Role of the lateral hypothalamus in alerting effects of light

除了让我们感知周围的世界外，视网膜检测到的光对我们的生理和精神状态产生深远而广泛的影响，包括对警觉性/睡眠，情绪，代谢活动和激素释放的影响。因此，众所周知，光和视觉环境是人类和动物健康的重要决定因素，并且对于利用光的这些“非成像”作用以获得治疗和实际益处存在显著的兴趣。不幸的是，我们对生物学机制的理解仍然不完整。特别是，虽然我们知道视网膜投射到下丘脑在这些过程中起着关键作用，但目前的研究集中在下丘脑的一个特定部分，它容纳了我们的内部生物钟（因此有助于我们生理学许多方面的日常变化）。然而，事实上，光也可以更直接和快速地影响警觉性和相关的生理方面，而不依赖于它对生物钟的影响。由于控制这些光的直接效应的能力将是特别实用的，确定（目前未知的）机制负责现在是一个关键的goal.One特别有吸引力的候选调节这些光的直接效应是视网膜输出的第二个主要下丘脑目标，喙侧下丘脑区（LHr）。事实上，LHr与控制唤醒、自主神经系统和行为驱动的大脑网络有着广泛的联系。然而，令人惊讶的是，到目前为止，还没有人研究视网膜信号如何影响LHr神经元的活动及其调节的功能。我们现在第一次调查了LHr神经元的视觉反应特性。这一发现揭示了LHr中至少有两种主要类型的细胞，一种对光量或颜色的逐渐变化敏感，另一种只对光照的快速变化敏感。值得注意的是，后一种类型的细胞也可以检测移动的物体。总的来说，这些数据表明，LHr非常适合调节警觉性和相关的生理和行为反应，既作为环境照明的数量或质量变化的函数，也响应于视觉环境的特定变化（例如即将发生的碰撞）。在这项提案中，我们现在将全面确定这种新视觉通路的作用，包括建立LHr细胞可用的全部视觉信号，负责产生它们的光感受器和视网膜通路，这些信号如何影响调节唤醒，自主功能和行为驱动的连接大脑区域中的细胞，以及最终它们如何影响生理和行为的相关方面。我们将使用小鼠来解决这个问题，在那里我们将能够监测LHr（以及与它们通信的其他大脑区域）内神经元的电活动如何响应各种不同类型的视觉信号而变化。我们还将采用复杂的遗传方法，根据需要选择性地“关闭”视网膜信号的特定子集到下丘脑的这一部分（或LHr细胞本身），使我们能够最终确定它们如何控制视觉环境变化的生理和行为反应。重要的是，由于LHr视觉通路在哺乳动物（包括人类）中是保守的，虽然我们的研究将在小鼠中进行，但我们的发现也将很容易适用于了解该系统如何影响人类和其他动物的生理学。因此，我们希望这个项目的结果能够开辟重要的新途径，通过这些途径可以操纵视觉环境，以造福人类和动物的健康。

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.