Publications by authors named "Alena Sumová"

60 Publications

Targeted modification of the Per2 clock gene alters circadian function in mPer2luciferase (mPer2Luc) mice.

PLoS Comput Biol 2021 May 28;17(5):e1008987. Epub 2021 May 28.

Laboratory of Biological Rhythms, Institute of Physiology, the Czech Academy of Sciences, Prague, Czech Republic.

Modification of the Per2 clock gene in mPer2Luc reporter mice significantly alters circadian function. Behavioral period in constant dark is lengthened, and dissociates into two distinct components in constant light. Rhythms exhibit increased bimodality, enhanced phase resetting to light pulses, and altered entrainment to scheduled feeding. Mechanistic mathematical modelling predicts that enhanced protein interactions with the modified mPER2 C-terminus, combined with differential clock regulation among SCN subregions, can account for effects on circadian behavior via increased Per2 transcript and protein stability. PER2::LUC produces greater suppression of CLOCK:BMAL1 E-box activity than PER2. mPer2Luc carries a 72 bp deletion in exon 23 of Per2, and retains a neomycin resistance cassette that affects rhythm amplitude but not period. The results show that mPer2Luc acts as a circadian clock mutation illustrating a need for detailed assessment of potential impacts of c-terminal tags in genetically modified animal models.
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http://dx.doi.org/10.1371/journal.pcbi.1008987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191895PMC
May 2021

Hormonal fine-tuning of clock in decidual region of mouse placenta by dopamine, melatonin, insulin, leptin and ghrelin.

Placenta 2021 May 27;108:55-63. Epub 2021 Mar 27.

Laboratory of Biological Rhythms, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic. Electronic address:

Introduction: The maternal part of the rodent placenta harbors a circadian clock which robustly responds to glucocorticoids, however, its sensitivity to other hormones has not been elucidated. In this study, we tested five selected hormones (dopamine, melatonin, insulin, leptin and ghrelin) for their effectiveness to affect the clock in decidual region of mouse placenta in vitro.

Methods: We administered the hormones or corresponding vehicles at various time points over 24 h to organotypic placental explants of mPer2 mice containing the decidua basalis (DB) region and monitored their effects on amplitude, period, median expression level (mesor) and phase of PER2-driven bioluminescence rhythms.

Results: Dopamine significantly increased the amplitude, robustly dampened the mesor, and during a narrow time interval (corresponding to daytime) induced phase delays of the rhythms. In contrast, melatonin had no effect on amplitude, but induced phase advances of the rhythms at the opposite time window than dopamine (corresponding to nighttime). Leptin and ghrelin, but not insulin, slightly increased amplitudes and moderately modulated phase delays of the clock, suggesting that the DB clock, in contrast to other peripheral clocks, is rather resilient to abrupt changes in levels of feeding- and metabolism-related hormones.

Discussion: The results demonstrate for the first time that dopamine and melatonin exhibit delicate yet specific effects on parameters of the DB clock and may thus potentially contribute to fine-tuning of its phase under in vivo conditions. It also implies that dysregulation of their levels, which accompany various pathologies, may account for malfunction of the clock in DB.
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http://dx.doi.org/10.1016/j.placenta.2021.03.015DOI Listing
May 2021

Challenging the Integrity of Rhythmic Maternal Signals Revealed Gene-Specific Responses in the Fetal Suprachiasmatic Nuclei.

Front Neurosci 2020 7;14:613531. Epub 2021 Jan 7.

Laboratory of Biological Rhythms, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia.

During fetal stage, maternal circadian system sets the phase of the developing clock in the suprachiasmatic nuclei (SCN) via complex pathways. We addressed the issue of how impaired maternal signaling due to a disturbed environmental light/dark (LD) cycle affects the fetal SCN. We exposed pregnant Wistar rats to two different challenges - a 6-h phase shift in the LD cycle on gestational day 14, or exposure to constant light (LL) throughout pregnancy - and detected the impact on gene expression profiles in 19-day-old fetuses. The LD phase shift, which changed the maternal SCN into a transient state, caused robust downregulation of expression profiles of clock genes (, , and ), clock-controlled () genes, as well as genes involved in sensing various signals, such as and . Removal of the rhythmic maternal signals via exposure of pregnant rats to LL abolished the rhythms in expression of and in the fetal SCN. We identified as the gene primarily responsible for sensing rhythmic maternal signals because its expression profile tracked the shifted or arrhythmic maternal SCN clock. Pathways related to the maternal rhythmic behavioral state were likely not involved in driving the expression rhythm. Instead, introduction of a behavioral rhythm to LL-exposed mothers via restricted feeding regime strengthened rhythm in expression in the fetal SCN. Our results revealed for the first time that the fetal SCN is highly sensitive in a gene-specific manner to various changes in maternal signaling due to disturbances of environmental cycles related to the modern lifestyle in humans.
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http://dx.doi.org/10.3389/fnins.2020.613531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817817PMC
January 2021

Modulation of single cell circadian response to NMDA by diacylglycerol lipase inhibition reveals a role of endocannabinoids in light entrainment of the suprachiasmatic nucleus.

Neuropharmacology 2021 03 12;185:108455. Epub 2021 Jan 12.

The Czech Academy of Sciences, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, Prague 4, 14220, Czech Republic.

