found that adiponectin-knockout mice exhibited amyloid-β deposition, circadian rhythm disorders and abnormal expression of Bmal1. Adiponectin ameliorated the abnormal expression of the Bmal1 mRNA/protein caused by Aβ31-35 by inhibiting the activity of glycogen synthase kinase 3β (GSK3β). These results suggest that adiponectin deficiency could induce circadian rhythm disorders and abnormal expression of the Bmal1 mRNA/protein, whilst exogenous administration of adiponectin may improve Aβ31-35-induced abnormal expression of Bmal1 by inhibiting the activity of GSK3β, thus providing a novel idea for the treatment of AD., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The aim of this study is to compare the regulatory abilities of citrus flavonoids on the oscillating expression of circadian genes. Seven varieties of citrus fruits and twenty-five citrus flavonoids were selected and evaluated. Per2 luciferase bioluminescence report system and serum shock were used to induce circadian gene expression in mouse microglia BV-2 cells. In vivo experiments were carried out using C57BL6/J mice to evaluate the regulation of flavonoids on the oscillatory expression of liver biorhythm genes. Lipopolysaccharide was used to interfere the gene oscillating expression. QRT-PCR was performed to detect the expression of circadian rhythm-related genes, including Clock , Bmal1 , Per1 , Per2 , Per3 , Cry1 , Cry2 , Rev-erbα , Rev-erbβ , Rorα , Dbp , and Npas2 . The results show that the polymethoxyflavones (PMFs) exerted stronger circadian gene regulatory capability, while the flavonoids containing glycosides showed no biological activity. Also, all tested flavonoids decreased LPS-induced nitric oxide release, but only polymethoxyflavones inhibited circadian rhythm disorder. PMFs inhibited Nlrp3 inflammasome-related genes and proteins, including Nlrp3, IL-1 β , ASC, and Caspase1, while other flavonoids only affected IL-1 β and Caspase1 expression. This mechanism was preliminarily verified using the Nlrp3 inhibitor INF39., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Yue Wang et al.)

The accumulation of adenosine is strongly correlated with the need for sleep and the detection of sleep pressure is antagonised by caffeine. Caffeine also affects the circadian timing system directly and independently of sleep physiology, but how caffeine mediates these effects upon the circadian clock is unclear. Here we identify an adenosine-based regulatory mechanism that allows sleep and circadian processes to interact for the optimisation of sleep/wake timing in mice. Adenosine encodes sleep history and this signal modulates circadian entrainment by light. Pharmacological and genetic approaches demonstrate that adenosine acts upon the circadian clockwork via adenosine A 1 /A 2A receptor signalling through the activation of the Ca 2+  -ERK-AP-1 and CREB/CRTC1-CRE pathways to regulate the clock genes Per1 and Per2. We show that these signalling pathways converge upon and inhibit the same pathways activated by light. Thus, circadian entrainment by light is systematically modulated on a daily basis by sleep history. These findings contribute to our understanding of how adenosine integrates signalling from both light and sleep to regulate circadian timing in mice.

Over the past decades, circadian rhythm has drawn a great attention in cardiovascular diseases. The expressions of rhythm genes fluctuate in accordance with the diurnal changes of vascular physiology, which highlights the pivotal effect of vascular clock. Recent researches show that the circadian clock can directly regulate the synthetic and secretory function of endothelial cells and phenotypic switch of vascular smooth muscle cells to adjust vascular relaxation and contraction. Importantly, dysfunction of vascular cells is involved in vascular calcification. Secretion of osteogenic cytokines and calcified vesicles in the vessel, osteogenic phenotype switch of vascular smooth muscle cells are all implicated in the calcification process. Moreover, circadian rhythm disorder can lead to abnormal hormone secretion, oxidative stress, inflammatory reaction, and autophagy, all of which should not be ignored in vascular calcification. Vascular senescence is another pathogenetic mechanism in vascular calcification. Accelerated vascular senescence may act as an important intermediate factor to promote vascular calcification in circadian rhythm disorders. In this review, we elaborate the potential effect of circadian rhythm disorder in vascular calcification and try to provide a new direction in the prevention of vascular calcification.

Circadian organization of physiology and behavior is an important biological process that allows organisms to anticipate and prepare for daily changes and demands. Disruptions in this system precipitates a wide range of health issues. In patients with neurodegenerative diseases, alterations of circadian rhythms are among the most common and debilitating symptoms. Although a growing awareness of these symptoms has occurred during the last decade, their underlying neuropathophysiological circuitry remains poorly understood and consequently no effective therapeutic strategies are available to alleviate these health issues. Recent studies have examined the neuropathological status of the different neural components of the circuitry governing the generation of circadian rhythms in neurodegenerative diseases. In this review, we will dissect the potential contribution of dysfunctions in the different nodes of this circuitry to circadian alterations in patients with neurodegenerative diseases. A deeper understanding of these mechanisms will provide not only a better understanding of disease neuro-pathophysiology, but also hold the promise for developing effective and mechanisms-based therapies., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: This article provides an overview of circadian physiology and discusses common presentations and treatment strategies for the circadian rhythm sleep-wake disorders., Recent Findings: Circadian rhythms are present throughout the body, and appreciation for the role that circadian dysregulation plays in overall health is increasing, with mounting associations between circadian disruption and cardiometabolic disease risk., Summary: It is important to recognize the ubiquitous role that circadian rhythms play throughout the brain and body. An understanding of circadian neurophysiology will provide insight into the means by which patients with a variety of neuropathologies at the level of the retina, optic nerve, or hypothalamus may also be at risk for circadian dysfunction.

The rapidly expanding elderly population and obesity endemic have become part of continuing global health care problems. The hypothalamus is a critical center for the homeostatic regulation of energy and glucose metabolism, circadian rhythm, and aging-related physiology. Nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase sirtuins are referred to as master metabolic regulators that link the cellular energy status to adaptive transcriptional responses. Mounting evidence now indicates that hypothalamic sirtuins are essential for adequate hypothalamic neuronal functions. Owing to the NAD + -dependence of sirtuin activity, adequate hypothalamic NAD + contents are pivotal for maintaining energy homeostasis and circadian physiology. Here, we comprehensively review the regulatory roles of the hypothalamic neuronal NAD + -sirtuin axis in a normal physiological context and their changes in obesity and the aging process. We also discuss the therapeutic potential of NAD + biology-targeting drugs in aging/obesity-related metabolic and circadian disorders., Competing Interests: The authors declare no conflicts of interest.

