Light direct effects on mood and cognitive functions

描述（由申请人提供）：在轮班工作和跨子午线旅行期间经历的异常光照条件，以及白天长度的季节性变化，导致情绪和认知缺陷。流行的观点是，这些行为影响是由睡眠和昼夜节律的中断引起的。然而，我们最近发现，异常的光照时间表直接导致情绪和认知缺陷。哺乳动物视网膜包含三种主要的光感受器，视杆细胞、视锥细胞和固有光敏视网膜神经节细胞（ipRGC），是所有光依赖行为的光检测部位。ipRGC表达色素黑视蛋白，并通过黑视蛋白色素内在地对光作出响应，但也通过视杆/视锥回路外在地对光作出响应，类似于常规RGC。此外，ipRGC投射到各种大脑区域，包括主昼夜节律起搏器以及涉及情绪和影响调节的区域。我们已经将ipRGC确定为回路中的关键节点，该回路是破坏性光照时间表对情绪和认知的直接影响的基础。在这项提案中，我们的主要目标是确定视网膜回路和大脑目标，这些目标是异常光导致情绪和学习缺陷所必需的。具体来说，我们有几个视网膜小鼠突变体，这将使我们能够描绘的相对贡献的内在黑视蛋白为基础的光转导与外在杆/锥输入的破坏性影响异常光的情绪和认知。此外，我们已经产生了多个小鼠品系，其中我们已经特异性消融或特异性保留了一个ipRGC子集，其投射到主昼夜节律起搏器并驱动昼夜节律光诱导。为了鉴定足以产生畸变光负面影响的脑区域，我们将使用光遗传学特异性激活ipRGC末端，以模拟畸变光对单个脑区域的影响。突变小鼠品系与这种光遗传学方法的结合将使我们能够开始识别介导异常光照时间表如何导致情绪和学习缺陷的电路。从该提案中获得的结果将为在家庭，学校和工作环境中设计更好的照明环境提供依据，以改善情绪和认知，从而提高生产力。此外，识别 影响情绪调节的新大脑回路将为更好地利用光进行治疗提供新的神经元靶点。

DESCRIPTION (provided by applicant): Aberrant light conditions experienced during shift-work and transmeridian travel, as well as seasonal changes in day length, cause mood and cognitive deficits. The prevailing view is that these behavioral effects arise from disruptions in sleep and circadian rhythms. However, we have recently shown that aberrant light schedules directly lead to mood and cognitive deficits. The mammalian retina, which contains three major photoreceptors, rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs), is the site of light detection for all light-dependent behaviors. The ipRGCs express the photopigment melanopsin and respond to light both intrinsically via the melanopsin photopigment but also extrinsically through rod/cone circuitry, similar to conventional RGCs. Furthermore, ipRGCs project to a variety of brain regions that include the master circadian pacemaker as well as areas that have been implicated in mood and affect regulation. We have identified ipRGCs as a critical node in the circuit underling the direct effects of disruptive ligh schedule on mood and cognition. In this proposal, our major goals are to identify the retinal circuits and the brain targets that are necessary for aberrant light to cause mood and learning deficits. Specifically, we have several retinal mouse mutants that will allow us to delineate the relative contributions of the intrinsic melanopsin-based phototransduction versus the extrinsic rod/cone input to the disruptive effects of aberrant light on mood and cognition. In addition, we have generated multiple mouse lines where we have either specifically ablated or specifically retained a subset of ipRGCs that project to the master circadian pacemaker and drive circadian photoentrainment. To identify brain regions that are sufficient for the negative effects of aberran light, we will specifically activate ipRGC terminals using optogenetics, to mimic the effects of aberrant light on individual brain regions. The combination of mutant mouse lines with this optogenetic approach will allow us to begin to identify the circuits that mediate how aberrant light schedules lead to mood and learning deficits. The findings obtained from this proposal will provide a basis to design better lighting environments at homes, schools and work environment to improve mood and cognition leading to increased productivity. In addition, the identification of new brain circuits that impinge on mood regulation will provide new neuronal targets for the better use of light for therapeutic purposes.