Suprachiasmatic nucleus (SCN) of the hypothalamus is the master clock that drives circadian rhythms in physiology and behavior and adjusts their timing to external cues. Neurotransmitter glutamate and glutamatergic receptors sensitive to N-methyl-d-aspartate (NMDA) play a dual role in the SCN by coupling astrocytic and neuronal single cell oscillators and by resetting their phase in response to light. Recent reports suggested that signaling by endogenous cannabinoids (ECs) participates in both of these functions. We have previously shown that ECs, such as 2-arachidonoylglycerol (2-AG), act via CB1 receptors to affect the SCN response to light-mimicking NMDA stimulus in a time-dependent manner. We hypothesized that this ability is linked to the circadian regulation of EC signaling. We demonstrate that circadian clock in the rat SCN regulates expression of 2-AG transport, synthesis and degradation enzymes as well as its receptors. Inhibition of the major 2-AG synthesis enzyme, diacylglycerol lipase, enhanced the phase delay and lowered the amplitude of explanted SCN rhythm in response to NMDAR activation. Using microscopic PER2 bioluminescence imaging, we visualized how individual single cell oscillators in different parts of the SCN respond to the DAGL inhibition/NMDAR activation and shape response of the whole pacemaker. Additionally, we present strong evidence that the zero amplitude behavior of the SCN in response to single NMDA stimulus in the middle of subjective night is the result of a loss of rhythm in individual SCN cells. The paper provides new insights into the modulatory role of endocannabinoid signaling during the light entrainment of the SCN.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108455DOI Listing
March 2021

Glucocorticoids reset circadian clock in choroid plexus via period genes.

J Endocrinol 2021 Feb;248(2):155-166

Laboratory of Biological Rhythms, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.

The epithelial cells of choroid plexus (CP) in brain ventricles produce cerebrospinal fluid and act as the blood-cerebrospinal fluid barrier. In this study, we confirmed that CP in the 4th ventricle is composed of cellular oscillators that all harbor glucocorticoid receptors and are mutually synchronized to produce a robust clock gene expression rhythm detectable at the tissue level in vivo and in vitro. Animals lacking glucocorticoids (GCs) due to surgical removal of adrenal glands had Per1, Per2, Nr1d1 and Bmal1 clock gene rhythmicity in their CP significantly dampened, whereas subjecting them to daily bouts of synthetic GC analog, dexamethasone (DEX), reinforced those rhythms. We verified these in vivo effects using an in vitro model of organotypic CP explants; depending on the time of its application, DEX significantly increased the amplitude and efficiently reset the phase of the CP clock. The results are the first description of a PRC for a non-neuronal clock in the brain, demonstrating that CP clock shares some properties with the non-neuronal clocks elsewhere in the body. Finally, we found that DEX exhibited multiple synergic effects on the CP clock, including acute activation of Per1 expression and change of PER2 protein turnover rate. The DEX-induced shifts of the CP clock were partially mediated via PKA-ERK1/2 pathway. The results provide the first evidence that the GC rhythm strengthens and entrains the clock in the CP helping thus fine-tune the brain environment according to time of day.
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http://dx.doi.org/10.1530/JOE-20-0526DOI Listing
February 2021

Chronotype assessment via a large scale socio-demographic survey favours yearlong Standard time over Daylight Saving Time in central Europe.

Sci Rep 2020 Jan 29;10(1):1419. Epub 2020 Jan 29.

Institute of Physiology, the Czech Academy of Sciences, Prague, Czech Republic.

Abandoning daylight saving time in Europe raises the topical issue of proper setting of yearlong social time, which needs mapping of various socio-demographic factors, including chronotype, in specific geographic regions. This study represents the first detailed large scale chronotyping in the Czech Republic based on data collected in the complex panel socio-demographic survey in households (total 8760 respondents) and the socio-physiological survey, in which chronotyped participants also provided blood samples (n = 1107). Chronotype assessment based on sleep phase (MCTQ questions and/or time-use diary) correlated with a self-assessed interval of best alertness. The mean chronotype of the Czech population defined as mid sleep phase (MSFsc) was 3.13 ± 0.02 h. Chronotype exhibited significant east-to-westward, north-to-southward, and settlement size-dependent gradients and was associated with age, sex, partnership, and time spent outdoors as previously demonstrated. Moreover, for subjects younger than 40 years, childcare was highly associated with earlier chronotype, while dog care was associated with later chronotype. Body mass index correlated with later chronotype in women whose extreme chronotype was also associated with lower plasma levels of protective HDL cholesterol. Based on the chronotype prevalence the results favour yearlong Standard Time as the best choice for this geographic region.
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http://dx.doi.org/10.1038/s41598-020-58413-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989656PMC
January 2020

Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion.

Autism Res 2020 03 21;13(3):397-409. Epub 2020 Jan 21.

Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida.

Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, lack of speech, and ataxia. The gene responsible for AS was identified as Ube3a and it encodes for E6AP, an E3 ubiquitin ligase. Currently, there is very little known about E6AP's mechanism of action in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. Elucidating the mechanistic action of E6AP would enhance our understanding of AS and drive current research into new avenues that could lead to novel therapeutic approaches that target E6AP's various functions. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat phenotypically mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. Autism Res 2020, 13: 397-409. © 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, difficulty speaking, and ataxia. The gene responsible for AS was identified as UBE3A, yet very little is known about its function in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS.
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http://dx.doi.org/10.1002/aur.2267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787396PMC
March 2020

Circadian profiling reveals distinct regulation of endocannabinoid system in the rat plasma, liver and adrenal glands by light-dark and feeding cycles.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 12 29;1864(12):158533. Epub 2019 Oct 29.

Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, Prague 4 14220, Czech Republic.

