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.