Circadian clocks in health and disease

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Chemical Cell Biology / Molecular Cell Biology.

Aim and focus

The aim of our research program is to understand the physiological bases of circadian rhythms and sleep, and their influence on diseases, such as depression, metabolic syndrome, and aging. Rhythms of 24-hours are generated in an evolutionary old part of the brain, called the suprachiasmatic nuclei (SCN). Individual cells of this structure produce rhythms of about 24-hours. The clock cells are mutually synchronized and are responsive to light to adapt to the external light-dark cycle. Clock disturbances arise as a consequence of aging, abundance of artificial light in modern society and shift work. Disturbances in the clock give rise to a wide range of health problems, including sleep disturbances, obesity, depression, immune disorders and general characteristics of frailty. It is our aim to implement the consequences of our findings in clinical settings and society. For instance, we are interested in light conditions in IC’s, neonatal units and nursery homes, and have developed an app for nursing staff in shift work StAZ and SoFoKleS, the two occupational national organizations that work for academic and non-academic hospitals respectively.

Current focus

  • Neuronal network organization of the circadian clock
  • Light effects on the SCN clock; the visual circadian system
  • Clinical: aging, sleep, metabolic syndrome, depression, ADHD
  • Sleep, fatigue and behavioural activity
  • Complexity theory; emergent properties of hierarchical neuronal networks
  • Chronopharmacology: optimizing time of drug application
  • Field research, animal welfare, population dynamics

Position in international context

  • Prof. JH Meijer is visiting professor in Oxford and member of the Royal Holland Society of Science. She was appointed as a member at large of the Society for Research of Biological Rhythms (2013-2015). In 2016, she received the international Aschoff-Honma price for Chronobiology. She is board member of the Life Sciences Board of the Lorentz Centre, Leiden.
  • Dr. T. De Boer is member of the board of the European Sleep Research Society. 
  • We frequently organize and present at international meetings. International collaborations exist with a number of foreign institutions: University of California, UCLA (Prof G.D. Block, Prof C. Colwell), University of Massachusetts Medical School (Prof W.J. Schwartz), University of Oxford (Prof R. Foster, V.V. Vyazovskiy). University of Zurich (Prof. P. Achermann), University of Basel (K. Krauchi), Harvard and Boston University (Prof. E Stanley, Prof F Scheer). Meijer is appointed on the board of the international summer school on biological rhythms (organized yearly in Oxford).

Content / highlights / achievements

  • The major contributions of our group concern the demonstration of robust biophysical and cellular attributes of the pacemaker of the circadian clock – the SCN. We have unravelled the neural mechanisms that confer on SCN neurons their unique pacemaking qualities. We have then demonstrated how the network of clock cells operates, according to time of day, time of year and time of life (aging). Our strength is the combination of approaches, from bioluminescence clock gene expression to single cell ionic channels, to neuronal networks to the behaviour and sleep wake cycle. Our ability to perform in vivo recordings in the SCN of freely moving (transgenic) mice is unique.
  • Light is the most important Zeitgeber for the timing of mammalian behaviour and so defining the light-response characteristics of SCN neurons is crucial for understanding entrainment of the circadian system. We have shown that classical photoreceptors activate the central SCN clock, with short wavelength-cones playing a major role in entrainment. Furthermore, glutamate is the major transmitter signalling between the retina and the SCN, and day length is integrated via the inhibition-excitation balance in GABA action within the SCN.
  • We have defined the emergent properties of neuronal networks in the SCN, exploiting complexity theory, also in collaboration of the depts. of math and physics. Communication within the neural network is diminished with aging, an observation that elaborates weaker circadian rhythms (contributing to loss of sleep consolidation) in the elderly.
  • At the level of the whole organism, sleep and exercise feed back to the SCN and acutely change the output of the SCN. We have shown how feedback leads to enhanced rhythm amplitude and clock robustness.
  • We have shown that disturbances of the clock are brought about by a lack of a proper light dark cycle. In collaboration with other LUMC teams we have shown that this leads rather rapidly to deficiencies in the immune system, metabolic disorders, to muscle weakness and osteoporosis. The characteristics of frailty are reversible upon return to normal light-dark cycles. The findings have repercussions for clinical settings.

Future themes

We will further enhance the translational value of our research by including the analysis of circadian systems of day-active animal models. We will study the influence of light on the SCN function its consequence for the neuronal network organization in the SCN and other brain circuits throughout the lifetime. The use of in vivo and ex vivo electrophysiological techniques will measure the excitatory/inhibitory balance in the brain and show the influence of environmental light pollution on brain function. We will implement a combination of genetically engineered reporters for membrane potential, intracellular calcium and clock gene expression, to identify potential targets for interventions in broken clocks. Clock-enhancing small molecules and transcriptional modifiers will be evaluated for treatment of aging-related dysfunctions and of fatigue caused by cancer therapy. A direct measurement of the function of the human SCN has been challenging, but our recently developed ability to stimulate subjects with specific intensities and wavelengths of light while in the LUMC 7-Tesla fMRI scanner will provide the first real-time measure of SCN activity in humans under these conditions.

At the biological level, our program will provide an in-depth physiological description of the diurnal clock, which is a clear prerequisite for understanding the human clock. This ambition is strengthened by the use of diurnal animal models. In addition, we will perform the first analysis of sex-related differences in in diurnal clock function. At the technical level, the use of transgenic diurnal animals that express fluorescent/bioluminescent reporter activity under the control of a clock gene promoter is highly innovative and will provide the chronobiology field with a much-needed tool for studying the clock, not only in nocturnal but also in diurnal animals.
This will be input for applications in the IC and neonatal settings in the hospital. Lastly, combining our in vivo multi-electrode recordings with clock-modifying compounds is a completely new approach in both diurnal and nocturnal species. At the pharmacological level, we will investigate two novel target sites, providing an innovative approach to developing therapeutic strategies designed to restore healthy circadian rhythmicity.

Cohesion within LUMC

Investigating rhythm disturbances on metabolism and health (Prof P. Rensen, Internal Medicine; Prof A.M. Aartsma-Rus, Human genetics). fMRI studies of the SCN (Dr. T. van Osch, Prof S. Rombouts, Gorter Center) Epigenetics and computational analysis (Prof. P. Slagboom, Medical Statistics and Bio-informatics). Investigating the SCN with electron microscopy (Prof A.J. Koster, Molecular Cell Biology). Introducing the use of viral vectors (Prof. R.C. Hoeben, Molecular Cell Biology; Dr. I. Berlin, Chemical Immunology). Investigation of sleep disorders (Dr G.J. Lammers Dr. R. Fronczek, Neurology). - Investigation of the roles of circadian rhythms in episodic disorders (Prof M. Ferrari, Neurology; Prof. A van den Maagdenberg, Dr. E. Tolner Human genetics). - Chronopharmacology research (Prof H.J. Guchelaar, Clinical Pharmacy & Toxicology). New lines: Investigating sleep, fatigue and rhythm disorders as commonly induced by cytostatics (Prof. J. Neefjes), and investigating possibilities to restore clock function by application of Foxo 4 and CEM3 (Prof. A. Ijzerman, LACDR, Prof. H. Ovaa, LUMC).