Circadian clocks coordinate physiological and behavioral rhythms that allow the organism to anticipate and adapt to daily changes in environment. The clock-driven cellular oscillations are highly tissue specific to efficiently fine-tune local signaling, manage energy use and segregate incompatible processes. In most peripheral tissues, food acts as the main cue that entrains the oscillations to external time. Food intake and energy balance are under control of endocannabinoid (EC) signaling. Despite this obvious link between the circadian and EC systems, evidence for their interaction started to emerge only recently. We used targeted lipidomics to analyze circadian variations in EC tone in rat plasma, liver and adrenal tissue. The results provide the evidence that ECs, monoacylglycerols, N-acylethanolamines and their precursors oscillate with a tissue-specific circadian phase in plasma and liver. We then identified a set of rhythmically expressed genes likely responsible for the variations in EC tissue tone. In contrast to the liver, EC levels did not oscillate in the adrenal glands. Instead, we revealed that local EC receptor genes are under circadian regulation. To explore the impact of metabolic signals on expression of these genes, we used daytime-restricted feeding schedule. We subsequently showed that daytime feeding strongly suppressed liver-expressed fatty acid binding protein 5 (Fabp5) and adrenal-expressed non-canonical endocannabinoid receptors Gpr55 and Trpv1, whereas it upregulated liver-expressed Trpv1 and glycerophosphodiester phosphodiesterase 1 (Gde1). Our results reveal tissue-specific mechanisms involved in interaction between endocannabinoid signaling, circadian system and metabolism.
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http://dx.doi.org/10.1016/j.bbalip.2019.158533DOI Listing
December 2019

Withdrawn: Dexamethasone resets the circadian clock in hippocampus via multiple mechanisms involving lithium-independent GSK3β signalling.

Br J Pharmacol 2020 09;177(17):4074

Department of Neurohumoral Regulations, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.

The above article from British Journal of Pharmacology, published online as an Accepted Article on 19 August 2019 in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the authors, the journal Editor-in-Chief Professor Amrita Ahluwalia, and John Wiley & Sons Limited. The withdrawal has been agreed owing to new findings that necessitate re-interpretation of the results.
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http://dx.doi.org/10.1111/bph.14834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429476PMC
September 2020

Modulation of NMDA-Mediated Clock Resetting in the Suprachiasmatic Nuclei of Mouse by Endocannabinoids.

Front Physiol 2019 29;10:361. Epub 2019 Mar 29.

Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czechia.

Light entrains the master circadian clock in the suprachiasmatic nucleus (SCN) predominantly through glutamatergic signaling via NMDA receptors. The magnitude and the direction of resulting phase shifts depend on timing of the photic stimulus. Previous reports based on behavioral and electrophysiological data suggested that endocannabinoids (EC) might reduce the ability of the SCN clock to respond to light. However, there is little direct evidence for the involvement of EC in entrainment of the rhythmic clock gene expression in the SCN. We have used luminescence recording of cultured SCN slices from mice to construct a complete phase response curve (PRC) for NMDA receptor activation. The results demonstrated that NMDA administration phase-shifts the PER2 rhythm in a time-specific manner. A stable "singularity," in the course of which the clock seemingly stops while the overall phase is caught between delays and advances, can occur in response to NMDA at a narrow interval during the PER2 level decrease. NMDA-induced phase delays were affected neither by the agonist (WIN 55,212-2 mesylate) nor by the antagonist (rimonabant hydrochloride) of EC receptors. However, the agonist significantly reduced the NMDA-induced phase advance of the clock, while the antagonist enhanced the phase advance, causing a shift in the sensitivity window of the SCN to NMDA. The modulation of EC signaling in the SCN had no effect by itself on the phase of the PER2 rhythm. The results provide evidence for a modulatory role of EC in photic entrainment of the circadian clock in the SCN.
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http://dx.doi.org/10.3389/fphys.2019.00361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450388PMC
March 2019

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

J Biol Rhythms 2019 06 11;34(3):307-322. Epub 2019 Mar 11.

Department of Neurohumoral Regulations, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.

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 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.
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http://dx.doi.org/10.1177/0748730419835360DOI Listing
June 2019

Implicit time-place conditioning alters Per2 mRNA expression selectively in striatum without shifting its circadian clocks.

Sci Rep 2018 10 19;8(1):15547. Epub 2018 Oct 19.

Department of Psychology, University of Toronto, Toronto, Ontario, Canada.

Animals create implicit memories of the time of day that significant events occur then anticipate the recurrence of those conditions at the same time on subsequent days. We tested the hypothesis that implicit time memory for daily encounters relies on the setting of the canonical circadian clockwork in brain areas involved in the formation or expression of context memories. We conditioned mice to avoid locations paired with a mild foot shock at one of two Zeitgeber times set 8 hours apart. Place avoidance was exhibited only when testing time matched the prior training time. The suprachiasmatic nucleus, dorsal striatum, nucleus accumbens, cingulate cortex, hippocampal complex, and amygdala were assessed for clock gene expression. Baseline phase dependent differences in clock gene expression were found in most tissues. Evidence for conditioned resetting of a molecular circadian oscillation was found only in the striatum (dorsal striatum and nucleus accumbens shell), and specifically for Per2 expression. There was no evidence of glucocorticoid stress response in any tissue. The results are consistent with a model where temporal conditioning promotes a selective Per2 response in dopamine-targeted brain regions responsible for sensorimotor integration, without resetting the entire circadian clockwork.
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http://dx.doi.org/10.1038/s41598-018-33637-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195625PMC
October 2018

The McGill Transgenic Rat Model of Alzheimer's Disease Displays Cognitive and Motor Impairments, Changes in Anxiety and Social Behavior, and Altered Circadian Activity.

Front Aging Neurosci 2018 28;10:250. Epub 2018 Aug 28.

Department of Neurophysiology of Memory, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia.

