Neural circuits of non-image-forming vision

Lead Research Organisation: University of Manchester
Department Name: Earth Atmospheric and Env Sciences


Humans have a strong tendency to underestimate the degree to which their behaviour is defined by sub-conscious processes. Thus, for example, we think of the eye as the origin of visual perception, but ignore its equally important role in adjusting our physiology and behaviour according to time of day. It achieves this latter task by measuring the level of ambient illumination, which throughout our evolutionary history (indeed until the recent advent of electric lighting) has provided accurate indication of time of day. This information about ambient light levels is communicated a set of brain regions that specifically regulate these so-called non-image forming (NIF) visual processes, including setting the 'body-clock', regulation of sleep, hormonal systems and pupil size. In particular, through actions on the body clock, light intensity indirectly regulates almost all body processes from athletic ability to cognitive performance. Aside from their key role in regulating 'healthy' physiology, understanding these subconscious light responses is particularly important since disruption of their normal functioning (as can occur in shift workers, business travellers or as a consequence of various neurological disorders) has been linked to serious health consequences. These include sleep and metabolic disorders, cancer, depression and increased risk of work-related accidents. At present we know that a network of interconnected brain regions control these subconscious responses to light, yet we have very little idea how these different brain regions interact to produce these responses. Specifically, we know that each of these regions contains various types of cells which use different chemical messengers to communicate, but we do not know which of these cell types connect to one another. This is particularly important because existing studies of brain networks tell us that many of their most important properties arise through the interactions between cells rather than being inherent to the individual cells that make them up. Indeed, understanding how these cellular interactions enable the brain to perform its many functions is currently the major challenge facing neuroscience. I propose to address these substantial gaps in our knowledge as to how the brain uses information about ambient light levels to regulate physiology. Using cutting edge experimental and theoretical approaches this research will determine which cells in the NIF visual system communicate with which other cells, how they influence each other and how they communicate to other brain systems to regulate physiology and behaviour in response to the external lighting environment. This detailed understanding of the NIF visual system will put us in a position to devise more effective strategies to modulate it, with substantial therapeutic and practical implications. These applications include the identification of targets against which we can design new drugs or particular time-windows at which drugs or light application would be most effective at correcting dysfunction of the system such as occur in normal ageing, mental health disorders, shift work or when crossing time zones. Moreover, this work may potentially open up new avenues for the use of light as a therapeutic tool in its own right; potentially allowing for the selective manipulation of various body systems without the side effects that associated with pharmacological treatments.

Technical Summary

To date, studies of vision have concentrated overwhelmingly on the processes of perception. However, a significant portion of the retinal output targets elements of a non-image forming (NIF) visual system, responsible for a fundamental realignment of behaviour and physiology according the level of ambient illumination. The important brain nuclei of this NIF visual system are well established. However, there is abundant evidence of interconnections between these nuclei, implying that they interact to define NIF responses. The concentration until now on studying each region in isolation likely underestimates the importance of this network organisation. My aim is to bridge that gap by determining the degree to which sensory capabilities of NIF vision are an emergent property of the interconnected network, and how these contribute to its function. Achieving this goal requires the ability to assess the visual responses of cells with known NIF system connectivity, to selectively modulate specific cells/regions from which they receive input and rigorous methods for quantifying the visual information they encode. My expertise with NIF system neurophysiology and analytical approaches make me uniquely placed to undertake this work. I propose to use cutting-edge multielectrode recording/stimulation techniques, advanced computational analyses, neuroanatomical and pharmacological approaches to reveal: 1) the functional circuitry linking NIF system cells, 2) the roles of defined cell types and specific neurochemical messengers in various NIF responses and 3) the significance of the NIF system circuitry for the sensory coding properties of individual cells and the system as a whole. By furthering our understanding of how NIF system output drives such a wide array of responses, this research should also uncover mechanisms through which light directly modulates various aspects of physiology, potentially opening up new avenues for the use of light as a therapeutic tool.

