Effect of Network Architecture on Synchronization and Entrainment Properties of the Circadian Oscillations in the Suprachiasmatic Nucleus

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus constitutes the central circadian pacemaker. The SCN receives light signals from the retina and controls peripheral circadian clocks (located in the cortex, the pineal gland, the liver, the kidney, the heart, etc.). This hierarchical organization of the circadian system ensures the proper timing of physiological processes. In each SCN neuron, interconnected transcriptional and translational feedback loops enable the circadian expression of the clock genes. Although all the neurons have the same genotype, the oscillations of individual cells are highly heterogeneous in dispersed cell culture: many cells present damped oscillations and the period of the oscillations varies from cell to cell. In addition, the neurotransmitters that ensure the intercellular coupling, and thereby the synchronization of the cellular rhythms, differ between the two main regions of the SCN. In this work, a mathematical model that accounts for this heterogeneous organization of the SCN is presented and used to study the implication of the SCN network topology on synchronization and entrainment properties. The results show that oscillations with larger amplitude can be obtained with scale-free networks, in contrast to random and local connections. Networks with the small-world property such as the scale-free networks used in this work can adapt faster to a delay or advance in the light/dark cycle (jet lag). Interestingly a certain level of cellular heterogeneity is not detrimental to synchronization performances, but on the contrary helps resynchronization after jet lag. When coupling two networks with different topologies that mimic the two regions of the SCN, efficient filtering of pulse-like perturbations in the entrainment pattern is observed. These results suggest that the complex and heterogeneous architecture of the SCN decreases the sensitivity of the network to short entrainment perturbations while, at the same time, improving its adaptation abilities to long term changes

The Role of Doublecortin-like in the Suprachiasmatic Nucleus

The hypothalamic Suprachiasmatic Nucleus (SCN) is known as the central biological clock that regulates circadian rhythmicity in mammals. Through vasopressin (AVP) processing in its shell, the SCN signals to other brain areas and peripheral organs in the body. A novel protein, Doublecortin-like (DCL) was identified to have overlapping expression with that of AVP. Mice with SCN-specific DCL-knockdown show abnormal activity adaption after a change in light-phase, and immunohistochemical AVP staining indicate a distortion of AVP in the SCN of DCL-knockdown mice. Together, we conclude that DCL may be a novel regulator of AVP signalling in the SCN

Molecular mechanisms that regulate the coupled period of the mammalian circadian clock

In mammals, most cells in the brain and peripheral tissues generate circadian (~24hr) rhythms autonomously. These self-sustained rhythms are coordinated and entrained by a master circadian clock in the suprachiasmatic nucleus (SCN). Within the SCN, the individual rhythms of each neuron are synchronized through intercellular signaling. One important feature of SCN is that the synchronized period is close to the cell population mean of intrinsic periods. In this way, the synchronized period of the SCN stays close to the periods of cells in peripheral tissues. This is important for SCN to entrain cells throughout the body. However, the mechanism that drives the period of the coupled SCN cells to the population mean is not known. We use mathematical modeling and analysis to show that the mechanism of transcription repression plays a pivotal role in regulating the coupled period. Specifically, we use phase response curve analysis to show that the coupled period within the SCN stays near the population mean if transcriptional repression occurs via protein sequestration. In contrast, the coupled period is far from the mean if repression occurs through highly nonlinear Hill-type regulation (e.g. oligomer- or phosphorylation-based repression). Furthermore, we find that the timescale of intercellular coupling needs to be fast compared to that of intracellular feedback to maintain the mean period. These findings reveal the important relationship between the intracellular transcriptional feedback loop and intercellular coupling. This relationship explains why transcriptional repression appears to occur via protein sequestration in multicellular organisms, mammals and Drosophila, in contrast with the phosphorylation-based repression in unicellular organisms. That is, transition to protein sequestration is essential for synchronizing multiple cells with a period close to the population mean (~24hr).Comment: 21 pages, 16 figure

Representation without Informative Signalling

Various writers have attempted to use the sender-receiver formalism to account for the representational capacities of biological systems. This paper has two goals. First, I argue that the sender-receiver approach to representation cannot be complete. The mammalian circadian system represents the time of day, yet it does not control circadian behaviours by producing signals with time of day content. Informative signalling need not be the basis of our most basic representational capacities. Second, I argue that representational capacities are primarily about control, and only when specific conditions obtain does this control require informative signalling