The present study investigated the effects of circadian rhythm disorder (CRD) on the hippocampus of SHR and WKY rats. Male SHR rats (n = 27) and WKY rats (n = 27) were randomly divided into six groups: SHR and WKY normal (N)CR, SHR and WKY CRD 16/8 (CRD16/8), and SHR and WKY CRD 12/12 (CRD12/12). Activity patterns were adjusted using different photoperiods over 90 days and any changes were recorded. Rats were tested in the Morris water maze and in a novel object recognition experiment; serologic analysis, magnetic resonance imaging (diffusion tensor imaging + arterial spin labeling), hippocampal Nissl staining, Fluoro-Jade B staining, and immunohistochemistry were also performed. The results showed that both types of inverted photoperiod reduced CR amplitude and prolonged the circadian period. CRD and hypertension reduced memory performance and novel object recognition and preference. The decreases in memory and preference indices were greater in rats in the CRD12/12 group compared to the CRD16/8 group. CRD and hypertension decreased fractional anisotropy values, the number of neurons and astrocytes in the hippocampus, and the expression of brain-derived neurotrophic factor and synapsin 1; it also enhanced the degeneration of neurons and microglia and reduced blood flow in the hippocampus, and increased nuclear factor κB, caspase, neuron-specific enolase, and interleukin-6 levels. These findings reveal a biological basis for the link between CRD and cognitive decline, which has implications for CRD caused by shift work and other factors., Competing Interests: Declaration of Competing Interest The author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1. LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide. Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate. Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide. Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin. Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA). Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function. Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology. Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS). The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology. NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology. This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate.

Atrophy of the medial temporal lobe of the brain is key to memory function and memory complaints in old age. While age and some morbidities are major risk factors for medial temporal lobe atrophy, individual differences remain, and mechanisms are insufficiently known. The largest combined neuroimaging and whole genome study to date indicates that medial temporal lobe volume is most associated with common polymorphisms in the GRIN2B gene that encodes for the 2B subunit (NR2B) of the NMDA receptor. Because sleep disruption induces a selective loss of NR2B from hippocampal synaptic membranes in rodents, and because of several other reports on medial temporal lobe sensitivity to sleep disruption, we hypothesized a contribution of the typical age-related increase in sleep-wake rhythm fragmentation to medial temporal lobe atrophy. Magnetic resonance imaging and actigraphy in 138 aged individuals showed that individual differences in sleep-wake rhythm fragmentation accounted for more (19%) of the variance in medial temporal lobe atrophy than age did (15%), or any of a list of health and brain structural indicators. The findings suggest a role of sleep-wake rhythm fragmentation in age-related medial temporal lobe atrophy, that might in part be prevented or reversible., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) patients often suffer from non-motor symptoms like sleep dysregulation, mood disturbances or circadian rhythms dysfunction. The melanopsin-containing retinal ganglion cells are involved in the control and regulation of these processes and may be affected in PD, as other retinal and visual implications have been described in the disease. Number and morphology of human melanopsin-containing retinal ganglion cells were evaluated by immunohistochemistry in eyes from donors with PD or control. The Sholl number of intersections, the number of branches, and the number of terminals from the Sholl analysis were significantly reduced in PD melanopsin ganglion cells. Also, the density of these cells significantly decreased in PD compared to controls. Degeneration and impairment of the retinal melanopsin system may affect to sleep and circadian dysfunction reported in PD pathology, and its protection or stimulation may lead to better disease prospect and global quality of life of patients.

The circadian rhythms influence the metabolic activity from molecular level to tissue, organ, and host level. Disruption of the circadian rhythms manifests to the host's health as metabolic syndromes, including obesity, diabetes, and elevated plasma glucose, eventually leading to cardiovascular diseases. Therefore, it is imperative to understand the mechanism behind the relationship between circadian rhythms and metabolism. To start answering this question, we propose a semimechanistic mathematical model to study the effect of circadian disruption on hepatic gluconeogenesis in humans. Our model takes the light-dark cycle and feeding-fasting cycle as two environmental inputs that entrain the metabolic activity in the liver. The model was validated by comparison with data from mice and rat experimental studies. Formal sensitivity and uncertainty analyses were conducted to elaborate on the driving forces for hepatic gluconeogenesis. Furthermore, simulating the impact of Clock gene knockout suggests that modification to the local pathways tied most closely to the feeding-fasting rhythms may be the most efficient way to restore the disrupted glucose metabolism in liver.

Photoperiod disruption, which occurs during shift work, is associated with changes in metabolism or physiology (e.g. hypertension and hyperglycaemia) that have the potential to adversely affect stroke outcome. We sought to investigate if photoperiod disruption affects vulnerability to stroke by determining the impact of photoperiod disruption on infarct size following permanent middle cerebral artery occlusion. Adult male Wistar rats (210-290 g) were housed singly under two different light/dark cycle conditions ( n = 12 each). Controls were maintained on a standard 12:12 light/dark cycle for nine weeks. For rats exposed to photoperiod disruption, every three days for nine weeks, the lights were switched on 6 h earlier than in the previous photoperiod. T 2 -weighted magnetic resonance imaging was performed at 48 h after middle cerebral artery occlusion. Disruption of photoperiod in young healthy rats for nine weeks did not alter key physiological variables that can impact on ischaemic damage, e.g. blood pressure and blood glucose immediately prior to middle cerebral artery occlusion. There was no effect of photoperiod disruption on infarct size after middle cerebral artery occlusion. We conclude that any potentially adverse effect of photoperiod disruption on stroke outcome may require additional factors such as high fat/high sugar diet or pre-existing co-morbidities.

