Award details

Chronotype and circadian reafference: the impact of free will on the mammalian circadian clock

Reference	BB/V011111/1
Principal Investigator / Supervisor	Professor Robert Lucas
Co-Investigators / Co-Supervisors	Professor Timothy Brown
Institution	The University of Manchester
Department	School of Biological Sciences
Funding type	Research
Value (£)	650,061
Status	Current
Type	Research Grant
Start date	01/09/2021
End date	31/08/2024
Duration	36 months

Abstract

Circadian rhythms are a fundamental feature of life, and an important consideration in agriculture and human/animal health. Recent decades have seen enormous strides in understanding the basic architecture of circadian clocks and the mechanisms by which they influence physiology and behaviour. An important next challenge is to understand how these circadian rhythms function in the real world and respond to anthropogenic changes in the environment. Here we address a ubiquitous but currently understudied aspect of that problem. The advent of artificial lighting has allowed humans unprecedented freedom to choose when to be active and exposed to light. Such choices are strongly influenced by circadian phase, and can themselves change clock phase and period. Thus, a new feedback loop is established in which the clock produces actions that themselves create reafferent inputs to the clock. Understanding how this arrangement impacts circadian rhythms requires a model organism in which activity and arousal usually co-occur with light exposure and which is capable of controlling its own light exposure. In Manchester, we have developed the diurnal murid rodent Rhabdomys pumillio as a new model for circadian research and shown that it meets these criteria. We have trained Rhabdomys to switch lights on/off and found that they do so with a strong circadian rhythm, choosing light while awake and dark to sleep. We will now use long term behavioural studies and focussed neuro-anatomical and electrophysiological approaches in this animal to establish how: 1) access to self-selected light changes fundamental parameters of the circadian clock (intrinsic period, alpha, amplitude, and phase angle of entrainment); 2) activities facilitated by access to light (exercise and arousal) function as 'non-photic' influences on the clock and modulate the effects of light; 3) imposed changes to light exposure can alter the circadian impact of these re-afferent sensations.

Summary

Why can't you tickle yourself? Because we experience sensations that are a product of our own actions as quite distinct from those that arise from the action of external agents. Sensations produced by ourselves are termed 'reafferent' and are a common feature of our everyday experience. Importantly, the same sensation can have a quite different meaning if it is reafferent - when running through a forest stationary trees appear to rush towards you, distinguishing this apparent motion from the real motion of a tiger jumping out could be a matter of life and death. As a result, recognising reafferent sensations and responding accordingly is one of our brain's most important functions. However, there is a class of reafferent sensation which presents a particular challenge because it is entirely a product of modern-day life. Access to artificial light has disrupted the previously inviolable relationship between ambient light intensity and time of day. An event (the appearance of light), that previously always signalled daytime, can now instead reflect our own actions (be reafferent). We might wish that the brain was able to distinguish the rising sun from the light switch, but because the latter is an entirely artificial situation it cannot. An additional problem is the activities which artificial light facilitates - both arousal and exercise were previously tied to the light:dark cycle and reinforced that sense of daytime. The brain still takes them as time cues, but now their timing is often a function of our own choices. These newly reafferent sensations impinge upon our internal biological (circadian) clock which provides an internal reflection of external time. It has been suggested that our ability to self-select the timing of light exposure and associated activities explains why there is so much variation in preferred sleep time ('chronotype') among humans. 'Larks' (early to bed, early to rise) and 'owls' (stay up late) can show very different preferences. Fitting such divergent preferred sleep times to a uniform 9-5 work/school routine disrupts biological rhythms, the most obvious manifestation of which is so called 'social jetlag' in which owls are sleep deprived during the week and sleep in at weekends. Such disrupted rhythms impair school/work performance and contribute to widespread and intractable public health problems including mood disorders and obesity. There is thus an urgent need to understand how reafference impacts biological clocks and what we may be able to do about it. Addressing this question in laboratory animals, in which we can achieve high control over experimental conditions and uncover mechanisms, is an important element of this endeavour. Unfortunately, common lab animals (mice and rats) do not recapitulate important aspects of reafference because they are nocturnal. They typically avoid light, and display arousal and activity during their night-time. We have established a new laboratory rodent, the 4-striped mouse, which is strongly day active. In preparation for this proposal, we have shown that these animals can be trained to switch their lights on and off, and use this freedom to express familiar preferences - choosing bright light during the day and darkness to sleep at night. This breakthrough provides the first opportunity to study the impact of self-selected light in lab animals. We will use the 4-striped mice to determine how daily rhythms in rest/activity are impacted by access to self-selected light and how this appears on simulated 'work' (when they are woken in the morning) and 'free' (when they can choose their own wakeup time) days. We will establish how arousal and exercise impact rhythms by studying the part of the brain that houses the clock and by looking at how they alter rhythms in rest/activity. We will finally trial strategies for supporting good biological rhythms in the face of reafference.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Industrial Partnership Award (IPA)

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