Neural circuits of non-image-forming vision

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.

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.

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.