Award details

Determining the membrane circadian clock across evolution

Reference	BB/W000865/1
Principal Investigator / Supervisor	Dr James Hodge
Co-Investigators / Co-Supervisors	Dr Mino Belle, Dr Edgar Buhl, Professor Hugh Piggins, Professor Krasimira Tsaneva-Atanasova
Institution	University of Bristol
Department	Physiology and Pharmacology
Funding type	Research
Value (£)	545,754
Status	Current
Type	Research Grant
Start date	01/06/2022
End date	31/05/2025
Duration	36 months

Abstract

Circadian rhythms are vital for the health, well-being and productivity of individuals with desynchronization of circadian rhythms and misalignment of sleep causing severe health implications and shortening life. With ageing populations, understanding how circadian rhythms changes during senescence is of growing interest and increasing medical and socio-economic relevance. The molecular clock, which is conserved from flies to mammals, drives a circadian rhythm in clock neuron excitability generated by ion channels. This so-called membrane clock is poorly understood but is thought to synchronise clock neurons and convey circadian information to the rest of the brain and body. In flies and mammals, daily rhythms in the molecular clock, clock neuron excitability and behaviour dampen and fragment with age. Our overall aim is to determine the components and mechanism of the membrane clock using flies, mouse and in silico models testing the hypothesis that there is a conserved set of ion channels that generate daily electrical variations in fly and mouse clock neurons. We will then use fly and computational modelling to understand the effect of ageing on the membrane clock testing the hypothesis that ageing alters the daily changes in ion channel mediated membrane properties of clock neurons. Our objectives are to determine which ion channels generate day/night differences in electrical activity of clock neurons in 1) flies 2) mice 3) ageing. This will reveal how the membrane clock has changed during evolution and between a diurnal and nocturnal animal. This work will only be possible by our unique multi-disciplinary and cross species approach integrating computational modelling and dynamic clamp. This research will show how ageing affects neuronal clocks identifying the clock neuron ion channels needed to generate robust circadian rhythms throughout the health span thereby revealing new drug targets and novel treatments for circadian, sleep and ageing disorders.

Summary

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: 1: In flies and mice determine which ion channels generate the day/night differences in electrical activity of clock neurons 2: In flies and mice generate ion channel-based computational models of clock neurons and use dynamic clamp (DC) to test causality 3: In flies determine the circadian consequences of making specific changes in clock neuron ion channels predicted by our models and DC 4: 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.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour, Systems Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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