Planned Impact

The project encompasses several different fields of biological research (circadian biology, vision research and computational neuroscience) and will be of specific interest to scientists in those broad areas but also, more generally, to all neuroscientists and animal biologists since it will provide a model for studying and understanding how the activities of neural networks give rise to behaviour and physiology. This includes the development of experimental and analytical approaches as well as conceptual insights into the organisation of brain networks. Impacts will be maximised by publishing the results in well respected journals and by presentations at well-attended national and international meetings (SFN-regularly attended by > 25,000 scientists and SRBR-attended by all major biological rhythms groups). My career so far has resulted in regular publications (including 15 in the last 5 years) and it is anticipated that the proposed studies will result in 5-6 major publications (2-3 in high-impact journals e.g. Nature Neuroscience, Neuron, Journal of Neuroscience etc. and 2-3 mid-level, e.g. Journal of Neurophysiology). Disruptions in the circadian system, such as those associated with shift work, business travel, ageing and mental health disorders are known to significantly contribute to reduced quality of life and are also associated with serious health consequences in their own right including increased risk of cancer and work related accidents. This proposal addresses the major gaps in our knowledge regarding how the brain uses light information to regulate the circadian clock, and other non-image forming visual processes, and as such may potentially identify strategies that can rectify the dysfunctions that occur in the situations discussed above. Such strategies might be pharmaceutical agents, perhaps applied at particular times of day, but could also include identification of particular shift patterns or light exposure paradigms to minimise disruptions of the biological clock. As such, in the long-term insights arising from these studies are of potential benefit to the general public health and to businesses and government (by increasing staff productivity, reducing healthcare expenditure etc.). This proposal will also have significant impact for the staff working on the project. On my part, it will enable me to establish myself as an independent researcher and a leader in the field. This fellowship will also allow me to expand my skill set into more advanced areas of experimental and theoretical neuroscience and develop my experience with the managerial aspects of running a research group. For staff working on the project it will give them the opportunity to experience a wide range of cutting edge scientific techniques as well as developing a range of highly transferable skills (e.g. IT, organisation, time management) that will be of great use to them through their future careers.


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Howarth M (2014) Binocular integration in the mouse lateral geniculate nuclei. in Current biology : CB

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Lucas RJ (2014) Measuring and using light in the melanopsin age. in Trends in neurosciences

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Storchi R (2015) Melanopsin-driven increases in maintained activity enhance thalamic visual response reliability across a simulated dawn. in Proceedings of the National Academy of Sciences of the United States of America

Description We have made several important discoveries:
1) We have provided fundamental new insight into the sensory signals regulating biological rhythms:

The established view of how the body clock (the hypothalamic suprachasimatic nucleus; SCN) estimates time of day is by measuring the overall amount of light in the environment.

a) We find that the SCN is unable to accurately measure the amount of light when faced with inhomogeneous illumination of the two eyes (Walmsley and Brown 2015).

b) We show for the first time that, in fact, SCN cells measures changes in the colour of daylight occurring around dawn and dusk to estimate time of day (Walmsley et al 2015).

We have thus uncovered a completely new sensory mechanism regulating biological timing in mammals with wide-ranging practial implications/applications (see below).

2) We provide a new origin for the emergence of binocular integration in the primary visual pathway:

Textbook descriptions of visual processing indicate that signals from the left and right eye are not combined until they reach the visual cortex. We show that binocular integration this in fact occurs in the thalamus (Howarth et al 2014). Our work has thus been instrumental in revising a longstanding view of how the thalamus contributes to visual processing with significance for our understanding of the evolution of mammalian visual systems and models of cortical plasticity which are based on the assumption that binocular convergence is purely cortical in origin.

3) We have contributed to the development and validation of new metrics for quantifying the biological effects of light (Brown et al 2013; Lucas et al 2014) that have been widely endorsed by leading academic and the international lighting regulator (CIE). These constitute important new tools for comparing research findings between labs and for quantifying the impact of real world lighting.