The McGill-R-Thy1-APP transgenic rat is an animal model of the familial form of Alzheimer's disease (AD). This model mirrors several neuropathological hallmarks of the disease, including the accumulation of beta-amyloid and the formation of amyloid plaques (in homozygous animals only), neuroinflammation and the gradual deterioration of cognitive functions even prior to plaque formation, although it lacks the tauopathy observed in human victims of AD. The goal of the present study was a thorough characterization of the homozygous model with emphasis on its face validity in several domains of behavior known to be affected in AD patients, including cognitive functions, motor coordination, emotionality, sociability, and circadian activity patterns. On the behavioral level, we found normal locomotor activity in spontaneous exploration, but problems with balance and gait coordination, increased anxiety and severely impaired spatial cognition in 4-7 month old homozygous animals. The profile of social behavior and ultrasonic communication was altered in the McGill rats, without a general social withdrawal. McGill rats also exhibited changes in circadian profile, with a shorter free-running period and increased total activity during the subjective night, without signs of sleep disturbances during the inactive phase. Expression of circadian clock gene was found to be increased in the parietal cortex and cerebellum, while expression was not changed. The clock-controlled gene expression was found to be elevated in the parietal cortex and hippocampus, which might have contributed to the observed changes in circadian phenotype. We conclude that the phenotype in the McGill rat model is not restricted to the cognitive domain, but also includes gait problems, changes in emotionality, social behavior, and circadian profiles. Our findings show that the model should be useful for the development of new therapeutic approaches targeting not only memory decline but also other symptoms decreasing the quality of life of AD patients.
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http://dx.doi.org/10.3389/fnagi.2018.00250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121039PMC
August 2018

Mystery of rhythmic signal emergence within the suprachiasmatic nuclei.

Eur J Neurosci 2020 01 27;51(1):300-309. Epub 2018 Sep 27.

Department of Neurohumoral Regulations, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.

The circadian system provides organisms with a temporal organization that optimizes their adaptation to environmental fluctuations on a 24-hr basis. In mammals, the circadian clock in the suprachiasmatic nuclei (SCN) develops during the perinatal period. The rhythmicity first appears at the level of individual SCN neurons during the fetal stage, and this step is often misinterpreted as the time of complete SCN clock development. However, the process is only finalized when the SCN begin to play a role of the central clock in the body, that is, when they are able to generate robust rhythmicity at the cell population level, entrain the rhythmic signal with external light-dark cycles and convey this signal to the rest of the body. The development is gradual and correlates with morphological maturation of the SCN structural complexity, which is based on intercellular network formation. The aim of this review is to summarize events related to the first emergence of circadian oscillations in the fetal SCN clock. Although a large amount of data on ontogenesis of the circadian system have been accumulated, how exactly the immature SCN converts into a functional central clock has still remained rather elusive. In this review, the hypothesis of how the SCN attains its rhythmicity at the tissue level is discussed in context with the recent advances in the field. For an extensive summary of the complete ontogenetic development of the circadian system, the readers are referred to other previously published reviews.
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http://dx.doi.org/10.1111/ejn.14141DOI Listing
January 2020

Alteration in glucose homeostasis and persistence of the pancreatic clock in aged mPer2 mice.

Sci Rep 2018 08 3;8(1):11668. Epub 2018 Aug 3.

Department of Neurohumoral Regulations, Institute of Physiology, the Czech Academy of Sciences, Prague, Czech Republic.

The physiological function of the pancreas is controlled by the circadian clock. The aim of this study was to determine whether aging-induced changes in glucose homeostasis affect properties of the circadian clock in the pancreas and/or its sensitivity to disturbances in environmental lighting conditions. mPer2 mice aged 24-26 months developed hyperinsulinemic hypoglycaemia, which was likely due to the Pclo-mediated insulin hyper-secretion and Slc2a2-mediated glucose transport impairment in the pancreas, and due to the alterations in Pp1r3c-related glycogen storage and Sgk1-related glucose transport in the liver. In the pancreatic tissue, aging affected clock gene expression only marginally, it upregulated Bmal1 and downregulated Clock expression. Whereas aging significantly impaired the circadian clock in lung explants, which were used as a control tissue, the properties of the pancreatic clock in vitro were not affected. The data suggest a non-circadian role of Bmal1 in changes of pancreatic function that occur during aging. Additionally, the pancreatic clock was more sensitive to exposure of animals to constant light conditions. These findings provide an explanation for the previously demonstrated relationship between disturbances in the circadian system and disordered glucose homeostasis, including diabetes mellitus type 2, in subjects exposed to long-term shift work.
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http://dx.doi.org/10.1038/s41598-018-30225-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076295PMC
August 2018

Circadian alignment in a foster mother improves the offspring's pathological phenotype.

J Physiol 2018 12 10;596(23):5757-5775. Epub 2018 May 10.

Department of Neurohumoral Regulations.

Key Points: In mammals, the mother-offspring interaction is essential for health later in adulthood. The impact of altered timing and quality of maternal care on the offspring's circadian system was assessed using a cross-strain fostering approach. Better maternal care facilitated the development of amplitudes of Bmal1 clock gene expression in the central clock, as well as the clock-driven activity/rest rhythm, and also its entrainment to the external light/dark cycle. Worse maternal care impaired entrainment of the central clock parameters in the Wistar rat during the early developmental stages. Better maternal care remedied the dampened amplitudes of the colonic clock, as well as cardiovascular functions. The results provide compelling evidence that the circadian phenotype of a foster mother may affect the pathological symptoms of the offspring, even if they are genetically programmed.

