Network properties of the mammalian circadian clock

The biological clock regulates daily and seasonal rhythms in mammals. This clock is located in the suprachiasmatic nuclei (SCN), which are two small nuclei each consisting of 10,000 neurons. The neurons of the SCN endogenously generate a rhythm of approximately 24 hours. Under the influence of the light-dark cycle, the SCN produce a coordinated output that is subjected to daily environmental changes. The adaptation to the light-dark cycle is a property of the neuronal network of the SCN. This neuronal network also explains the adjustment to long summer days and short winter days, and to shifts in the light-dark cycle caused by transatlantic flights or shift work. In this thesis the neuronal network of the SCN is investigated using computational techniques. The computer simulations were directed by experimental results, while, vice versa, new experiments were guided by results from the simulations. These coordinated efforts of computational science and life sciences show how properties emerge at the neuronal network level, that are not present in individual cells.NWO, program grant nr 805.47.212 ‘From Molecule to Cell’ and ASCI graduate schoolUBL - phd migration 201

Dissociation between two subgroups of the suprachiasmatic nucleus affected by the number of damped oscillated neurons

Circadian clocks in health and diseas

Uncovering functional signature in neural systems via random matrix theory

Neural systems are organized in a modular way, serving multiple functionalities. This multiplicity requires that both positive (e.g. excitatory, phase-coherent) and negative (e.g. inhibitory, phase-opposing) interactions take place across brain modules. Unfortunately, most methods to detect modules from time series either neglect or convert to positive, any measured negative correlation. This may leave a significant part of the sign-dependent functional structure undetected. Here we present a novel method, based on random matrix theory, for the identification of sign-dependent modules in the brain. Our method filters out both local (unit-specific) noise and global (system-wide) dependencies that typically obfuscate the presence of such structure. The method is guaranteed to identify an optimally contrasted functional signature', i.e. a partition into modules that are positively correlated internally and negatively correlated across. The method is purely data-driven, does not use any arbitrary threshold or network projection, and outputs only statistically significant structure. In measurements of neuronal gene expression in the biological clock of mice, the method systematically uncovers two otherwise undetectable, negatively correlated modules whose relative size and mutual interaction strength are found to depend on photoperiod. Author Summary In recent years an increasing number of studies demonstrate that functional organization of the brain has a vital importance in the manifestation of diseases and aging processes. This functional structure is composed of modules sharing similar dynamics, in order to serve multiple functionalities. Here we present a novel method, based on random matrix theory, for the identification of functional modules in the brain. Our approach overcomes known inherit methodological limitations of current methods, breaking the resolution limits and resolves a cell to cell functional networks. Moreover, the results represent a great potential for detecting hidden functional synchronization and de-synchronization in brain networks, which play a major role in the occurrence of epilepsy, Parkinson's disease, and schizophrenia.Theoretical Physic

Use of very short answer questions compared to multiple choice questions in undergraduate medical students: an external validation study

Multiple choice questions (MCQs) offer high reliability and easy machine-marking, but allow for cueing and stimulate recognition-based learning. Very short answer questions (VSAQs), which are open-ended questions requiring a very short answer, may circumvent these limitations. Although VSAQ use in medical assessment increases, almost all research on reliability and validity of VSAQs in medical education has been performed by a single research group with extensive experience in the development of VSAQs. Therefore, we aimed to validate previous findings about VSAQ reliability, discrimination, and acceptability in undergraduate medical students and teachers with limited experience in VSAQs development. To validate the results presented in previous studies, we partially replicated a previous study and extended results on student experiences. Dutch undergraduate medical students (n = 375) were randomized to VSAQs first and MCQs second or vice versa in a formative exam in two courses, to determine reliability, discrimination, and cueing. Acceptability for teachers (i.e., VSAQ review time) was determined in the summative exam. Reliability (Cronbach's & alpha;) was 0.74 for VSAQs and 0.57 for MCQs in one course. In the other course, Cronbach's & alpha; was 0.87 for VSAQs and 0.83 for MCQs. Discrimination (average R-ir) was 0.27 vs. 0.17 and 0.43 vs. 0.39 for VSAQs vs. MCQs, respectively. Reviewing time of one VSAQ for the entire student cohort was & PLUSMN;2 minutes on average. Positive cueing occurred more in MCQs than in VSAQs (20% vs. 4% and 20.8% vs. 8.3% of questions per person in both courses). This study validates the positive results regarding VSAQs reliability, discrimination, and acceptability in undergraduate medical students. Furthermore, we demonstrate that VSAQ use is reliable among teachers with limited experience in writing and marking VSAQs. The short learning curve for teachers, favourable marking time and applicability regardless of the topic suggest that VSAQs might also be valuable beyond medical assessment.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Network properties of the mammalian circadian clock

