Role of the lateral hypothalamus in alerting effects of light

除了让我们感知周围的世界，视网膜探测到的光线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，人们对利用光的这些“非图像形成”作用来治疗和实际获益非常感兴趣。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，但目前的研究主要集中在下丘脑的一个特定部分，该部分包含我们的内部生物钟（因此有助于我们生理的许多方面的日常变化）。然而，事实上，光也可以更直接、更迅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影响的能力将具有特殊的实际效用，确定（目前未知的）机制是现在的关键目标。光的这些直接影响的一个特别有吸引力的候选调节器是视网膜输出的第二个主要下丘脑目标，下丘脑吻侧区（LHr）。事实上，LHr与控制觉醒、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，直到现在，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。我们首次研究了LHr神经元的视觉反应特性。这一惊人发现揭示了LHr中至少有两大类细胞，一类对光线数量或颜色的逐渐变化敏感，另一类只对光照的快速变化有反应。值得注意的是，后一种细胞还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，既可以作为环境照明数量或质量变化的函数，也可以作为对视觉环境特定变化的反应（如即将发生的碰撞）。在本提案中，我们将全面确定这种新的视觉通路的作用，包括建立LHr细胞可用的所有视觉信号，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的细胞，以及最终它们如何影响生理学和行为的相关方面。我们将用老鼠来解决这个问题，我们将能够监测LHr（以及与它们交流的其他大脑区域）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”下丘脑这部分（或LHr细胞本身）的视网膜信号的特定子集，使我们能够最终确定它们如何控制对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，而我们的研究将在小鼠中进行，我们的发现也将很容易适用于理解该系统如何影响人类和其他动物的生理。因此，我们期望这个项目的结果能够开辟重要的新途径，通过这种途径可以操纵视觉环境，使人类和动物健康受益。

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.