Role of the lateral hypothalamus in alerting effects of light

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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.