The circadian system is the responsible to organise the internal temporal order in relation to the environment of every process of the organisms producing the circadian rhythms. These rhythms have a fixed phase relationship among them and with the environment in order to optimise the available energy and resources. From a cellular level, circadian rhythms are controlled by genetic positive and negative auto-regulated transcriptional and translational feedback loops, which generate 24h rhythms in mRNA and protein levels of the clock components. It has been described about 10% of the genome is controlled by clock genes, with special relevance, due to its implications, to the cell cycle. Ageing is a deleterious process which affects all the organisms' structures including circadian system. The circadian system's ageing may produce a disorganisation among the circadian rhythms, arrhythmicity and, even, disconnection from the environment, resulting in a detrimental situation to the organism. In addition, some environmental conditions can produce circadian disruption, also called chronodisruption, which may produce many pathologies including accelerated ageing. Finally, some strategies to prevent, palliate or counteract chronodisruption effects have been proposed to enhance the circadian system, also called chronoenhancement. This review tries to gather recent advances in the chronobiology of the ageing process, including cell cycle, neurogenesis process and physiology., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Alteration of circadian rhythms and sleep disruption are prominent trait-like features of bipolar disorder (BD). Diffusion tensor imaging (DTI) measures suggest a widespread alteration of white matter (WM) microstructure in patients with BD. Sleep promotes myelination and oligodendrocyte precursor cells proliferation. We hypothesized a possible association between DTI measures of WM microstructure and sleep quantity measures in BD., Methods: We studied 69 inpatients affected by a depressive episode in course of type I BD. We used whole brain tract-based spatial statistics on DTI measures of WM microstructure: axial, radial, and mean diffusivity (AD, RD, MD), and fractional anisotropy (FA). Self-assessed measures of time asleep (TA) and total sleep time (TST) were extracted from the Pittsburgh Sleep Quality Index (PSQI). Actigraphic recordings were performed on a subsample of 23 patients., Results: We observed a positive correlation of DTI measures of FA with actigraphic measures of TA and TST, and with PSQI measure of TA. DTI measures of RD inversely associated with actigraphic measure of TA, and with PSQI measures of TA and TST. Several WM tracts were involved, including corpus callosum, cyngulate gyrus, uncinate fasciculus, left superior and inferior longitudinal and fronto-occipital fasciculi, thalamic radiation, corona radiata, retrolenticular part of internal capsule and corticospinal tract., Limitations: The study is correlational in nature, and no conclusion about a causal connection can be drawn., Conclusions: Reduced FA with increased RD and MD indicate higher water diffusivity associated with less organized myelin and/or axonal structures. Our findings suggest an association between sleep disruption and these measures of brain microstructure in specific tracts contributing to the functional connectivity in BD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this study was to investigate lithium and 2,4-dichlorophenol (2,4-DCP)-induced circadian rhythm disorder and their genome-wide effects in zebrafish. Zebrafish larvae were exposed to 250 ppm LiCl (n = 40) or 20 ppm 2,4-DCP. RNA was subsequently extracted and determined quantitatively. The mRNA levels of circadian clock-related genes, including clock1a, bmal1b, per2, and per1b, were determined. Microarray datasets were generated and the differentially expressed genes (DEGs) were identified. The mRNA levels of some upregulated and downregulated DEGs were examined by quantitative real-time polymerase chain reaction (RT-PCR). Finally, gene ontology (GO) enrichment analysis was applied to determine the roles of the DEGs. The mRNA expression levels of circadian rhythm-related genes in the daily cycle were significantly affected after incubation of zebrafish with LiCl and 2,4-DCP. Many genes were differentially expressed during the light phase (97 h) and RT-PCR validation tests revealed that the expression patterns of DEGs were in accordance with those obtained by microarray analysis. GO functional enrichment analysis showed that the DEGs in LiCl- and 2,4-DCP-treated groups were associated with signal transduction and development. Collectively, our findings indicate that LiCl and 2,4-DCP could affect signal transduction pathways and immune response, thereby inducing circadian rhythm disorder.

Unlabelled: Serotonin (5-HT) is a crucial neuromodulator linked to many psychiatric disorders. However, after more than 60 years of study, its role in behavior remains poorly understood, in part because of a lack of methods to target 5-HT synthesis specifically in the adult brain. Here, we have developed a genetic approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system by stereotaxic injection of an adeno-associated virus expressing Cre recombinase (AAV-Cre) into the midbrain/pons of mice carrying a loxP-conditional tryptophan hydroxylase 2 (Tph2) allele. We investigated the behavioral effects of deficient brain 5-HT synthesis and discovered a unique composite phenotype. Surprisingly, adult 5-HT deficiency did not affect anxiety-like behavior, but resulted in a robust hyperactivity phenotype in novel and home cage environments. Moreover, loss of 5-HT led to an altered pattern of circadian behavior characterized by an advance in the onset and a delay in the offset of daily activity, thus revealing a requirement for adult 5-HT in the control of daily activity patterns. Notably, after normalizing for hyperactivity, we found that the normal prolonged break in nocturnal activity (siesta), a period of rapid eye movement (REM) and non-REM sleep, was absent in all animals in which 5-HT deficiency was verified. Our findings identify adult 5-HT as a requirement for siestas, implicate adult 5-HT in sleep-wake homeostasis, and highlight the importance of our adult-specific 5-HT-synthesis-targeting approach in understanding 5-HT's role in controlling behavior., Significance Statement: Serotonin (5-HT) is a crucial neuromodulator, yet its role in behavior remains poorly understood, in part because of a lack of methods to target specifically adult brain 5-HT synthesis. We developed an approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system. Using this technique, we discovered that adult 5-HT deficiency led to a novel compound phenotype consisting of hyperactivity, disrupted circadian behavior patterns, and elimination of siestas, a period of increased sleep during the active phase. These findings highlight the importance of our approach in understanding 5-HT's role in behavior, especially in controlling activity levels, circadian behavior, and sleep-wake homeostasis, behaviors that are disrupted in many psychiatric disorders such as attention deficit hyperactivity disorder., (Copyright © 2016 the authors 0270-6474/16/369828-15$15.00/0.)