Abstract: In mammals, the mother-offspring interaction is essential for health later in adulthood. Maternal care is determined by the circadian phenotype of the mother. The impact of altered timing and quality of maternal care on the circadian system was assessed using a cross-strain fostering approach, with 'abnormal' (i.e. circadian misaligned) care being represented by spontaneously hypertensive rats (SHR) and 'normal' care by Wistar rats. The SHR mothers worsened synchrony of the central clock in the suprachiasmatic nuclei with the light/dark cycle in Wistar rat pups, although this effect disappeared after weaning. The maternal care provided by Wistar rat mothers to SHR pups facilitated the development of amplitudes of the Bmal1 expression rhythm in the suprachiasmatic nuclei of the hypothalamus, as well as the clock-driven activity/rest rhythm and its entrainment to the external light/dark cycle. The peripheral clocks in the liver and colon responded robustly to cross-strain fostering; the circadian phenotype of the Wistar rat foster mother remedied the dampened amplitudes of the colonic clock in SHR pups and improved their cardiovascular functions. In general, the more intensive maternal care of the Wistar rat mothers improved most of the parameters of the abnormal SHR circadian phenotype in adulthood; conversely, the less frequent maternal care of the SHR mothers worsened these parameters in the Wistar rat during the early developmental stages. Altogether, our data provide compelling evidence that the circadian phenotype of a foster mother may positively and negatively affect the regulatory mechanisms of various physiological parameters, even if the pathological symptoms are genetically programmed.
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http://dx.doi.org/10.1113/JP275585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265554PMC
December 2018

Chronic disruptions of circadian sleep regulation induce specific proinflammatory responses in the rat colon.

Chronobiol Int 2017 17;34(9):1273-1287. Epub 2017 Oct 17.

a Department of Neurohumoral Regulations , Institute of Physiology, Czech Academy of Sciences , Prague , Czech Republic.

Exposure to environmental conditions that disturb the daily rhythms has been shown to enhance the proinflammatory responses of immunostimulant-challenged immune system. However, it is not known whether circadian disturbances may stimulate unchallenged immune responses and thus contribute per se to the development of inflammation-related diseases. Our aim was to ascertain an effect of various conditions threatening the behavioral activity/rest cycle regulation, namely aging with or without melatonin, 6 h advance/delay phase shifts in the light/dark cycle repeated with a 2-day frequency and constant light, on expression of immune markers in the rat colon. The impact of these conditions on parameters of behavioral activity and mRNA levels of selected immune markers in the colonic mucosa of Wistar rats, namely TNFα (Tnf), IL1a (Il1a), IL17RA (Il17ra), STAT3 (Stat3) and Rgs16 (Rsg16), were detected. Our results demonstrate that aging with or without melatonin as well as repeated 6 h advance/delay phase shifts in the light/dark cycle, which increased inactivity as a correlate of sleep during the dark phase of the light/dark cycle (i.e. during the active phase for nocturnal animals), had a minor effect on immune state in the colonic mucosa; all these conditions caused downregulation of gene Rgs16 which is involved in attenuation of the inflammatory response in the colon but did not affect expression of the other immune markers. Interestingly, a long-term absence of melatonin facilitated the aging-induced effect on immune state in the colon. In contrast, exposure to constant light, which perturbed the interval of inactivity (sleep) and led to the complete abolishment of activity/inactivity cycles, activated robustly proinflammatory state in the colon selectively via Stat3-dependent pathway. In spite all these experimental conditions (aging with or without melatonin, shifts in light/dark cycles, constant light) perturbed the activity/rest cycles, none of them induced sleep deprivation. These results provided the first evidence that disruptions in the behavioral activity/inactivity cycles may spontaneously (without immuno-stimulant) induce selective proinflammatory responses in the colonic mucosa. Such effects may take part in the mechanisms of modern lifestyle-induced inflammatory diseases of the gut.

Abbreviations: B2M: β2-microglobulin; DSS: dextran sodium sulfate; Gapdh: glyceraldehyde-3-phosphate dehydrogenase; Ifng: interferon g; Il1a: interleukin 1a; Il1b: interleukin 1b; Il2: interleukin 2; Il6: interleukin 6; Il17ra: interleukin 17 receptor a; LD: light/dark cycle; LL: constant light; LPS: lipopolysaccharide; Mntr1a: melatonin receptor 1a; PINX: pinealectomy; Rgs16: regulator of G protein signaling 16; RT qPCR: quantitative reverse transcription polymerase chain reaction; Stat3: signal transducer and activator of transcription 3; Th17: type 17 T helper cells; Tnfα: tumor necrosis factor α; Tnfrsf1b: tumor necrosis factor receptor superfamily member 1b.
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http://dx.doi.org/10.1080/07420528.2017.1361436DOI Listing
August 2018

Melatonin and cortisol secretion profile in patients with pineal cyst before and after pineal cyst resection.

J Clin Neurosci 2017 May 10;39:155-163. Epub 2017 Feb 10.

Department of Neurosurgery of 1st Faculty of Medicine of Charles University and Military University Hospital Prague, Czech Republic.

A pineal cyst is a benign affection of the human pineal gland on the borderline between pathology and normality. Only a small percentage of patients present with symptoms and a surgical treatment is indicated in highly selected cases. A melatonin secretion in patients with a pineal cyst before and after a pineal cyst resection has not been studied yet and the effect of surgery on human metabolism is unknown. The present study examined melatonin, cortisol and blood glucose secretion profiles perioperatively in a surgical group of 4 patients. The control group was represented by 3 asymptomatic patients with a pineal cyst. For each patient, 24-h circadian secretion curves of melatonin, cortisol and glycemia were acquired. An analysis of melatonin profiles showed an expected diurnal pattern with the night peak in patients before the surgery and in the control group. In contrast, melatonin levels in patients after the surgery were at their minimum throughout the whole 24-h period. The cortisol secretion was substantially increased in patients after the surgery. Blood glucose sampling showed no statistically significant differences. Clinical results demonstrated statistically significant headache relief measured by Visual Analogue Scale in patients after the surgery. Despite the small number of examined patients, we can conclude that patients with a pineal cyst preserved the physiological secretion of the hormone melatonin while patients who underwent the pineal cyst resection experienced a loss of endogenous pineal melatonin production, which equated with pinealectomy. Surprisingly, cortisol secretion substantially increased in patients after the surgery.
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http://dx.doi.org/10.1016/j.jocn.2017.01.022DOI Listing
May 2017

Aging does not compromise in vitro oscillation of the suprachiasmatic nuclei but makes it more vulnerable to constant light.

