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A systems biology approach using electrophysiology and modelling to determine the membrane clock

Bristol student theses: Doctoral ThesisDoctor of Philosophy (PhD)

Authors

  • Phil Smith

Research units

Abstract

Circadian rhythms (endogenous 24-hour rhythms of physiology and behaviour) are vital to health and wellbeing; disruption of these rhythms has been linked with health problems such as depression, diabetes, and cancer. Modern times have seen an increase in the use of artificial lighting at night, which has been associated with growing circadian disruption in the general population. This means that understanding of the circadian machinery is increasingly important. Previous studies have shown that clock neurons in the fruit fly Drosophila melanogaster called the lateral neurons ventral (LNvs) are an important part of the circadian system and display electrical properties that vary with the time of day, particularly in action potential firing rate. However, the mechanism of how these neurons produce this change is not yet fully understood.

To address this, we investigated the role of voltage-gated potassium channels in generating different activity profiles during the day and night. We utilised electrophysiological techniques, computational modelling, and behavioural assays to show that changes in the current of certain ion channels, namely Shaw (Kv3) current being highest at dawn and Shal (Kv4) current being highest at dusk, support a shift between the more active morning state and the less active evening state of LNv neuronal activity. These ion channels are key in the generation of functional circadian rhythms, where disruption is detrimental to sleep patterns, and in supporting good overall health of the fly. Computational modelling of these channels led to a model of the LNv neuronal activity that allowed the first implementation of an electrophysiological and modelling technique called dynamic clamp in Drosophila. The model was subsequently applied to investigation of human essential tremor and the associated channel Kv9 showing increased neuronal hyperexcitation. These results enhance the understanding of how the LNvs function and potentially offer more insight into their physiological importance.

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
  • James Hodge (Supervisor)
  • Krasimira Tsaneva-Atanasova (Supervisor)
Award date23 Jan 2019

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