A time to every purpose: SCN cell-specific control of daily physiological timing

Lead Research Organisation: University of Manchester
Department Name: School of Medical Sciences


Almost every bodily function is influenced by a dominant biological clock within the brain, the suprachiasmatic nucleus (SCN). The timing information provided by the SCN serves to optimise our internal physiology in anticipation of expected demands across the 24h day. Since the timing of peak demand varies between different behavioural or physiological processes (e.g. sleep, cardiovascular and gastrointestinal), particular aspects of physiology need to be individually timed to ensure health and well-being. The impact of temporary disruptions to this internal coordination will be familiar to anyone who has experienced jet-lag. Unfortunately, it is now clear that longer-term disruptions to our internal timing mechanism are associated with a number of serious health consequences including increased risk of cancer and metabolic disease. Accordingly, here we seek to understand the biological mechanisms by which the SCN clock coordinates activity across the rest of brain and body, and how this is disturbed during shifts in the environment.

In particular, we will determine whether the ability of the SCN clock to differentially control so many different aspects of physiology stems from the presence of multiple subsets of 'clock cells', each with unique properties. In support of this view, it is well known that clock cells produce a variety of different neurochemical messengers and/or send signals to different regions of the brain. Our own recent work indicates that the functional properties of clock cells are also diverse, with different groups of clock cells becoming electrically active at different times of day. Similarly, it is well established that the major signal required for synchronising the SCN clock to the external world is supplied by the retina, and we and others have now identified various groups of clock cells that exhibit distinct responses to changes in lighting conditions.

Until now a major impediment to answering this fundamental question as to how the SCN orchestrates physiology has been an inability to directly connect the functional properties of particular subgroups of clock cells to specific aspects of physiology. Recent advances in viral and genetic targeting now make this goal achievable. We will employ these cutting-edge approaches to allow us to selectively identify and monitor the activity of groups of clock cells communicating to specific brain regions and/or producing particular chemical messengers. We will thus be able to determine the nature of the timing signals supplied to key regulatory centres across the brain and how these are influenced by short or longer term changes in the light environment. We will then use similar approaches to specifically manipulate the activities of the these cell groups during comprehensive physiological and behavioural monitoring, allowing us to unequivocally link the activity of particular groups of SCN cells to specific body functions (such as metabolic rate, feeding behaviour, heart rate, etc).

This project will produce a crucial advance in our understanding of how our internal clock influences the rest of the body. Moreover, by determining how the activities of various groups of SCN cells are influenced by changes in light environment, this work will also provide new insight into the mechanistic basis of the physiological disruptions that occur as a result of shift work or crossing time zones. Finally, we expect this work to uncover new ways of using light to selectively adjust the activities of specific SCN cell groups with particular physiological roles. Such strategies that could be of substantial practical benefit to the wide sections of society whose internal clocks are misaligned with their societally imposed schedules.

Technical Summary

The master clock in the suprachiasmatic nucleus (SCN) coordinates diverse behavioural and physiological processes across the day. Such temporal coordination is critical to anticipate and adapt body systems to changing demands and physiological status (e.g. sleep/arousal, fed/fasted). As a consequence, specific aspects of physiology must be individually tuned to exhibit optimal activity at different times relative to each other and to the environment. We seek to understand how the SCN achieves this impressive feat.

The basic function of the SCN is well established; retinal inputs align cellular clocks with the environmental light cycle, which then relay this temporal signal to regulatory centres across the brain. In the face of overwhelming evidence indicating that SCN cells are both neurochemically and functionally heterogeneous, this simplistic view of clock function is now inadequate. Our recent data indicates the presence of multiple SCN subgroups exhibiting electrical activity at different times of day and divergent responses to changes in lighting condition.

We propose that these functionally distinct cell groups also differ with respect to anatomical connectivity and/or neurochemistry and, as a consequence, control different aspects of physiology. To test this, we will employ cutting-edge viral and genetic targeting in combination with large-scale electrophysiological recordings to identify and manipulate defined populations of SCN output neurons. We will first use these approaches to characterise patterns of daily electrical output, sensory properties and longer-term influences of light on SCN neurons with defined anatomical connectivity and/or neurochemistry. We will then employ selective cell ablation or activation alongside comprehensive physiological measures to confirm the functional roles of these populations of SCN output neurons. In sum, this work will provide the vital information required to understand how the SCN orchestrates physiology.

Planned Impact

The research questions addressed in this proposal are of major interest to ACADEMIC GROUPINGS in Biological and BioMedical Sciences. The academic community will benefit from elucidation of novel mechanisms through which the circadian system impact on our physiology. Understanding the neural basis for homeostatic control, and how altered environmental lighting impact clock function presents clear implication to human health and welfare. As such, research findings will impact greatly on the HEALTH CARE COMMUNITY. We will disseminate findings by publishing primary papers and reviews in high impact journals, and presenting work at national and international meetings. We anticipate that the work will produce 3-4 high-quality primary research papers.