Chronobiol Int 2017 28;34(1):105-117. Epub 2016 Oct 28.

a Department of Neurohumoral Regulations , Institute of Physiology, The Czech Academy of Sciences , Prague , Czech Republic.

Circadian regulation of behavior worsens with age, however, the mechanism behind this phenomenon is still poorly understood. Specifically, it is not clear to what extend the ability of the circadian clock in the suprachiasmatic nuclei (SCN) to generate the rhythm is affected by aging. This study aimed to ascertain the effect of aging on the functioning of the SCN of mPer2 mice under unnatural lighting conditions, such as constant light (LL). Under LL, which worsened the age-induced effect on behavioral rhythms, a marginal age-dependent effect on in vitro rhythmicity in explants containing the middle, but not the rostral/caudal, regions of the SCN was apparent; the proportion of mice in which middle-region SCN explants were completely arrhythmic or had an extremely long period (>30 h) was 47% in aged mice and 27% in adults. The results suggest that in some of the aged animals, LL may weaken the coupling among oscillators in specific sub-regions of the SCN, leaving other sub-regions better synchronized. In the standard light/dark cycle and in constant darkness, the SCN ability to produce bioluminescence rhythms in vitro was not compromised in aged mice although aging significantly affected their SCN-driven locomotor activity rhythms. Therefore, our results demonstrate that although age worsened the SCN output rhythm, the SCN molecular core clock mechanism itself was relatively resilient to aging in these same animals. The results suggest the involvement of pathways downstream of the core clock mechanism which are responsible for this phenomenon.
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http://dx.doi.org/10.1080/07420528.2016.1242491DOI Listing
January 2018

Mechanisms of hormonal regulation of the peripheral circadian clock in the colon.

Chronobiol Int 2017 23;34(1):1-16. Epub 2016 Sep 23.

a Department of Neurohumoral Regulations.

Colonic function is controlled by an endogenous clock that allows the colon to optimize its function on the daytime basis. For the first time, this study provided evidence that the clock is synchronized by rhythmic hormonal signals. In rat colon, adrenalectomy decreased and repeated applications of dexamethasone selectively rescued circadian rhythm in the expression of the clock gene Per1. Dexamethasone entrained the colonic clock in explants from mPer2 mice in vitro. In contrast, pinealectomy had no effect on the rat colonic clock, and repeated melatonin injections were not able to rescue the clock in animals maintained in constant light. Additionally, melatonin did not entrain the clock in colonic explants from mPer2 mice in vitro. However, melatonin affected rhythmic regulation of Nr1d1 gene expression in vivo. The findings provide novel insight into possible beneficial effects of glucocorticoids in the treatment of digestive tract-related diseases, greatly exceeding their anti-inflammatory action.
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http://dx.doi.org/10.1080/07420528.2016.1231198DOI Listing
January 2018

Melatonin is a redundant entraining signal in the rat circadian system.

Horm Behav 2016 07 7;83:1-5. Epub 2016 May 7.

Department of Neurohumoral Regulations, Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 14220, Prague, Czech Republic. Electronic address:

The role of melatonin in maintaining proper function of the circadian system has been proposed but very little evidence for such an effect has been provided. To ascertain the role, the aim of the study was to investigate impact of long-term melatonin absence on regulation of circadian system. The parameters of behavior and circadian clocks of rats which were devoid of the melatonin signal due to pinealectomy (PINX) for more than one year were compared with those of intact age-matched controls. PINX led to a decrease in spontaneous locomotor activity and a shortening of the free-running period of the activity rhythm driven by the central clock in the suprachiasmatic nuclei (SCN) in constant darkness. However, the SCN-driven rhythms in activity and feeding were not affected and remained well entrained in the light/dark cycle. In contrast, in these conditions PINX had a significant effect on amplitudes of the clock gene expression rhythms in the duodenum and also partially in the liver. These results demonstrate the significant impact of long-term melatonin absence on period of the central clock in the SCN and the amplitudes of the peripheral clocks in duodenum and liver and suggest that melatonin might be a redundant but effective endocrine signal for these clocks.
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http://dx.doi.org/10.1016/j.yhbeh.2016.05.006DOI Listing
July 2016

Moderate Changes in the Circadian System of Alzheimer's Disease Patients Detected in Their Home Environment.

PLoS One 2016 4;11(1):e0146200. Epub 2016 Jan 4.

Department of Neurohumoral Regulations, Institute of Physiology, the Czech Academy of Sciences, Prague, Czech Republic.

