Role of the lateral hypothalamus in alerting effects of light

In addition to allowing us to perceive the world around us, light detected by the retina exerts profound and wide-ranging effects on our physiological and mental state, including effects on alertness/sleep, mood, metabolic activity and hormone release. As such, it is well established that light and the visual environment are important determinants of human and animal health and there is significant interest in harnessing these 'non-image-forming' actions of light for therapeutic and practical benefit. Unfortunately our understanding of the biological mechanisms responsible is still incomplete. In particular, while we know that retinal projections to the hypothalamus play a key role in these processes, current research has focused on one specific part of the hypothalamus that houses our internal body-clock (and therefore contributes to daily changes in many aspects of our physiology). In fact, however, light can also more directly and rapidly influence alertness and associated aspects of physiology independent of its effect on the clock. Since the ability to control these direct effects of light would be of particular practical utility, determining the (currently unknown) mechanisms responsible is now a key goal.

One especially attractive candidate regulator of these direct effects of light is a second major hypothalamic target of retinal output, the rostral lateral hypothalamic area (LHr). Indeed, the LHr is extensively connected to brain networks that control arousal, the autonomic nervous system and behavioural drives. Surprisingly, however, until now, no one has investigated how retinal signals influence the activity of LHr neurons and the functions they regulate.

We have now for the first time, surveyed the visual response properties of LHr neurons. Striking this has revealed at least two major classes of cells in the LHr, one that is sensitive to gradual changes in the amount or colour of light and a second type that only responds to rapid changes in illumination. Remarkably, this latter type of cell can also detect moving objects. Collectively then these data indicate that the LHr is very well positioned to modulate alertness and associated physiological and behavioural responses, both as a function of changes in the quantity or quality of environmental illumination but also in response to specific changes in the visual enviroment (such as impending collision).

In this proposal, we will now comprehensively determine the roles of this new visual pathway, including establishing the full range of visual signals available to LHr cells, the photoreceptors and retinal pathways responsible for generating them, how those signals influence cells in connected brain regions regulating arousal, autonomic function and behavioural drives and ultimately how they influence relevant aspects of physiology and behaviour. We will tackle this problem using mice, where we will be able to monitor how the electrical activity of neurons within the LHr (and other brain regions with which they communicate) change in response to a wide array of different types of visual signals. We will also employ sophisticated genetic approaches to selectively 'switch-off' specific subsets of the retinal signals to this portion of the hypothalamus (or LHr cells themselves) on demand, allowing us to conclusively define how they control physiological and behavioural responses to changes in the visual environment.

Importantly, since the LHr visual pathway is conserved across mammals (including humans), while our studies will be in mice, our findings will be also be readily applicable to understanding how this system influences physiology in humans and other animals. As such, we expect the results of this project to open up important new avenues through which the visual environment could be manipulated to benefit human and animal health.

The visual environment can profoundly influence physiology and behaviour and is therefore a key determinant of health and well-being. Current research in this area has focused on the impact of light on the circadian clock in the hypothalamus, which coordinates daily variations in physiology. By contrast the mechanisms by which visual stimuli more directly and rapidly modulate alertness, autonomic and neuroendocrine function remain poorly understood.

Here we test the hypothesis that a second major retinal target in the hypothalamus - the rostal lateral hypothalamic area (LHr) - represents a key integration site for visual control of physiological/behavioural state. Hence, the LHr is extensively connected to brain circuits regulating alertness, autonomic function and behavioural drives and our latest data reveals that LHr cells are responsive to diverse features of the visual environment. This includes cells that could provide information about the ambient light levels, but also many that selectively respond to rapid changes in illumination and, remarkably, can detect visual motion. Collectively this provides a means by which the LHr could regulate physiological/ behavioural responses to anything from simple variations in ambient illumination to discrete visual 'events' such as impending collision.

Here we thus comprehensively determine the functions of this new visual pathway in mice via large scale electrophysiological recordings, sophisticated visual stimuli, intersectional opto-/chemogenetic manipulation and an array of physiological and behavioural measures. These will tell us the range of visual signals encoded by LHr cells, their retinal origins, impact on downstream neural circuits and ultimately how they influence specific aspects of physiology/behaviour. In sum, this will provide vital new insight into on how the visual environment impacts behavioural/physiological state with significant potential applications for enhancing animal and human health.

This proposal aligns closely with several BBSRC strategic priorities and therefore has potential with significant benefits to Animal and Human health.

There is substantial interest in understanding how light effects mental and physiological state and in harnessing these effects for practical benefit. Unfortunately, information about how best to achieve this is currently incomplete. This project will define for the first time the properties of a new visual pathway that is uniquely positioned to regulate arousal, behavioural drives and associated physiological responses (cardiovascular function, metabolism, neuroendocrine function) according to the visual environment. As such, we foresee considerable practical applications.

In the first instance, these will be immediately relevant to rodent husbandry and health. Hence, we expect to be able to define optimal daytime lighting conditions which synergise with underlying circadian processes to ensure healthy diurnal variations in physiology and also lighting and/or housing conditions that minimise the appearance of visual events that trigger unwanted alerting responses and/or stress (e.g. sudden changes in intensity/rapid motion in the external environment). Recent technological advances make interventions of this kind straightforward to test and implement, providing readily achievable ways to enhance animal welfare, reproductive success and improve reproducibility in experimental data. Importantly, since the LHr visual pathway is widely conserved across mammals, our findings should also translate to other species, including humans. In addition then to significant benefits for animal care/husbandry in general, the outcomes of our project also have the potential to inform the design of light and/or visual display-based interventions to promote human well-being and productivity and reduce stress.
Our strategy to achieve these impacts has two main arms:

i) Where our findings suggest direct practical application we will approach established leaders in the lighting industries to gauge interest (where the project team have extensive contacts). Working with our institutional knowledge transfer organisation to protect our IP, we can then formally approach industrial contacts with a view to developing these commercially. From experience, we anticipate it would be possible to make an initial patent filling before the project completes and that a commercial device could, in principle, follow as early as 3-5 years later. Alternatively, we may seek industrial/academic partners for collaborative research and/or proof of concept funding where potential applications need further development.

ii) In order to influence lighting design and regulations a key first step will be to publicise our findings as widely as possible. We will first achieve this through presentations at major international neuroscience meetings, the premier relevant specialist scientific meetings and via high profile publications (we aim for 3-4 in leading journals). Our recent, related, work has captured the public's imagination and we thus expect the important new findings arising from this project to do likewise - further increasing the reach of our work and helping to build interest in how light affects their health. To ensure our findings specifically reach those in the best possible position to drive change, however, we will also engage with our audience in the applied lighting and regulatory communities. Our ongoing relationships with the relevant regulatory bodies and industry advocates will be hugely beneficial here, however, in the immediate term we will also present our work also at the most relevant applied lighting meetings during the project. In addition, we propose to produce a targeted and accessible review article towards the end of the project, consolidating key findings from our own work and that of others into a set of practical guidelines regarding effects of light on physiology and behaviour.