The internal clock located in the suprachiasmatic nuclei of the anterior hypothalamus is controlled by external (environment and social life) and genetic factors. Desynchronisation of the organism occurs when the clock does no longer work in harmony with the environ- mentalfactors. Rhythm desynchronization can be related to a conflict between the clock and environmentalfactors (shift work, night shift, transmeridianflight), to inefficient synchro- nizers (aging, psychiatric diseases..), to badly received synchronizers (circadian rhythm sleep disorders with e.g delayed or advanced sleep phase syndromes), or to the use of some drugs (lithium, propofol, alcohol...). In the long term rhythm desynchronisation can result in serious illnesses and the use of resynchronizing agents like melatonin or bright light are useful to the clock resynchronization.

Nuclear receptors are a superfamily of transcription factors including the steroid hormone receptors, non-steroid hormone receptors and the orphan nuclear receptor family. Retinoic acid-related orphan receptor (ROR)β, as a member of the orphan nuclear receptor family, plays an important regulatory role in the maintenance of a variety of physiological and pathological processes. RORβ has been determined to act as an osteogenic repressor in regulating bone formation, and is involved in regulating circadian rhythm. The findings of recent studies concerning the association between tumorigenesis and circadian rhythm have shown that an aberrant circadian rhythm may promote tumorigenesis and tumor progression. The mechanisms discussed in this review demonstrate how aberrant RORβ-induced circadian rhythm may become a new direction for future studies on tumorigenesis and strategy design for cancer prevention.

Background: Retinopathy of prematurity is a serious potentially blinding disease of pre-term infants. There is extensive vascular remodeling and tissue stress, but data concerning alterations in retinal neurons and glia, and long-term functional sequelae are still incomplete., Methods: ROP was induced using the oxygen-induced retinopathy (OIR) mouse model. Postnatal day 7 (P7) 129SVE mice were exposed to hyperoxia (75 ± 0.5 % oxygen) for 5 days, and then returned to normoxia to induce OIR. Exposed animals were euthanized at 5 (P17-OIR) and 14 days (P26-OIR) after return to normal air, together with corresponding age-matched control mice (P17-C and P26-C respectively) raised only in room air. Their retinas were examined by immunohistochemistry using a battery of antibodies against key glial and neuronal proteins. A further group of OIR mice and controls were examined at 10 weeks of age for their ability to re-entrain to changing 12 h light/12 h dark cycles, assayed by wheel-running actimetry. In this protocol, animals were subjected to three successive conditions of 300 lux, 15 lux and 1 lux ambient light intensity coupled with 6 hours of jetlag. Animals were euthanized at 4 months of age and used in immunoblotting for rhodopsin., Results: Compared to P17-C, immunohistochemical staining of P17-OIR sections showed up-regulation of stress-related and glutamate-regulatory proteins in astrocytes and Müller glial cells. In contrast, glial phenotypic expression in P26-OIR retinas largely resembled that in P26-C. There was no loss in total retinal ganglion cells (RGC) at either P17-OIR or P26-OIR compared to corresponding controls, whereas intrinsically photosensitive RGC showed significant decreases, with 375 ± 13/field in P26-OIR compared to 443 ± 30/field in P26-C (p < 0.05). Wheel actimetry performed on control and OIR-treated mice at 4 months demonstrated that animals raised in hyperoxic conditions had impaired photoentrainment at low illuminance of 1 lux, as well as significantly reduced levels of rhodopsin compared to age-matched controls., Conclusions: OIR leads to transient up-regulation of retinal glial proteins involved in metabolism, and partial degeneration of intrinsically photosensitive RGC and rod photoreceptors. OIR affects circadian photo-entrainment at low illuminance values, possibly by affecting the rod pathway and/or intrinsically photosensitive RGC input to the circadian clock. This study hence shows that retinopathy of prematurity affects light-regulated circadian behavior in an animal model, and may induce similar problems in humans.

This review consolidates research employing human correlational and experimental work across brain and body with experimental animal models to provide a more complete representation of how circadian rhythms influence almost all aspects of life. In doing so, we will cover the morphological and biochemical pathways responsible for rhythm generation as well as interactions between these systems and others (e.g., stress, feeding, reproduction). The effects of circadian disruption on the health of humans, including time of day effects, cognitive sequelae, dementia, Alzheimer's disease, diet, obesity, food preferences, mood disorders, and cancer will also be discussed. Subsequently, experimental support for these largely correlational human studies conducted in non-human animal models will be described., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Ventilator-induced lung injury (VILI), the most serious complication of mechanical ventilation therapy, is an excessive inflammatory response in lung tissue characterized by infiltration of inflammatory cells and overproduction of inflammatory mediators. The pathogenesis of VILI is very complex. It is becoming increasingly evident that disruption of circadian rhythm affects the immune response. Whether the pathogenesis of VILI is associated with circadian rhythm disruption has not been reported. In this study, we establish VILI model in SD rat by performing an endotracheal intubation and placing the rat on a mechanical ventilator (tidal volume of 40 ml/kg or 10 ml/kg without positive end-expiratory pressure). To examine the effect of VILI on clock gene expression, real-time quantitative PCR was performed to measure bmal1, clock, per2 and Rev-erbα mRNA expression. We found that Rev-erbα mRNA was significantly decreased in high tide volume mechanical ventilation group compared with spontaneous group, the same as REV-ERBα protein product which was tested by Western blot approach. Stimulation of REV-ERBα activity by SR9009 greatly diminished VILI-induced lung edema, inflammatory cell infiltration and the production of the pro-inflammatory cytokine TNF-α. Collectively, our findings are the first to show that REV-ERBα plays an important role in VILI and inflammation, and circadian rhythm disorder in inflammation response may be a novel pathogenesis of VILI., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Depression is strongly associated with the circadian system, disruption of the circadian system leads to increased propensity to disease and to mood disorders including depression. The present study explored in rats the effects of circadian disruption by constant light on behavioral and hormonal indicators of a depressive-like condition and on the biological clock, the suprachiasmatic nucleus (SCN). Exposure to constant light for 8 weeks resulted in loss of circadian patterns of spontaneous general activity, melatonin and corticosterone. Moreover these rats exhibited anhedonia in a sucrose consumption test, and increased grooming in the open-field test, which reflects an anxiety-like condition. In the SCN decreased cellular activation was observed by c-Fos immunohistochemistry. In rats exposed to constant darkness, circadian behavioral and hormonal patterns remained conserved, however mild depressive-like indicators were observed in the anhedonia test and mild anxiety-like behaviors were observed in the open field test. Data indicate that chronic conditions of LL or DD are both disruptive for the activity of the SCN leading to depression- and anxiety-like behavior. Present results point out the main role played by the biological clock and the risk of altered photoperiods on affective behavior., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Melanoma-associated antigen-D1 (MAGE-D1) was discovered in bone marrow stromal cells. MAGE-D1 is detected in progenitor cells in the neuroepithelia and subventricular regions as well as in the postmitotic neuronal cells in the entire brain in the developing embryo and is also detected in most adult tissues, predominantly in the brain. Herein, we provide an overview of the roles of MAGE-D1 in the central nervous system. MAGE-D1 participates in neurotrophin-induced neuronal differentiation and survival by modulating Trk-dependent phosphorylation. MAGE-D1 regulates Dlx-dependent migration-related transcription by binding to necdin or praja-1. MAGE-D1 regulates a number of apoptotic pathways, each caused by distinct input signals, such as bone morphogenetic protein, p75 neurotrophin receptor, and uncoordinated gene-5 homologue. MAGE-D1 knockout mice show depressive behavior and impairments of circadian rhythm caused by decreased ubiquitylation of serotonin transporter and regulated transcription of RORα, respectively. The gene for necdin, a MAGE-D1-binding protein, has been described as responsible for Prader-Willi syndrome. In conclusion, MAGE-D1 plays important roles in the central nervous system in both developmental and adult stages and would be an invaluable target in the development of novel diagnostic and therapeutic agents for depression and Prader-Willi syndrome and also for providing new insights into the pathogenesis/pathophysiology of these diseases.

