Determining the membrane circadian clock across evolution
Funder: Biotechnology and Biological Sciences Research Council (BBSRC) (£550k)
Project duration: 2022-2025
Principal Investigator: Prof James Hodge, University of Bristol
Collaborating Institutions: University of Bristol, University of Exeter, University of Manchester,
Circadian clocks are found in all animals and are fundamental to life allowing the study of clocks in animals that are easy to keep, age and do experiments with. Hence, nearly all clock genes and how they form a molecular clock were identified in flies and later found to be conserved in mice and humans. This and the fact that circadian rhythms profoundly affect all aspects of physiology and health, led to Nobel prizes being awarded to fly circadian researchers.
The molecular clock consists of clock genes that switch themselves on and off every 24hours in the clock neurons of the brain. In our '24/7 society', an increasing proportion of the population experience de-synchronisation of their circadian clock with the external world, due to shift-work, access to technology, anti-sleep drugs, irregular sleep and eating patterns. This so-called 'social jetlag', like jetlag can contribute to an alarming increase in health risks, being associated with the mental health crisis, cancer, diabetes, addiction, metabolic and sleep disorders, with 30% of people experiencing insomnia. Furthermore 40-70% of the elderly population experiences chronic sleep disturbances with Alzheimer's and Parkinson's causing more pronounced circadian and sleep deficits contributing to their pathology. We have also shown that insect clocks are important for pollinator health and food security and are negatively impacted by insecticides that target clock neuron ion channels.
The master clock in the brain consists of a neural circuit of clock neurons that receive and transmit time of day information via electrical signals that are bi-directionally influenced by the molecular clock. Electrical signals are generated by ion channels in the membrane which control the release of chemical signals between neurons relaying temporal information throughout the clock and to the rest of the brain and body. We have shown that the membrane of clock neurons is more electrically excitable in the day than at night in flies and mice. These ion channel generated electrical signals are thought to help synchronise clock neurons and interact with the molecular clock to generate an overall strong and sustained circadian rhythm. We have shown this weakens with age.
However there is a knowledge gap in the exact components and mechanism of this so-called membrane clock and how it is affected by ageing.
We wish to determine the clock neuron ion channels that generate day v night differences in clock neuron excitability in flies, mice and ageing. Therefore our aim is to decipher the components and mechanism of the membrane clock using flies, mouse and computational models testing the hypothesis that there is a conserved set of ion channels that generate daily electrical variations in fly and mouse clock neurons. This will reveal the electrical basis of diurnal v nocturnal behaviour and whether by manipulating the membrane clock to become mouse like you can make a fly become nocturnal. We will test if ageing alters these daily changes and what effect it has on circadian rhythms and health span.
Therefore the objectives are:
In flies and mice determine which ion channels generate the day/night differences in electrical activity of clock neurons
In flies and mice generate ion channel-based computational models of clock neurons and use dynamic clamp (DC) to test causality
In flies determine the circadian consequences of making specific changes in clock neuron ion channels predicted by our models and DC
In flies, determine the effect of ageing on ion channels that generate day/night differences in clock neuron electrical activity
This research will identify the clock neuron ion channels required to generate robust circadian rhythms throughout the health span revealing interventions that we will test to rejuvenate the excitability of old clock neurons and reverse circadian ageing. This will develop new drug targets and treatments for circadian, sleep and ageing disorders.