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Circadian Rhythm Research

 

Circadian rhythms may become desynchronized in infectious diseases, neurodegenerative diseases, psychiatric disorders and ageing (“Timeless” . From Lundkvist 2001, Doctoral thesis).

Humans and other organisms are adapted to the solar cycle and our physiology and behavior undergo daily (circadian = 24 hr) rhythms that are generated by an internal “body clock”. When these rhythms become desynchronized by internal or external factors, we experience stress and discomfort that leads to decreased physical and mental capacity. A classical example of desynchronization of bodily rhythms is during “jet lag”, which occurs after rapid traveling across time zones because the internal body clock is out of phase with the external environment. Disturbed rhythms are also common in psychiatric diseases, neurodegenerative diseases and aging. Strategies to restore circadian rhythms of physiological functions as well as chronobiological approaches to classical medical therapies are therefore rapidly developing in order to treat rhythm disturbances and to optimize effects and minimize toxicity of drug administration. The master clock generating circadian rhythms is located in the bilateral suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN generate and drive physiological rhythms such as the daily sleep-wake cycle, hormonal fluctuations and immune activities. Circadian rhythms appear to be generated by molecular feedback loops of rhythmically expressed genes and their protein products, which, through interactions, generate a circa 24-h cycle of transcription and translation of clock and clock-controlled genes. Recent studies suggest that also neuronal membrane activity may play a crucial role in circadian rhythm generation.

Interactions between transmembrane ion fluxes and clock gene expression in rhythm generation and expression.

To understand alterations of circadian rhythms it is vital to gain knowledge about how rhythms are generated. Circadian rhythms appear to be generated by negative feedback loops of rhythmically expressed genes and their protein products. However, it is less clear whether electrical activity, postsynaptic events, and transmembrane ion fluxes also are essential elements in rhythm generation. We have recently found that neuronal membrane activity and voltage gated calcium flux may indeed play a crucial role in circadian rhythm generation. This project addresses the question of whether membrane potential and calcium influx are involved in generation of mammalian circadian rhythmicity, rhythm entrainment and mechanisms underlying transmembrane ion fluxes and intracellular clock gene expression. In combination with electrophysiology, molecular biology techniques and calcium imaging, we will measure rhythmic expression of a clock gene, Period, real time by using tissue from transgenic animals carrying a luciferase reporter that is linked to the Period gene. In this in vitro system we can manipulate membrane potential and calcium signalling while monitor rhythms in a non-invasive manner. The project will be undertaken as collaboration between Gabriella Lundkvist and Gene Block, University of Virginia, USA. We hope these studies will provide novel information about the role of membrane potential and calcium in mammalian circadian timing (Supported by 2 R01 MH062517-04A1).

Relevant publications

1.      Lundkvist, G.B., Kwak, Y., Davis, E., Tei, H. and Block, G. D. A calcium flux is required for circadian rhythm generation in mammalian pacemaker neurons. J Neurosci 2005 25(33):7682-6

2.       Lundkvist G. B. and Block G. D. The role of neuronal membrane events in circadian rhythm generation (2005). Methods in Enzymology 393:623-42.

The Ageing Clock—ageing and inflammation

During aging several features of circadian rhythms are altered. Some of these alterations seem to be related to changes in the SCN in aged animals. We use electrophysiological techniques (whole cell patch clamp and extracellular multi-unit recordings) to investigate the SCN of young and old mice. In this way we can detect age-related changes of the SCN network both on a synaptic and a multi-unit level. These studies are complemented with immunohistochemistry and real-time PCR analysis of relevant molecules involved in neurotransmission.

            Aging is associated with increased inflammation in the periphery and the brain. We know that cytokines can affect circadian rhythms and neurons of the SCN and are therefore investigating whether neuro-immune interactions in the SCN are affected during aging.

Relevant publications

  1. Sadki A., Bentivoglio M., Kristensson K. and Nygard M. Suppressors, receptors and effects of cytokines on the aging mouse biological clock. Neurobiol Aging. 2006 in press.

  1. Nygard M., Hill R.H., Wikstrom M.A. and Kristensson K. Age-related changes in electrophysiological properties of the mouse suprachiasmatic nucleus in vitro. Brain Res Bull. 2005 Mar 15;65(2):149-54.

Circadian Disturbances in African Sleeping Sickness (Trypanosomiasis)

African Sleeping Sickness is characterized by a severe disruption of the sleep-wake cycle. We are investigating the impact of the circadian component of this disease. The project is described under the “Sleeping Sickness” section.

Rhythm Dysfunctions in Bipolar Disorder and Seasonal Affective Disorder

Bipolar Disorder appears to be characterized by alterations in circadian rhythms such as the sleep-wake pattern. As for unipolar disorder (major depression), it has been hypothesized that the circadian clock is affected in bipolar patients. In collaboration between G Lundkvist and Professor Jerker Hetta and his co-workers, Affektiva mottagningen, Huddinge sjukhus, circadian disturbances of patients with bipolar disorder and seasonal affective disorder (SAD) will be examined.

 

Division of Neurodegenerative Disease Reseach, Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77
Stockholm, Sweden
webmaster@neuro.ki.se

Updated: Wednesday, October 17, 2007