Cognitive impairments are observed when learned associations are being acquired or retrieved during a period of circadian disruption. However, the extent of the functional impacts on previously acquired associations following circadian rhythm re-entrainment is unknown. The impacts of repeated photoperiod shifts on learning and memory in male and female rats were examined. For these experiments, rats were trained on a spatial version of the Morris water task (MWT) and a visual discrimination task designed for the 8-arm radial maze. Following asymptotic performance on these tasks, rats experienced a repeating photoperiod shift procedure and were then re-entrained. Following circadian re-entrainment, retention of pre-photoperiod-shift-acquired associations was tested. In addition, an extra-dimensional set shift was performed using the 8-arm radial maze. Impaired retention of the MWT platform location was observed in photoperiod-shifted subjects relative to subjects with stable, unmanipulated photoperiods. Repeated photoperiod shifts negatively impacted retention in males and females compared with subjects with stable photoperiods. Retention and the ability to detect extra-dimensional shifts on the visual discrimination task were also impaired, though not consistently by sex or photoperiod condition. Running wheel availability was also included in the analyses to determine whether exercise influenced the effects of photoperiod shifting. The absence of a running wheel produced significant declines in memory retention on both MWT and the visual discrimination task, but only for male rats. The observed impairments indicate that multiple neural systems supporting different learning and memory functions are susceptible to circadian disruption, even if the association is acquired prior to rhythm fragmentation and tested following rhythm re-entrainment.

The expression of passive avoidance (PA) learning in rats displays a daily or circadian rhythm in that optimal performance is displayed when the time of testing matches the time of training. Lesions of the suprachiasmatic nucleus (SCN) were later shown to abolish this rhythm. Using golden hamsters, we have since demonstrated similar rhythms of performance in a conditioned place avoidance (CPA) task but unlike the PA results in rats, the rhythmic expression of CPA was maintained in arrhythmic hamsters with lesions of the SCN. We determined whether PA performance in hamsters is dependent on the SCN (as in the rat) or independent (as in the hamster CPA). Performance on the PA task was rhythmic in intact control animals with optimal performance occurring when training and testing time matched and significantly diminished at both 6h before and 6h after training time. SCN-lesions, verified by the loss of behavioral circadian rhythms, had no effect on the rhythmic expression. Therefore, time of day modulation of PA performance in the hamster does not depend on the SCN circadian clock., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Exposure to shiftwork has been associated with multiple health disorders and cognitive impairments in humans. We tested if we could replicate metabolic and cognitive consequences of shiftwork, as reported in humans, in a rat model comparable to 5 wks of non-rotating night shifts. The following hypotheses were addressed: (i) shiftwork enhances body-weight gain, which would indicate metabolic effects; and (ii) shiftwork negatively affects learning of a simple goal-directed behavior, i.e., the association of lever pressing with food reward (instrumental learning), which would indicate cognitive effects. We used a novel method of forced locomotion to model work during the animals' normal resting period. We first show that Wistar rats, indeed, are active throughout a shiftwork protocol. In contrast with previous findings, the shiftwork protocol attenuated the normal weight gain to 76 ± 8 g in 5 wks as compared to 123 ± 15 g in the control group. The discrepancy with previous work may be explained by the concurrent observation that with our shiftwork protocol rats did not adjust their between-work circadian activity pattern. They maintained a normal level of activity during the "off-work" periods. In the control experiment, rats were kept active during the dark period, normally dominated by activity. This demonstrated that forced activity, per se, did not affect body-weight gain (mean ± SEM: 85 ± 11 g over 5 wks as compared to 84 ± 11 g in the control group). Rats were trained on an instrumental learning paradigm during the fifth week of the protocol. All groups showed equivalent increases in lever pressing from the first (3.8 ± .7) to the sixth (21.3 ± 2.4) session, and needed a similar amount of sessions (5.1 ± .3) to reach a learning criterion (≥ 27 out of 30 lever presses). These results suggest that while on prolonged non-rotating shiftwork, not fully reversing the circadian rhythm might actually be beneficial to prevent body-weight gain and cognitive impairments.

