Neurophysiology

Projectleader/contact

Prof. Dr.Meijer, J.H. (Joke)

Principal Investigators

Dr. S. Michel
Dr. T. de Boer
Dr. R.J. van den Berg
Dr. P.C. Molenaar
Dr. J.J. Plomp

Research Overview

The laboratory for neurophysiology has the following lines of research:

1. Neurophysiology of the circadian system (Prof. Dr. J.H.Meijer)
2. Cellular mechanisms for circadian timing (Dr. S. Michel)
3. Circadian rhythms and sleep (Dr. T. de Boer)
4. Ion channels and fusion pores in neural membranes (Dr. R.J. van den Berg, Dr. P.C. Molenaar) 

Neurophysiogical studies are performed on the circadian pacemaker system of mammals, as a model for research in the neurosciences, and on the regulation of ion channels which underly neurophysiological signaling. Ion channels are investigated in different preparations such as in the circadian clock, peripheral nerves and in cultured neuroendocrine cells. The circadian pacemaker (circa: about; dies: day) drives 24 hour rhythms in many of our physiological functions. For instance, sleep, hunger, performance, brain and peripheral organ activity are all subject to circadian modulation. Recent estimations indicate that also 10% of our genes may be under circadian control, and are expressed at certain times of the day-night cycle, but not at others. In addition to a role in daily cycles, the circadian pacemaker is strongly involved in seasonal cycles and tracks the changes in day length. The Neurophysiology group has a strong interest in the circadian timing system and sleep regulation. In mammals, the circadian pacemaker is located in the suprachiasmatic nucleus of hypothalamus. Single cells of the clock are able to generate 24 h rhythms on the basis of transcriptional-translational feedback loops, in which protein products inhibit the expression of clock genes. The protein products also seem to drive circadian patterns in ion channels, membrane potential and electrical activity of the cell, which is a primary output of the clock.

Topics

Understanding the circadian pacemaker at a neuronal network level. While single SCN neurons have the capacity to generate 24 h rhythms, they may not be able to code for day length. Instead we hypothesize that day length encoding is a neuronal network property. We also propose that resetting to new time zones (shift work) is critically dependent on the interaction between different anatomical areas within the circadian pacemaker that are mutually coupled. Techniques: mathematical simulations, acute slice preparations, in vivo electrophysiology, behavioral experiments. Main researcher: Prof. Dr. J.H. Meijer (see highlight 1, 3, 5 and 6)

Understanding the interaction between gene expression and membrane potential. To this purpose, gene expression measurements will be combined with electrical activity recordings. While genes code for a rhythm in membrane potential, recent evidence indicates that membrane activity may vice versa be intimately involved in the rhythm generating mechanism. To study this interaction between membrane and genetic components of the clock, techniques are currently implemented such as: patch clamp recordings in combination with imaging techniques in acute as well as organotypic brain slices. Main researcher: Dr. S. Michel; Dr. R.J. van den Berg (see highlight 4 and 9)

The clock as an integrated part of the central nervous system. Sleep, wakefulness and behavioral activity are under strong circadian control. We found evidence that sleep, wakefulness and behavioral activity themselves are effective in altering circadian clock activity. These experiments have shown that the circadian pacemaker is not only responsive to light, but also to other stimuli. The electrical activity of the clock is investigated as an integrated part of the central nervous system in a behaving animal. Techniques: EEG recordings, in vivo electrophysiology, behavioral experiments. Main researcher: Dr. T. de Boer (see highlight 2, 7 and 8)

Ion channel investigation occurs in different preparations such as as in the circadian clock, peripheral nerves and in cultured neuroendocrine cells. In the peripheral nerve preparation, we investigate regeneration of the nerve following mild damage. Extracellular recordings are performed to asses the functional status of the nerve. In cultured neuroendocrine cells we study excotysosis of secretory granules. These are cultured PC12 cells, obtained from the adrenic medulla of the rat. With carbon fiber amperometry we measured the release of small packages of catecholamines. Furthermore we investigate the effects of local aneasthetics on cultured dorsal root ganglion cells.

Highlights

1. VanderLeest, H.T., Houben, T., Michel, S., Deboer,T., Albus, H., Vansteensel, M.J., Block, G.D. and Meijer, J.H., Seasonal encoding by the circadian pacemaker of the SCN, Current Biol. 17 (2007) 468-473.
2. Deboer, T., Détari, L., Meijer, J.H., Long term effects of sleep deprivation on the mammalian circadian pacemaker. Sleep, 30 (3) (2007) 257-262
3. Rohling, J., Wolters, L., Meijer, J.H., Simulation of day-length encoding in the SCN: from single-cell to  tissue-level organization. J. Biol. Rhythms, 4 (2006) 301-13.
4. Itri, J.N., Michel, S., Vansteensel, M.J., Meijer, J.H., and Colwell, C.S., Fast delayed rectifier potassium current is required for circadian neural activity, Nature Neuroscience, 8(5) (2005) 650-656.
5. Albus, H., Vansteensel, M.J., Michel, S., Block, G.D. and Meijer, J.H., A GABAergic mechanism is necessary for coupling dissociable ventral and dorsal regional oscillators within the circadian clock., Current Biol., 15 (2005) 886-893.
6. Schaap, J., Albus, H., van der Leest, H.T., Eilers, P.H.C., Détari, L., Meijer, J.H., Heterogeneity of rhythmic suprachiasmatic nucleus neurons: implications for circadian waveform and photoperiodic encoding, PNAS, 26 (2003) 15994-15999.
7. Deboer, T., Vansteensel, M.J., Détari, L., Meijer, J.H., Sleep states alter activity of suprachiasmatic nucleus neurons, Nature Neuroscience, 10 (2003) 1086-1090. see also: Colwell, C.S., Michel S (2003) Sleep and circadian rhythms: do sleep centers talk back to the clock? Nat Neurosci 6: 1005-1006
8. Vansteensel, M.J., Yamazaki, S., Albus, H., Deboer, T., Block G.D., Meijer J.H., Dissociation between circadian Per1 and neuronal and behavioral rhythms following a shifted environmental cycle, Current Biology, 13 (2003) 1538-1542.
9. Albus, H., Bonnefont, X., Chaves, I. Yasui, A., Doczy, J., van der Horst, G.T.J., Meijer, J.H., Cryptochrome-deficient mice lack circadian electrical activity in the suprachiasmatic nuclei, Current Biology 12 (2002) 1130-1133.
10. Walsh IB, van den Berg RJ and Rietveld WJ. Ionic currents in cultured rat suprachiasmatic neurons, Neuroscience 69 (1995) 915-29.

Relation with other LUMC research themes

Research in this group has strong links to research performed in the Departments of Human Genetics (Prof. R. Frants, Dr. A. van den Maagdenburg, Dr. K. Willems van Dijk) and the Departments of Neurology (Dr. J.J. Plomp, Dr. G.J. Lammers, Prof. M. Ferrari), Endocrinology (Prof. H. Romijn, Dr. H. Pijl), Klinische Farmacie en Toxicologie (Prof. H.J.Guchelaar), Neurochirurgie, (Dr. E. Lakke) and Anaesthesiology (Prof. A. Dahan).

Keywords

• Circadian rhythms
• neurophysiology
• neurotransmitter
• light
• ionic channels
• patch clamp
• electrophysiology
• biological clock
• sleep
• EEG