Our findings will be of interest to the GENERAL PUBLIC due to the 24hr lifestyles imposed by our modern society. At its most basic, the work will engage sections of the populous who wish to learn about their health and human physiology. This work also has realistic potential to inform the general public and GOVERNMENT REGULATORS about how lighting environments impact on our physiology, and advance therapeutic/practical applications of light. For example, TB recently participated in a workshop on non-image-forming effects of light (Manchester, Jan 2013) attended by representatives of the international lighting regulator CIE. The outcomes of this activity were a scientific consensus review (Trends Neurosci. 37:1-9) and a CIE report (CIE R6-42), to which TB is a scientific advisor. Information from this in turn informed US Department of Energy guidance on solid-state lighting (PNNL-SA-102586). Research findings will be delivered to the general public through public engagement activities (e.g. brain awareness week) and mass media. For example, our recent articles in PLoS Biol and Curr Biol were reported widely in national and international newspapers, radio, BBC television, and on the intranet.

This research is of interest to the COMMERCIAL SECTOR due to direct implications for lighting and electronics industries. Our research will inform the design of healthy lighting environments. Our project also has the potential to advance therapeutic/practical applications of lighting design to achieve specific effects on particular aspects of our physiology. The practical applications of such approaches are considerable given the ~20% of the workforce in industrialised nations whose circadian clocks are misaligned due to rotating shift work, and that circadian dysfunction has been linked to sleep disorders, mental health disorders, cancer, inflammation, and aging. In the context of "building partnerships to enhance take-up and impact, thereby contributing to the economic competitiveness of the United Kingdom", our labs are currently involved in collaborations with Pfizer and Phillips on circadian-related projects, and regular communication with these companies will ensure research findings are taken-up by and impact upon industrial beneficiaries. The Faculty of Life Science at UoM has taken a strong proactive role in developing links with industry, enhancing public communication of science, as well as development of commercialisation opportunities.

Through increased understanding of the impact of lighting environment on physiology and well-being, our work will also impact on ANIMAL HUSBANDRY and the WELFARE of MANAGED ANIMALS. Although long recognised that appropriate visual environments are an important component of good animal care, empirical data regarding what these should entail is relatively sparse. This will be highly relevant for both livestock management, as well as in biomedical research.

This proposal also offers a significant opportunity for high level in vivo training of the PDRA, technician, and any PhD students joining for related work. This is a significant benefit, as a lack of in vivo research training has been highlighted as a weakness in UK bioscience.
Description i) We identified a new role for one of the major cell-types in the central circadian clock in communication of circadian signals to downstream hypothalamic neurons involved in the control of heart rate and neuroendocrine function (Nat Commun; 2020). Specifically, the identified cells (VIP-expressing neurons of the SCN) display a specifically timed daily increase in neural activity that inhibits downstream cells and suppresses corticosterone release and heart rate. We also identify specific roles for both VIP and non-VIP-expressing neurons in driving circadian and light-dependent changes in the activities of discrete subsets of downstream hypothalamic and thalamic cells (BMC Biol; 2020).
ii) We developed an automated approach for analysing circadian control of cardiac conduction parameters, enabling us demonstrate a critical role for circadian alignment to the environmental light dark cycle in cardiovascular health (Nat Commun, 2017a)
iii) We developed new experimental tools for assessing cell-cell communication (J Physiol 2018) and sensory properties (Nat Commun, 2017b) with widespread applicability to understanding the organisation and function of circadian and visual circuits. As part of this activity we identified a new mode of binocualr integration in regions of the visual thalamus important for regulating circadian responses to light.
Exploitation Route As indicated above, our findings shed new light on the biological mechanisms by which the central clock (and light input to this region) coordinates key aspects of downstream physiology. These findings potentially open up new avenues for pharmaceutical or light based manipulations designed to adjust circadian physiology to promote health.

We also developed several new tools that of widespread use to the scientific community for understanding the impact of circadian misalignment in both animal and human models (ii) and for increasing understanding of the neural circuit mechanims that underly such effects (as a means to develop new treatments).
Sectors Energy,Environment,Healthcare,Pharmaceuticals and Medical Biotechnology

Title Automated ECG analysis 
Description Developed a set of computational tools for automated analysis of ECG waveform parameters suitable for assesment of circadian variation over mutli-day timeseries 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2017 
Provided To Others? Yes  
Impact Has facilitated a deeper undertsanding of fundamental controls on mammalian physiology with potential future benefit to human and animal health 
URL https://www.nature.com/articles/s41467-017-00462-2