4) We have established an important new in vitro model of the extended circadian system and used this to reveal the role of the thalamus in regulating circadian responses to retinal input (Hanna et al. 2017)
Exploitation Route We can identify several ways our work could be put to use by us/others:
1) Our identification that colour regulates biological timing provides important new ways that we can in principle use to adjust the impact of artificial lighting on humans or managed animals. There is already widespread acceptance of the importance of appropriate biological alignment for human and animal health. Based on our findings, we anticipate that moving forward it will be possible to design light sources that support optimal biological alignment e.g: Daytime lighting for workplaces/schools that produce most effective alignment of the body clock or evening lighting for the home, hospitals, rotating shiftworkers that allow for performance of visually guided tasks without undesired impacts on the clock.
2) Our findings above also open up the possibility that colour might be used in other ways e.g. it is now well established that light exerts a clinically relevant antidepressant effect that involves a similar type of retinal cell to that responsible for setting the clock. Future research on whether the antidepressant effect of light also involves colour could help to optimise current light-based therapies.
3) The new set of metrics we have established for measuring biological effects of light provide an important new (freely available) tool to facilitate comparison of results between laboratories and for predicting the likely biological effects one might expect for any given lighting condition.
4) The new in vitro tool we have developed opens up new possibilities for understanding how nuclei of the extended circadian system interact and allows for a reduction in the amount of in vivo experimentation required to answer such questions. We expect therefore than other labs working in this area will find this new tool of great use for their own research questions.
Sectors Aerospace, Defence and Marine,Communities and Social Services/Policy,Electronics,Healthcare

Description 1) Our validation of a novel metric for quantifying the biological effects of light (Brown et al. 2013) and subsequent consensus as to the validity of this approach among leading experts (Lucas et al. 2014) has lead to enorsement by the international lighting regulator (Commission Internationale de l'Eclairage; CIE report TN003: 2015), to whom I acted as scientific advisor. This activity has also informed US department of energy guidance on solid sate lighting (PNNL-SA-102586) and efforts are ongoing to establish our new metrics as a SI units. 2) Our research relating to the influence of colour on the circadian system (Walmsley et al 2005) was widely reported on national/international TV/Radio/print (including BBC TV, BBC World News TV, BBC Radio 4, BBC world service) and online sources (altmetric score=330; top 0.2% of all outputs ranked for online influence), contributing to public understanding of science and raising industry awareness of this important new area (e.g. resulting in consultancy work with electronics/aerospace companies on lighting design considerations).
First Year Of Impact 2015
Sector Aerospace, Defence and Marine,Electronics
Impact Types Societal

Title In vitro model of the extended circadain system 
Description The circadian system is a fundamental regulator of mammalian health and well being and comprises a set of subcortical nuclei widely distributed across the hypothalamus, thalamus and pretectum. Owing to this anatomically distributed arrangement, before now, the only way to study how these cells in these regions interact has been to perform in vivo experiments. We have now developed and validated an in vitro brain slice model that preserves all regions of the extended circadian system and their interconnections intact facilitating important new scientific insights without the need to resort to whole animal experimentation and the potential welfare implications associated with this. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2017 
Provided To Others? Yes  
Impact This tool has been important in allowing us to show for the first time how the thalamic input to the hypothalamus regulates circadian responses to light. Now the tool has been published we expect this to provide further impacts in allowing us to reduce the amount of in vivo experimentation required to answer our own research questions and to do the same for other groups working in this area. 
Title melanopic lux 
Description We established and validated an method for calculating the biological effects of light on the novel retinal photoreceptor melanopsin. This approach allows one to determine the relative effectiveness by which light sources with divergent spectral power distributions will produce biological effects associated with melanopsin phototransduction (such as effects on circadian function, sleep and the pupil light reflex). Since there is already significant interest among lighting and electronics industries directed towards exploiting the practical effects of light on biology (e.g. to aid healthy sleep), this constitutes an important tool with wide ranging 'real-world' applications. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2014 
Provided To Others? Yes  
Impact Following further validation and small modifications to the original methodology (2013), this approach was endorsed by a panel of leading academic experts and representatives of the international lighting regulator - International commission on illumination (CIE; report in process: R6-42).