The biological clock regulates daily and seasonal rhythms in mammals. This clock is located in the suprachiasmatic nuclei (SCN), which are two small nuclei each consisting of 10,000 neurons. The neurons of the SCN endogenously generate a rhythm of approximately 24 hours. Under the influence of the light-dark cycle, the SCN produce a coordinated output that is subjected to daily environmental changes. The adaptation to the light-dark cycle is a property of the neuronal network of the SCN. This neuronal network also explains the adjustment to long summer days and short winter days, and to shifts in the light-dark cycle caused by transatlantic flights or shift work. In this thesis the neuronal network of the SCN is investigated using computational techniques. The computer simulations were directed by experimental results, while, vice versa, new experiments were guided by results from the simulations. These coordinated efforts of computational science and life sciences show how properties emerge at the neuronal network level, that are not present in individual cells

Two-Community Noisy Kuramoto Model Suggests Mechanism for Splitting in the Suprachiasmatic Nucleus

Recent mathematical results for the noisy Kuramoto model on a 2-community network may explain some phenomena observed in the functioning of the suprachiasmatic nucleus (SCN). Specifically, these findings might explain the types of transitions to a state of the SCN in which 2 components are dissociated in phase, for example, in phase splitting. In contrast to previous studies, which required additional time-delayed coupling or large variation in the coupling strengths and other variations in the 2-community model to exhibit the phase-split state, this model requires only the 2-community structure of the SCN to be present. Our model shows that a change in the communication strengths within and between the communities due to external conditions, which changes the excitation-inhibition (E/I) balance of the SCN, may result in the SCN entering an unstable state. With this altered E/I balance, the SCN would try to find a new stable state, which might in some circumstances be the split state. This shows that the 2-community noisy Kuramoto model can help understand the mechanisms of the SCN and explain differences in behavior based on actual E/I balance.Circadian clocks in health and diseas

Sleep Network Deterioration as a Function of Dim-Light-At-Night Exposure Duration in a Mouse Model

Artificial light, despite its widespread and valuable use, has been associated with deterioration of health and well-being, including altered circadian timing and sleep disturbances, particularly in nocturnal exposure. Recent findings from our lab reveal significant sleep and sleep electroencephalogram (EEG) changes owing to three months exposure to dim-light-at-night (DLAN). Aiming to further explore the detrimental effects of DLAN exposure, in the present study, we continuously recorded sleep EEG and the electromyogram for baseline 24-h and following 6-h sleep deprivation in a varied DLAN duration scheme. C57BL/6J mice were exposed to a 12:12 h light:DLAN cycle (75lux:5lux) vs. a 12:12 h light:dark cycle (75lux:0lux) for one day, one week, and one month. Our results show that sleep was already affected by a mere day of DLAN exposure with additional complications emerging with increasing DLAN exposure duration, such as the gradual delay of the daily 24-h vigilance state rhythms. We conducted detrended fluctuation analysis (DFA) on the locomotor activity data following 1-month and 3-month DLAN exposure, and a significantly less healthy rest-activity pattern, based on the decreased alpha values, was found in both conditions compared to the control light-dark. Taking into account the behavioral, sleep and the sleep EEG parameters, our data suggest that DLAN exposure, even in the shortest duration, induces deleterious effects; nevertheless, potential compensatory mechanisms render the organism partly adjustable and able to cope. We think that, for this reason, our data do not always depict linear divergence among groups, as compared with control conditions. Chronic DLAN exposure impacts the sleep regulatory system, but also brain integrity, diminishing its adaptability and reactivity, especially apparent in the sleep EEG alterations and particular low alpha values following DFA.Circadian clocks in health and diseas

Dependence of the entrainment on the ratio of amplitudes between two subgroups in the suprachiasmatic nucleus

Circadian clocks in health and diseas

Heterogeneity induces rhythms of weakly coupled circadian neurons

Circadian clocks in health and diseas

Daily and seasonal adaptation of the circadian clock requires plasticity of the SCN neuronal network

Circadian rhythms are an essential property of many living organisms, and arise from an internal pacemaker, or clock. In mammals, this clock resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, and generates an intrinsic circadian rhythm that is transmitted to other parts of the CNS. We will review the evidence that basic adaptive functions of the circadian system rely on functional plasticity in the neuronal network organization, and involve a change in phase relation among oscillatory neurons. We will illustrate this for: (i) photic entrainment of the circadian clock to the light-dark cycle; and (ii) seasonal adaptation of the clock to changes in day length. Molecular studies have shown plasticity in the phase relation between the ventral and dorsal SCN during adjustment to a shifted environmental cycle. Seasonal adaptation relies predominantly on plasticity in the phase relation between the rostral and caudal SCN. Electrical activity is integrated in the SCN, and appears to reflect the sum of the differently phased molecular expression patterns. While both photic entrainment and seasonal adaptation arise from a redistribution of SCN oscillatory activity patterns, different neuronal coupling mechanisms are employed, which are reviewed in the present paper.Circadian clocks in health and diseas