Our earlier studies described a disruption of heart rate and blood pressure diurnal rhythms in mice with experimental autoimmune encephalomyelitis (EAE). The present study investigates whether these observations could be extended to additional clock-regulated rhythms in mice with EAE. Analysis of clock gene expression in the liver of EAE mice demonstrated significant variability associated with Per2 rhythmic expression. Corticosterone and leptin hormone rhythms were also altered in EAE mice. The results presented here indicate that disturbances in clock-regulated rhythms are associated with EAE and present a suitable model for investigating the relationship between circadian disruption and autoimmune inflammatory disease., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The purpose of this experiment was to clarify the effects of dietary protein levels on the gonadal development and sex hormones in male rats kept under constant darkness as a model of disturbed daily rhythm. Four-week-old male rats (Fischer 344 strain) were kept under constant darkness or normal lighting (12-h light/dark cycle). Two kinds of experimental diet were prepared, one with low dietary protein levels (9% casein) and one with normal levels (18% casein). Harper mineral mixture and Panvitan were used as mineral and vitamin sources, respectively. After 4 weeks, gonadal weight, serum testosterone, and other hormone contents were evaluated. The gonadal weight in the constant darkness groups (D-groups) was lower than that in the normal lighting groups (N-groups). Although the low-protein diet in the D-groups significantly reduced gonadal weight, the normal-protein diet mitigated the reduction of gonadal weight in rats kept under constant darkness. Serum testosterone and androstenedione concentrations were lower in D-group rats fed the low-protein diet. There were no effects of lighting condition or protein levels on serum luteinizing hormone (LH), follicle- stimulating hormone (FSH), or progesterone concentrations. These results indicate that the suppression of gonadal development in D-group rats fed the low-protein diet was caused by low testosterone, which we attribute to the inhibition of synthesized androstenedione, a precursor of testosterone. The present study showed that constant darkness and the low- protein diet inhibited the synthetic pathway from progesterone to androstenedione.

In mammals, the suprachiasmatic nuclei (SCNs) function as a circadian pacemaker that drives 24-h rhythms in physiology and behavior. The SCN is a multicellular clock in which the constituent oscillators show dynamics in their functional organization and phase coherence. Evidence has emerged that plasticity in phase synchrony among SCN neurons determines (i) the amplitude of the rhythm, (ii) the response to continuous light, (iii) the capacity to respond to seasonal changes, and (iv) the phase-resetting capacity. A decrease in circadian amplitude and phase-resetting capacity is characteristic during aging and can be a result of disease processes. Whether the decrease in amplitude is caused by a loss of synchronization or by a loss of single-cell rhythmicity remains to be determined and is important for the development of strategies to ameliorate circadian disorders., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Many affective disorders show episode cycling and the classic symptoms of these disorders show rhythmicity, such as diurnal variation in mood. There are several plausible stress-vulnerability models that suggest links between these observed phenomena and the circadian system. For example, an individual with increased sensitivity to social rhythm disruption may be more at risk of circadian rhythm (CR) dysregulation. Furthermore, there are hypothesized neurobiological mechanisms that may explain how CR dysregulation might lead to sleep, activation, and mood changes in unipolar and bipolar disorders. There are gaps in our understanding, but this paper highlights that clinical measures of sleep and activation are increasingly useful for monitoring the onset and course of affective disorders. Also, evidence suggests that CR disruptions may represent core elements not simply epiphenomena of affective disorders., (Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.)

The human pineal gland is a neuroendocrine transducer that forms an integral part of the brain. Through the nocturnally elevated synthesis and release of the neurohormone melatonin, the pineal gland encodes and disseminates information on circadian time, thus coupling the outside world to the biochemical and physiological internal demands of the body. Approaches to better understand molecular details behind the rhythmic signalling in the human pineal gland are limited but implicitly warranted, as human chronobiological dysfunctions are often associated with alterations in melatonin synthesis. Current knowledge on melatonin synthesis in the human pineal gland is based on minimally invasive analyses, and by the comparison of signalling events between different vertebrate species, with emphasis put on data acquired in sheep and other primates. Together with investigations using autoptic pineal tissue, a remnant silhouette of premortem dynamics within the hormone's biosynthesis pathway can be constructed. The detected biochemical scenario behind the generation of dynamics in melatonin synthesis positions the human pineal gland surprisingly isolated. In this neuroendocrine brain structure, protein-protein interactions and nucleo-cytoplasmic protein shuttling indicate furthermore a novel twist in the molecular dynamics in the cells of this neuroendocrine brain structure. These findings have to be seen in the light that an impaired melatonin synthesis is observed in elderly and/or demented patients, in individuals affected by Alzheimer's disease, Smith-Magenis syndrome, autism spectrum disorder and sleep phase disorders. Already, recent advances in understanding signalling dynamics in the human pineal gland have significantly helped to counteract chronobiological dysfunctions through a proper restoration of the nocturnal melatonin surge., (© 2011 John Wiley & Sons A/S.)

Circadian rhythms, generated in the suprachiasmatic nucleus (SCN), are synchronized to the ambient light/dark (LD) cycle. Long-term disruptions in circadian rhythms are associated with many health problems. However, the underlying mechanisms for such pathologies are not well understood. In the present study, we utilized a chronic jet lag paradigm consisting of weekly 6 h phase shifts in the LD cycle to investigate the circadian responses in behavior and in the functioning of the SCN following long-term circadian perturbation, and to explore the duration and direction dependent changes of the SCN using rats subjected to weekly phase advances or delays. Wheel-running activity was monitored over four weekly phase advances. The nocturnal activity pattern was re-established by the end of each shift, and the rate for recovering the nocturnality appeared to accelerate following multiple shifts. SCN function was assessed by the expressions of the protein product of clock gene PER1 and of two putative SCN output signals, arginine vasopressin (AVP) and prokineticin2 (Pk2). At the end of the 4th weekly advance, the amplitude of the PER1 rhythm in the SCN decreased, and this reduction was more prominent in the dorsomedial SCN than in the ventrolateral SCN. The levels of AVP and Pk2 expression were also attenuated in the SCN and in targets of its efferent projections. Comparing rats subjected to four or eight shifts of either delay or advance, the results revealed that the responses of the SCN depended on both duration and direction of the shifts, such that the level of PER1 expression further decreased at the end of the 8th compared to the 4th phase advance, but did not change significantly following phase delays. Taken together, the results suggest that rhythm perturbation could compromise the time-keeping function of the SCN, which could contribute to the associated health issues., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Circadian disturbances, including a fragmented sleep-wake pattern and sundowning, are commonly reported early in the progression of Alzheimer's disease (AD). These changes are distinctly different from those observed in non-pathological aging. Transgenic models of AD are a promising tool in understanding the underlying mechanisms and cause of disease. A novel triple-transgenic model of AD, 3xTg-AD, is the only model to exhibit both Abeta and tau pathology, and mimic human AD. The present study characterized changes pertaining to circadian rhythmicity that occur prior to and post-AD pathology. Both male and female 3xTg-AD mice demonstrated alterations to their circadian pacemaker with decreased nocturnal behavior when compared to controls. Specifically, males showed greater locomotor activity during the day and shorter freerunning periods prior to the onset of AD-pathology, and females had a decrease in activity levels during their typical active phase. Both sexes did not differ in terms of their freerunning periods or photic phase shifting ability. A decrease in vasoactive intestinal polypeptide-containing and vasopressin-containing cells was observed in the suprachiasmatic nucleus of 3xTg-AD mice relative to controls. This study demonstrates that abnormalities in circadian rhythmicity in 3xTg-AD mice precede expected AD pathology. This suggests that human studies may wish to determine if similar circadian dysfunction is predictive of early-onset AD., (Copyright 2010 Elsevier B.V. All rights reserved.)

