Regulation of cardiorespiratory control by a novel brainstemcircadian clock

Addtional supervisors: Dr Kate Ellacott (University of Exeter), Dr Jamie Walker (University of Exeter), Dr Craig Beall (University
of Exeter)

All cells in our brain and body contain default molecular clocks that drive daily (circadian) rhythms in our physiology and behaviour including patterns of sleeping, eating, drinking, and information processing. This bodily clock cycle is entrained to a master clock in the hypothalamus that synchronises with the earth’s own day-night cycle using light from the eyes. Intriguingly our heart and breathing
rates as well as blood pressure also fluctuate over the day and this variation emerges through interactions between daily clock cells in the brain and feedback from the heart, lungs and blood vessels. Importantly diseases of the circulation like heart attacks and strokes have a an increased risk in the morning – likely related to this circadian cycle.

How cardiovascular function is influenced by the circadian system is poorly understood. New evidence indicates that the nucleus tractus solitarius (NTS) of the brainstem is of importance. The NTS is the first site in the brain that receives information from the heart and lungs and it plays a key role in mediating protective cardiovascular reflexes. Intriguingly, we recently demonstrated daily rhythms in clock gene expression in the NTS, suggesting that this brainstem structure has its own intrinsic timekeeping capabilities – possibly forming a second central master clock. We also found daily rhythms in genes for neurotransmitter receptors in the NTS. We propose that this brainstem clock regulates how the brain controls the cardiovascular system by altering reflex responsivity.

In this project, state of the art neural recording and imaging approaches will be used in mice, in combination with novel vector tools to selectively control clock gene expression in the NTS. Using this strategy with specific rodent models, will establish how the local clock in the NTS responds to and integrates feedback signals from the body to organize and control daily cardiovascular rhythms. This
project also benefits from mathematical modelling that will inform and augment the design of experimental work. These studies will provide a detailed mechanistic understanding of a novel site for circadian cardiovascular control which may lead to improved approaches to optimise cardiovascular health.

Keywords: Circadian rhythm; brainstem; cardiovascular control; vagus; neuroscience.

Applications must be made before midnight on 3 December 2018