Noise Induces Hopping between NF-kappa B Entrainment Modes

Oscillations and noise drive many processes in biology, but how both affect the activity of the transcription factor nuclear factor κB (NF-κB) is not understood. Here, we observe that when NF-κB oscillations are entrained by periodic tumor necrosis factor (TNF) inputs in experiments, NF-κB exhibits jumps between frequency modes, a phenomenon we call “cellular mode-hopping.” By comparing stochastic simulations of NF-κB oscillations to deterministic simulations conducted inside and outside the chaotic regime of parameter space, we show that noise facilitates mode-hopping in all regimes. However, when the deterministic system is driven by chaotic dynamics, hops between modes are erratic and short-lived, whereas in experiments, the system spends several periods in one entrainment mode before hopping and rarely visits more than two modes. The experimental behavior matches our simulations of noise-induced mode-hopping outside the chaotic regime. We suggest that mode-hopping is a mechanism by which different NF-κB-dependent genes under frequency control can be expressed at different times.ISSN:2405-472

Mechanisms of maternal entrainment of the fetal circadian clock

Naše tělo je vystavené velkému množství cyklických změn ve svém okolí, jako je například střídání dne a noci nebo ročních období. Aby mohl organismus tyto změny předvídat a včas na ně reagovat, je vybaven vnitřními hodinami, které rytmicky ovlivňují fyziologické procesy, jako jsou spánek nebo metabolické rytmy. Vzhledem k tomu, že narušení naší vnitřní rytmicity na molekulární i behaviorální úrovni přispívá k mnoha závažným onemocněním, je nezbytné, aby byly všechny mechanismy těchto vnitřních hodin správně vyvinuty a seřízeny. Za prvotní nastavení našich cirkadiánních hodin je odpovědná matka, která za pomoci nejrůznějších signálů předává embryu rytmickou informaci o střídání dne a noci. Ačkoliv je tato synchronizace mezi matkou a mládětem tématem, kterému se věnuje čím dál více pozornosti, dosud není znám její přesný mechanismus. Tato práce si klade za cíl přispět k aktuálnímu poznání této problematiky. Experimenty, realizované v této práci, se týkají zkoumání schopnosti mateřských signálů synchronizovat centrální cirkadiánní hodiny embrya s okolními podmínkami. Březím samicím bylo manipulováno se světelným i potravním režimem a následně byl pozorován efekt těchto změn na neuronální aktivitu v suprachiasmatických jádrech 19ti denních embryí, měřený pomocí exprese genu c-fos.Our body is influenced by many cyclical changes in the environment, such as day and night or seasons. To predict these changes and react to them in time, the organism is equipped with inner clock, which rhythmically influences many physiological processes, such as sleep or metabolic rhythms. Disrupting our inner rhythms at molecular and behavioral levels contributes to many serious disorders. It is necessary that all mechanisms of the inner circadian clock are developed and set up properly. Circadian clocks are set up by the mother, who passes rhythmical information about day and night cycle on to her embryo. Though a great attention is devoted to revealing the nature of this synchronization between the mother and her pup, the mechanisms of this process have not been fully understood yet. The aim of this thesis is to contribute to actual understanding of this synchronization. Experiments, performed in this thesis, relate to studying the ability of maternal signals to synchronize embryos with the environment. Feeding and light regime of pregnant rats was manipulated and the effect of these changes on the neuronal activity within the suprachiasmatic nuclei of 19-day embryos was analyzed.Katedra fyziologieDepartment of PhysiologyFaculty of SciencePřírodovědecká fakult

Circadian regulation of STAT3 protein in the SCN and it's activation by leptin in the SCN, other parts of hypothalamus and the pineal gland