Continuous disruption of circadian rhythms, as seen in human shift workers, has been associated with the development of a number of adverse mental and physiological conditions. However, scientific evidence linking circadian disruption to overall health, particularly in animal models, is not well documented. In this study, we have demonstrated that exposing C57BL/6J mice to 12-h phase shifts every 5 days for 3 mo had no effect on body weight or intestinal physiology. However, when animals were further challenged with dextran sodium sulfate to induce colitis, chronic shifting of the light-dark cycle led to a dramatic increase in the progression of the colitis as indicated by reduced body weight, abnormal intestinal histopathology, and an exacerbated inflammatory response. These data indicate that circadian disruption is an important predisposing factor that may provoke the onset or worsening of various disease states such as inflammatory disorders. This study provides further evidence for continued investigations using animal models of circadian disruption to examine the consequences of circadian disruption on health when organisms are faced with a "challenging" environment.

The aim of this study was to determine circadian rhythm abnormalities in patients with acute cerebral infarction and their relationship with prognosis in the chronic phase. The subjects were 50 patients who were admitted within 48 h of onset. Rectal temperature and wrist motor activity were recorded during the acute phase. Time-series data were assayed by MEM spectral analysis. Functional prognosis (degree of handicap) was assessed at 3 months after stroke onset by the modified Rankin Scale. Ambulatory patients tended to exhibit circadian rhythm in rectal temperature and/or wrist activity rhythms, whereas non-ambulatory patients did not (P < 0.001) in the acute phase of ischemic stroke. Our findings suggest the biological rhythms of rectal temperature and wrist activity during the acute stroke phase might be a possible prognostic indicator of their chronic phase.

Many aspects of human physiology and behavior are dominated by 24-hour circadian rhythms that have a major impact on our health and well-being, including the sleep-wake cycle, alertness and performance patterns, and many daily hormone profiles. These rhythms are spontaneously generated by an internal "pacemaker" in the hypothalamus, and daily light exposure to the eyes is required to keep these circadian rhythms synchronized both internally and with the external environment. Sighted individuals take this daily synchronization process for granted, although they experience some of the consequences of circadian desynchrony when "jetlagged" or working night shifts. Most blind people with no perception of light, however, experience continual circadian desynchrony through a failure of light information to reach the hypothalamic circadian clock, resulting in cyclical episodes of poor sleep and daytime dysfunction. Daily melatonin administration, which provides a replacement synchronizing daily "time cue, " is a promising therapeutic strategy, although optimal treatment dose and timing remain to be determined.

Objective: To assess whether circadian desynchronization leads to metabolic alterations capable of promoting dietary obesity and/or impairing glucose tolerance., Design: Rats fed either with chow pellets (i.e., low-fat diet with 4% mass of fat) or high-fat diet (34% mass of fat). Half of each diet group was exposed to a fixed light-dark cycle or to a 10-h weekly shift in the light-dark cycle from Thursday to Sunday (20 shifts). To enforce the shifted animals to be active at unusual times of the day, food was available only during the daily dark period for all groups., Results: Shifting the light-dark cycle on a weekly basis was efficient to induce circadian desynchronization, as evidenced by strong disturbances in the daily expression of locomotor activity. Shifted rats fed with a nocturnal low-fat diet had lower plasma insulin and similar blood glucose compared to rats fed with the same diet under a fixed light-dark cycle. Nocturnal high-fat feeding led to an abdominal fat overload associated with increased plasma leptin and basal glucose. These metabolic changes were not significantly modified by circadian desynchronization., Conclusion: Chronic desynchronization with low-fat diet impaired insulin regulation. Metabolic changes induced by the high-fat diet were not aggravated by chronic desynchronization.

The aim of this research was to study the morpho-functional organization of liver and some organs of immune system in animals exposed to continous twenty-four-hour illumination (CI) for 14 days. Using the methods of light and electron microscopy and morphometric analysis of histological preparations, liver and regional lymph nodes (hepatic in rats and iliac in mice) were studied. It was found that CI resulted in a state of dyschronosis, which was structurally manifested by the changes of diurnal variations of morphometric parameters of liver and its draining lymph nodes, disturbances of hemo- and lymphocirculation, destruction of cellular membranes. Response of central and peripheral organs of immune system to CI included the changes of diurnal variations of blast forms and mature lymphocytes, that was also indicative of dyschronosis development.

Dysfunction of the limbic structures of the temporal lobe of the brain (predominantly the hippocampus), chiasma, hypothalamus, and epiphysis is accompanied by impairment of internal estimation of time periods. In patients with lesions of the temporal lobes and base of the skull, changes in measures of autochronometry were uniform, were the most marked, and were not directly associated with locomotor parameters or with changes in the general functional state of the CNS. In patients with spinal cord or vertebral lesions, including tumors, and in those with extensive lesions of the frontoparietal areas of the neocortex, there were no profound defects in endogenous time estimation, regardless of impairments of the functional state of the synaptic and motor system. These data identify the cerebral oscillatory formations--the hippocampus, the hypothalamic area, and the epiphysis--as structures directly involved in the physiological mechanisms controlling autochronometry.