Alzheimer's disease (AD) is a neurodegenerative disease often accompanied with disruption of sleep-wake cycle. The sleep-wake cycle is controlled by mechanisms involving internal timekeeping (circadian) regulation. The aim of our present pilot study was to assess the circadian system in patients with mild form of AD in their home environment. In the study, 13 elderly AD patients and 13 age-matched healthy control subjects (the patient's spouses) were enrolled. Sleep was recorded for 21 days by sleep diaries in all participants and checked by actigraphy in 4 of the AD patient/control couples. The samples of saliva and buccal mucosa were collected every 4 hours during the same 24 h-interval to detect melatonin and clock gene (PER1 and BMAL1) mRNA levels, respectively. The AD patients exhibited significantly longer inactivity interval during the 24 h and significantly higher number of daytime naps than controls. Daily profiles of melatonin levels exhibited circadian rhythms in both groups. Compared with controls, decline in amplitude of the melatonin rhythm in AD patients was not significant, however, in AD patients more melatonin profiles were dampened or had atypical waveforms. The clock genes PER1 and BMAL1 were expressed rhythmically with high amplitudes in both groups and no significant differences in phases between both groups were detected. Our results suggest moderate differences in functional state of the circadian system in patients with mild form of AD compared with healthy controls which are present in conditions of their home dwelling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146200PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701009PMC
July 2016

Diverse development and higher sensitivity of the circadian clocks to changes in maternal-feeding regime in a rat model of cardio-metabolic disease.

Chronobiol Int 2015 May 3;32(4):531-47. Epub 2015 Apr 3.

Department of Neurohumoral Regulations, Institute of Physiology, v.v.i., Academy of Science of the Czech Republic , Prague , Czech Republic.

Spontaneously hypertensive rats (SHR) develop cardiovascular and metabolic pathology in adulthood when their circadian system exhibits significant aberrances compared with healthy control rats. This study was aimed to elucidate how the SHR circadian system develops during ontogenesis and to assess its sensitivity to changes in maternal-feeding regime. Analysis of ontogenesis of clock gene expression rhythms in the suprachiasmatic nuclei, liver and colon revealed significant differences in SHR compared with Wistar rats. In the suprachiasmatic nuclei of the hypothalamus (SCN) and liver, the development of a high-amplitude expression rhythm selectively for Bmal1 was delayed compared with Wistar rat. The atypical development of the SHR circadian clocks during postnatal ontogenesis might arise from differences in maternal behavior between SHR and Wistar rats that were detected soon after delivery. It may also arise from higher sensitivity of the circadian clocks in the SHR SCN, liver and colon to maternal behavior related to changes in the feeding regime because in contrast to Wistar rat, the SHR SCN and peripheral clocks during the prenatal period and the hepatic clock during the early postnatal period were phase shifted due to exposure of mothers to a restricted feeding regime. The maternal restricted feeding regime shifted the clocks despite the fact that the mothers were maintained under the light/dark cycle. Our findings of the diverse development and higher sensitivity of the developing circadian system of SHR to maternal cues might result from previously demonstrated differences in the SHR circadian genotype and may potentially contribute to cardiovascular and metabolic diseases, which the animal model spontaneously develops.
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http://dx.doi.org/10.3109/07420528.2015.1014095DOI Listing
May 2015

The circadian system of patients with bipolar disorder differs in episodes of mania and depression.

Bipolar Disord 2015 May 31;17(3):303-14. Epub 2014 Oct 31.

Institute of Physiology, Academy of Sciences of the Czech Republic, Prague.

Objectives: Bipolar disorder is a common psychiatric disease characterized by mood disturbances with alternating episodes of mania and depression. Moreover, disturbances in the sleep/wake cycle are prevalent. We tested a hypothesis that the function of the circadian system, which drives the sleep/wake cycle, may differ in patients with bipolar disorder depending on whether they are experiencing an episode of mania or depression.

Methods: To assess the functional state of the central circadian clock, daily profiles of melatonin levels in saliva were determined. The functional state of the peripheral clocks was assessed by determining daily profiles of Per1 and Nr1d1 clock gene expression in buccal mucosa cells. Sixteen patients with bipolar disorder in a manic episode, 22 patients in a depressive episode, and 19 healthy control subjects provided samples at regular intervals during a 24-hour cycle.

Results: During episodes of mania, the daily profiles of melatonin differed compared with healthy controls and patients in an episode of depression, mainly due to elevated melatonin levels during the daytime. No difference was found between melatonin profiles of control subjects and patients in depression. The Per1 and Nr1d1 profiles were advanced in patients in mania compared with those in depression. Compared with controls, a trend toward an advance was apparent in the profiles of patients during an episode of mania but not depression. The amplitude of the Nr1d1 expression profile was higher in mania than in depression.

Conclusions: The data revealed differences in the functional state of the circadian system in patients with bipolar disorder depending on whether they were experiencing a manic or a depressive episode.
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http://dx.doi.org/10.1111/bdi.12270DOI Listing
May 2015

In vivo initiation of clock gene expression rhythmicity in fetal rat suprachiasmatic nuclei.

PLoS One 2014 25;9(9):e107360. Epub 2014 Sep 25.

Department of Neurohumoral Regulations, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.

The mammalian suprachiasmatic nuclei (SCN) and their intrinsic rhythmicity develop gradually during ontogenesis. In the rat, the SCN forms between embryonic day (E) 14 and E17, with gestation terminating at E21-22. Overt SCN rhythmicity is already present in the late embryonic stage. The aim of the present study was to determine when the fetal SCN clock develops in vivo and whether overt rhythmicity results from a functional fetal clock. To achieve this goal, the prenatal development of rhythmic expression of clock genes was measured with a more sensitive method for detection of the clock gene expression than previously. Fetal SCN were collected at 3 h intervals during the 24 h period on E19 and E21 by laser dissection and expression of clock genes (Per2, Nr1d1 and Bmal1) and genes related to cellular activity (c-fos, Avp and Vip) was measured by qRT PCR. At E19, the expression of canonical clock genes Per2 and Bmal1 was not rhythmic; however, the expression of all other studied genes followed clear circadian rhythms. At E21, Per2 and Bmal1 expression exhibited low amplitude but significant rhythmicity. From E19 to E21, the levels of the non-rhythmic transcripts (Per2 and Bmal1) decreased; however, the levels of the rhythmic transcripts (Nr1d1, c-fos, Avp and Vip) increased. In summary, these data demonstrate that at E19, rhythms in Per2 and Bmal1 expression were absent in the fetal SCN; however, the expression of Nr1d1 and other genes related to cellular activity was driven rhythmically. Therefore, at the early stage in vivo, the developing fetal SCN clock could theoretically be entrained by oscillation of Nr1d1 which may be driven by the maternal rather than fetal circadian system.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107360PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177808PMC
June 2015

Melatonin administered during the fetal stage affects circadian clock in the suprachiasmatic nucleus but not in the liver.