Signální dráha JAK/STAT je jedna z nejlépe prostudovaných intracelulárních kaskád přenášejících signály z extracelulárního prostředí do buněčného jádra s cílem ovlivnit expresi cílových genů. Cirkadiánní hodiny lokalizované v suprachiasmatických jádrech (SCN) hypotalamu jsou citlivé zejména ke světlu, mohou však reagovat na nesvětelné signály jako jsou růstové faktory, opioidy, cytokiny a leptin, u kterých bylo prokázáno, že vykonávají svoji funkci prostřednictvím JAK/STAT signální dráhy. Nedávné výsledky naší laboratoře ukázaly, že protein STAT3 je silně produkován SCN potkana. Naše experimenty měly primárně za cíl otestovat cirkadiánní regulaci produkce STAT3 v SCN a popsat vliv exogenně podaného leptinu na fosforylaci STAT3 v SCN, epifýze a strukturách hypotalamu zodpovědných za regulaci potravního chování a energetický metabolismus. Protože aktivace leptinových receptorů může stimulovat i řadu jiných signálních kaskád, zvolili jsme fosforylované formy kináz ERK1/2 a GSK-3β jako další markery intracelulárních změn po aplikaci leptinu ve studovaných strukturách. Naše výsledky prokázaly rytmickou produkci proteinu STAT3 v SCN potkana a naznačily cirkadiánní regulaci citlivosti hypotalamických struktur k leptinu. Získaná data také naznačila, že aktivita buněk SCN a epifýzy měřená zvolenými markery...JAK/STAT signaling pathway is one of the most studied intracellular cascades transmitting signals from the extracellular environment to the cell nucleus in order to affect expression of target genes. Circadian clocks localized in the suprachiasmatic nuclei (SCN) of the hypothalamus are sensitive especially to light but they can respond to non-photic stimuli such as growth factors, opioids, leptin and cytokines that have been demonstrated to perform its function via the JAK/STAT signaling pathway. The recent findings of our laboratory demonstrated that STAT3 protein is highly produced by SCN of rat. Primary aim of our experiments was to test the circadian regulation of STAT3 production in SCN and describe the effect of exogenously administered leptin on STAT3 phosphorylation in the SCN, pineal gland and hypothalamic structures responsible for regulated feeding behavior and energy metabolism. Because activation of leptin receptors may stimulate a number of other signaling cascades, we chose phosphorylated forms of kinase ERK1/2 and GSK-3β as other markers of intracellular changes after administration of leptin in the studied structures. Our results proved rhythmic production of STAT3 protein in SCN of rat and indicated circadian regulation of sensitivity to leptin in hypothalamic structures. The data...Department of PhysiologyKatedra fyziologiePřírodovědecká fakultaFaculty of Scienc

Cirkadiánní systém a spánek u jedinců s ADHD

Porucha pozornosti s hyperaktivitou (ADHD) je spojována s poruchami spánku a abnormalitami cirkadiánního systému. Studie z posledních let poukazují na souvislosti s pozdním chronotypem a syndromem opožděné spánkové fáze, polymorfismy hodinových genů, geografickou variabilitou v intenzitě slunečního záření, delší spánkovou latencí a narušenou kvalitou spánku. Výzkumy prováděné s dětskými a dospělými pacienty se však mnohdy neshodují ve svých závěrech. Přestože byla navržena nová diagnostická kategorie ADHD-SOM označující jedince, u kterých je část symptomů způsobena chronickými spánkovými potížemi, většina důkazů je korelační povahy. Práce shrnuje výzkumná zjištění týkající se cirkadiánních a spánkových korelátů ADHD a některé potenciální mechanismy, kterými by tyto koreláty mohly být s poruchou spojeny. Chronoterapie a spánkové intervence představují slibné metody v podpůrné léčbě ADHD.Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with sleep disorders and abnormalities of the circadian system. In recent studies, ADHD has been linked to late chronotype and delayed sleep phase disorder, clock gene polymorphisms, geographic variation in solar irradiation, longer sleep latency, and impaired sleep quality. However, research findings in children with ADHD often differ from those in adult patients. A new diagnostic category, ADHD-SOM, has been proposed to describe individuals whose symptoms are partially caused by chronic sleep issues. However, most of the evidence is correlational. The thesis summarizes research on sleep and circadian correlates of ADHD and some of the potential mechanisms explaining these associations. Chronotherapy and sleep interventions are promising methods of adjunctive ADHD treatment.Department of PhysiologyKatedra fyziologiePřírodovědecká fakultaFaculty of Scienc