Biography

In the early 1980s, I studied at the University of Edinburgh and graduated with a BSc in Psychology. Subsequently I worked as a research assistant in cognitive science before undertaking at PhD on behavioural effects of neuropeptides with Prof Zul Merali at the University of Ottawa in Canada. I then obtained fellowships from NSERC and MRC (Canada) to pursue post-doctoral studies on the neurobiology of circadian rhythms with Professors Ben Rusak and Kazue Semba at McMaster and Dalhousie Universities. In 1996 I set up my own lab at King’s College London and then moved to the University of Manchester in 1998. In Manchester my lab focused on the roles of neuropeptides in the brain’s master circadian clock in the suprachiasmatic nuclei (SCN). We used electrophysiological, neuroanatomical, and behavioural approaches to dissect the functions of gastrin-releasing peptide (GRP) and vasoactive intestinal polypeptide (VIP) in the SCN (McArthur et al., J Neurosci 2000; Cutler et al., Eur. J Neurosci 2003; Brown et al., J Neurosci 2005; J Neurophys 2007). We also pioneered imaging of bioluminescent reporters of the molecular circadian clock in extra-SCN brain regions (Guilding et al., 2009; 2010; 2013) and determined that daily rhythms in neurophysiological state and activity were present in extraSCN structures such as the medial and lateral habenula (Sakhi et al., 2014a,b). In collaboration with mathematicians, we modeled unusual electrophysiological states of SCN clock neurons (Belle et al., Science 2009; Diekman et al., PlosCompBiol 2013) as well as the role of GABA signalling in the SCN (DeWoskin et al., PNAS 2015). More latterly, we investigated how mutations that slow the speed of the molecular circadian clock influence SCN neuronal state and GABA signalling (Wegner et al., 2017). In collaboration with Steve Clapcote (Leeds), we recently characterized unusual circadian deficits in a mouse model of mania (Timothy et al., 2018).

I moved to the University of Bristol in January 2019 to take up the role of Head of School for Physiology, Pharmacology, and Neuroscience. Here in Bristol we are developing new collaborations to investigate circadian rhythms in the brainstem and other extraSCN brain sites. In collaboration with Catherine Lawrence and John Gigg (Manchester) we are also assessing whether scheduled exercise can be used an as intervention to prevent the effects of ageing on brain inflammation and cognitive function. Further, we are collaborating with Prof. Mark Boyett (Manchester) to explore intrinsic circadian mechanisms in the heart.

Research Summary

My lab focuses on intrinsic 24h or circadian rhythms in the brain and in peripheral tissues such as the heart and liver. These rhythms are expressed by almost all living organisms and their molecular basis is remarkably conserved. Circadian rhythms pervade all aspects of our physiology and behaviour including metabolic and cardiovascular processes, cognitive abilities, and motor skills. Therefore, understanding the basis of circadian rhythms is fundamental to biomedical sciences. Indeed, disruption in circadian rhythms such as that experienced by shift workers, elevates the risk of developing cardiovascular and metabolic disorders. We use a variety of approaches and experimental settings to determine how circadian rhythms are organised in the brain, how environmental stimuli reset circadian rhythms, how intracellular molecular clock mechanisms drive neuronal activity and intercellular communication within the brain, and how local clock cells influence the function of brain nuclei.

By convention, research in circadian neurobiology has concentrated on determining the properties and characteristics of neurons and glia in the brain’s main circadian clock in the hypothalamic suprachiasmatic nuclei (SCN). Here rhythmic transcription-translation of clock genes/proteins in neurons and glia of the SCN enable these cells to function as cell autonomous oscillators. However, since the period of each clock cell is slightly different from its neighbour, they must intercellular signals to coordinate their timekeeping. Current candidates for these signals include neuropeptides synthesised by SCN neurons as well as the inhibitory neurotransmitter, GABA, which is made by almost all SCN neurons. The coordinated activity of SCN cells drives daily rhythms in neuronal activity, with SCN neurons firing at a higher rate during the day than the night. This enables the SCN to communicate time of day information to the rest of the brain and body. Intriguingly, rhythmic clock gene expression also occurs in other brain sites and current research is focusing on how neuronal and function in such sites is regulated by ‘local clocks’ as well as how these ‘local clocks’ are aligned with the SCN.