Heterozygous APP23 mice, expressing human amyloid-precursor protein with the Swedish double mutation and control littermates, were subjected to behavioral and neuromotor tasks at the age of 6-8 weeks, 3 and 6 months. A hidden-platform Morris-type water maze showed an age-dependent decline of spatial memory capacities in the APP23 model. From the age of 3 months onwards, the APP23 mice displayed major learning and memory deficits as demonstrated by severely impaired learning curves during acquisition and impaired probe trial performance. In addition to the cognitive deficit, APP23 mice displayed disturbed activity patterns. Overnight cage-activity recording showed hyperactivity in the transgenics for the three age groups tested. However, a short 2-h recording during dusk phase demonstrated lower activity levels in 6-month-old APP23 mice as compared to controls. Moreover, at this age, APP23 mice differed from control littermates in exploration and activity levels in the open-field paradigm. These findings are reminiscent of disturbances in circadian rhythms and activity observed in Alzheimer patients. Determination of plaque-associated human amyloid-beta 1-42 peptides in brain revealed a fivefold increase in heterozygous APP23 mice at 6 months as compared to younger transgenics. This increase coincided with the first appearance of plaques in hippocampus and neocortex. Spatial memory deficits preceded plaque formation and increase in plaque-associated amyloid-beta 1-42 peptides, but probe trial performance did correlate negatively with soluble amyloid-beta brain concentration in 3-month-old APP23 mutants. Detectable plaque formation is not the (only) causal factor contributing to memory defects in the APP23 model.

Parkinson's disease (PD) patients with autonomic failure show no nocturnal decrease in blood pressure (BP). At present, it is not clear if this symptom is attributable to the disturbance of the dopaminergic (DA) system that is responsible for PD. In the present study, we determined that the mesolimbic DA system is involved in diurnal profiles of the mean BP (MBP) by destroying the A10 DA system in rats with 6-hydroxydopamine. In control rats, a clear dip in the MBP and heart rate (HR) occurs during the light, that is, resting period, analogous to the nocturnal dip in normal humans. This normal daytime decrease in MBP and HR was disturbed by inducing a lesion of the ventral tegmental area (VTA) DA neurons, although the rhythms of wake-sleep duration and behavioral activity remained relatively intact. On the basis of this evidence, the absence of a nocturnal dip in BP in PD patients is attributed to impairment of the mesolimbic DA system.

The present study examined the effects of high-altitude exposure on the pineal gland, the main source of production of melatonin. It was surmised that hypoxia experienced at high altitude, caused by decreased oxygen tension in the ambient air, might lead to some structural alterations in the pineal gland and, hence, affect its melatonin production. Adult Wistar rats were exposed to an altitude of 8,000 m for 2 hr in an altitude chamber and then sacrificed at various time intervals after the exposure. Normal rats kept at ground level were used as controls. Blood samples were collected at various time intervals for measurement of plasma melatonin level, and the pineal glands from both groups were processed for electron microscopy and immunohistochemistry. The plasma melatonin level showed a steady increase following altitude exposure peaking at 7 days and returned to control levels thereafter. Between 1 and 4 days after altitude exposure, the mitochondrial number and lipid droplets in the pinealocytes appeared to be reduced compared with those in control rats. At 7 days, however, the mitochondrial numbers and lipid droplets were noticeably increased. At the same time interval, the expression of complement type 3 receptors and major histocompatibility class II antigens as detected with the antibodies OX-42 and OX-6, respectively, in macrophages/microglia was up-regulated compared with that in the control rats and those killed at earlier times. This was attributed to the increased serum melatonin after the altitude exposure. By 14 and 21 days, the ultrastructure of pinealocytes and immunoreactivity of macrophages/microglia were comparable with those in the control rats. We conclude from this study that an altitude exposure in rats leads to an increase in melatonin production, which returned to control levels with passage of time., (Copyright 2002 Wiley-Liss, Inc.)

Rationale: Epileptic seizures may alter neuroendocrinological cycles. Light pulses induce phase shifts in circadian rhythms. Using hippocampal-kindled rats to ensure maximal clinical expression, we determined if seizures likewise induce phase shifts., Methods: We monitored the circadian rhythm of temperature (CRT) with intraperitoneal radiotelemetry in rats (n=21) isolated from time cues and light for 3-week trials. Seizures were triggered with hippocampal electrical stimulation at different circadian phases. Optimized, least-error phase shifts were calculated from preictal and postictal CRTs. Induced seizures were referenced to CRT (t(max)=00:00, 24-h circadian cycle)., Results: Phase shifts (individual responses=57) differed across the circadian cycle. Rather than forming a clear phase-response curve, phase shifts were especially variable between 00:00 and 06:00 h., Conclusions: This study demonstrates that electrically-induced seizures induce advances and delays in CRT in a phase-dependent fashion but in a pattern different from typical light-induced phase shifts. Disorders of circadian regulation may contribute to some of the altered endogenous cycles associated with epilepsy.

The effects of protracted cocaine administration (15 mg/kg i.p., twice a day for 9 days) on the circadian pattern of feeding behavior was studied in individually housed male Sprague-Dawley rats, maintained under a 12:12 light:dark cycle. Water and food were available ad libitum and food intake was measured twice a day before, during and after withdrawal of cocaine (or saline) treatment. Neither total 24-h food intake, nor body mass at the end of the experiment, was significantly different between cocaine-treated and control animals. However, cocaine administration affected the temporal distribution of food consumption. During the dark (activity) phase, rats receiving cocaine injections consumed significantly less food than control animals, and this effect persisted for up to 3 days of cocaine withdrawal. During the light (rest) phase, cocaine administration promoted food consumption and a significantly higher food intake was also observed during the first five cocaine withdrawal days. Continuous monitoring of locomotor activity did not reveal significant changes in the circadian pattern of activity between the two experimental groups during different treatment periods, except for an acute increase in locomotion within an hour after daytime cocaine injection. The results of this study demonstrate that sub-chronic cocaine administration alters the circadian pattern of rats' feeding behavior.