Dev Neurobiol 2015 Feb 23;75(2):131-44. Epub 2014 Jul 23.

Department of Neurohumoral Regulations, Institute of Physiology, v.v.i., Academy of Science of the Czech Republic, Videnska 1083, 14220, Prague, Czech Republic.

The mammalian circadian system develops gradually during ontogenesis, and after birth, the system is already set to a phase of the mothers. The role of maternal melatonin in the entrainment of fetal circadian clocks has been suggested, but direct evidence is lacking. In our study, intact or pinealectomized pregnant rats were exposed to constant light (LL) throughout pregnancy to suppress the endogenous melatonin and behavioral rhythms. During the last 5 days of gestation, the rats were injected with melatonin or vehicle or were left untreated. After delivery, daily expression profiles of c-fos and Avp in the suprachiasmatic nuclei (SCN), and Per1, Per2, Rev-erbα, and Bmal1 in the liver were measured in 1-day-old pups. Due to the LL exposure, no gene expression rhythms were detected in the SCN of untreated pregnant rats or in the SCN and liver of the pups. The administration of melatonin to pregnant rats entrained the pups' gene expression profiles in the SCN, but not in the liver. Melatonin did not affect the maternal behavior during pregnancy. Vehicle injections also synchronized the gene expression in the SCN but not in the liver. Melatonin and vehicle entrained the gene expression profiles to different phases, demonstrating that the effect of melatonin was apparently not due to the treatment procedure per se. The data demonstrate that in pregnant rats with suppressed endogenous melatonin levels, pharmacological doses of melatonin affect the fetal clock in the SCN but not in the liver.
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http://dx.doi.org/10.1002/dneu.22213DOI Listing
February 2015

New methods to assess circadian clocks in humans.

Indian J Exp Biol 2014 May;52(5):404-12

Proper function of the circadian system seems crucial for human health. New advances in methods for assessment of the functional state of the human circadian system facilitate our understanding of the relationship between the disruption of the circadian system and various diseases. Based on the results of such studies, new directions for the diagnosis and treatment of diseases emerge. This communication aims to summarize current methods for evaluating the human circadian system in the laboratory as well as in field studies. The advantages and limitations of the current methods and various approaches used for both in vivo and in vitro assessment of the human circadian system are discussed.
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May 2014

Cross-talk between the circadian clock and the cell cycle in cancer.

Ann Med 2014 Jun 30;46(4):221-32. Epub 2014 Apr 30.

Institute of Physiology, Academy of Sciences of the Czech Republic , Prague , Czech Republic.

The circadian clock is an endogenous timekeeper system that controls the daily rhythms of a variety of physiological processes. Accumulating evidence indicates that genetic changes or unhealthy lifestyle can lead to a disruption of circadian homeostasis, which is a risk factor for severe dysfunctions and pathologies including cancer. Cell cycle, proliferation, and cell death are closely intertwined with the circadian clock, and thus disruption of circadian rhythms appears to be linked to cancer development and progression. At the molecular level, the cell cycle machinery and the circadian clocks are controlled by similar mechanisms, including feedback loops of genes and protein products that display periodic activation and repression. Here, we review the circadian rhythmicity of genes associated with the cell cycle, proliferation, and apoptosis, and we highlight the potential connection between these processes, the circadian clock, and neoplastic transformations. Understanding these interconnections might have potential implications for the prevention and therapy of malignant diseases.
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http://dx.doi.org/10.3109/07853890.2014.892296DOI Listing
June 2014

Nogo-A-deficient Transgenic Rats Show Deficits in Higher Cognitive Functions, Decreased Anxiety, and Altered Circadian Activity Patterns.

Front Behav Neurosci 2014 18;8:90. Epub 2014 Mar 18.

Department of Neurophysiology of Memory, Institute of Physiology, Academy of Sciences of the Czech Republic , Prague , Czech Republic.

Decreased levels of Nogo-A-dependent signaling have been shown to affect behavior and cognitive functions. In Nogo-A knockout and knockdown laboratory rodents, behavioral alterations were observed, possibly corresponding with human neuropsychiatric diseases of neurodevelopmental origin, particularly schizophrenia. This study offers further insight into behavioral manifestations of Nogo-A knockdown in laboratory rats, focusing on spatial and non-spatial cognition, anxiety levels, circadian rhythmicity, and activity patterns. Demonstrated is an impairment of cognitive functions and behavioral flexibility in a spatial active avoidance task, while non-spatial memory in a step-through avoidance task was spared. No signs of anhedonia, typical for schizophrenic patients, were observed in the animals. Some measures indicated lower anxiety levels in the Nogo-A-deficient group. Circadian rhythmicity in locomotor activity was preserved in the Nogo-A knockout rats and their circadian period (tau) did not differ from controls. However, daily activity patterns were slightly altered in the knockdown animals. We conclude that a reduction of Nogo-A levels induces changes in CNS development, manifested as subtle alterations in cognitive functions, emotionality, and activity patterns.
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http://dx.doi.org/10.3389/fnbeh.2014.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957197PMC
March 2014