How do Clock Cells Communicate?

Clock cells in the SCN are intrinsic rhythmic, but to synchronize their activities across the SCN network, they must communicate with each other. Using transgenic and reporter models as pharmacological tools, we are investigating how impairments in neuropeptide signalling alter the properties and activities of clock neurons in the SCN. Such approaches reveal that in the absence of key neuropeptide signals, SCN neurons become quiescent and hyperpolarized. Further, investigation of the effects of such deficits on neural network activity with multi-electrode array technology shows alterations in spatiotemporal patterns of SCN neuronal firing rate. Currently, we are exploring how GABA signalling in the SCN is influenced through the loss of neuropeptide signalling.

How to Fix a Broken Clock?

Light is typically viewed as the dominant environmental signal synchronising our circadian system to the external world. However, stimuli that evoke internal arousal are also very effective at aligning our daily physiology. One such stimulus is timed physical exercise and we have found that scheduled voluntary exercise in a running-wheel has particularly profound effects on mice whose circadian system has been severely compromised through genetically targeted deficiencies in neuropeptide signalling. These mice cannot express 24h rhythms in behaviour, but a regimen of scheduled voluntary exercise rescues their 24h rhythms, suggesting that the broken SCN clock has been fixed by exercise. Currently we are examining how timed physical exercise influences brain activity and how it remodels synaptic signalling in the SCN. Further we are assessing how gene expression in brain and peripheral tissues is altered by scheduled voluntary exercise.

Circadian Clocks in the extraSCN brain sites?

Our understanding of the relationship between in the intracellular molecular clock and cellular activity derives from studies of SCN neurons, however, the core clock genes that constitute the molecular clock are rhythmically expressed at other brain sites and peripheral tissues. At present we lack understanding of the locations, characteristics, and functions of extraSCN brain sites. Through visualizing tissue slices in which the molecular circadian clock is reported by bioluminescence, we have detected clock gene rhythms in distinct structures of the hypothalamus, epithalamus, and brainstem. For example, in the mediobasal hypothalamus, a brain region key for homeostatic regulation of energy balance and body weight, we have identified that the arcuate nuclei express robust rhythms in clock gene bioluminescence. Targeted patch recordings from clock gene expressing arcuate neurons reveals that their action potential firing increases at night. This daily change in spiking is absent in mice lacking a functional molecular clock. Currently we are identifying neurochemical phenotype of these putative clock cells and are exploring the physiological role of this arcuate circadian clock.

Other brain areas such as the habenula of the epithalamus also express daily changes in clock genes and electrical activity. Since the habenula is implicated in addiction, we are studying how the sensitivity of habenula neurons to nicotine changes across the day. Similarly, we have found evidence that structures in brainstem that are important in appetite regulation and the control of blood pressure and heart rate also contain circadian clock cells. Currently we are studying the influence of this brainstem clock on daily patterns of physiology and behaviour.

Techniques

whole cell patch-clamp

multi-electrode array

calcium imaging

luminometry

bioluminescence microscopy

laser-capture microdissection

wheel-running

RNAseq

qPCR

immunohistochemistry

ingestive behaviour monitoring

Selected Publications

Timothy et al., (2018) Biological Psychiatry

Wegner et al., (2017) Journal of Neuroscience

DeWoskin et al., (2015) PNAS

Hughes et al., (2015) Scientific Reports

Belle et al., (2014) Journal of Neuroscience

Sakhi et., (2014a) Journal of Physiology

Sakhi et al., (2014b) Journal of Physiology

Guilding et al., (2013) Journal of Physiology

Power et al., (2010) Journal of Biological Rhythms

Belle et al., (2009) Science

Guilding et al., (2009) Molecular Brain

View complete publications list in the University of Bristol publications system.

Some Research-related roles

Guest co-editor, Current Opinion in Physiological Sciences (2018-19)

Editorial Board, Scientific Reports (2016-present)

Editorial Board, Physiological Reports (2014-17)

BBSRC Panel A member (2017-present)

Organiser European Biological Rhythms Society Meeting (2015)

Board Member, European Biological Rhythms Society (2012-present)

Wellcome Trust College of Reviewers (2012-2016)