CAREER: The Role of Inhibition in light adaptation of the OFF Retinal Pathway

当从黑暗的电影院走进明亮的阳光中时，视觉最初会被突如其来的强光所淹没，但过了一段时间我们又能看得很清楚了。这个过程被称为光适应，涉及眼睛视网膜神经元敏感度的变化。虽然视网膜对更明亮的光线的适应是视觉系统的一项重要功能，但视网膜中发生的变化使这种适应还没有被很好地理解。之前的研究表明，视网膜神经元释放的化学物质多巴胺负责光适应，但这一过程的细节尚不清楚。这项研究将确定视网膜正在发生哪些变化，以适应不断增加的光线水平，并确定多巴胺如何改变视觉信号。此外，由于视网膜是大脑中一个容易接近的部分，这些实验可以作为多巴胺如何改变神经元组的反应的模型。多巴胺信号在整个大脑和帕金森氏症等疾病中都很重要。作为这项研究的一部分，还将与学生一起开发教育材料，解释光线适应是如何工作的，以及这一过程对正常视力的重要性。这些材料将被用来增加高中生对科学的兴趣，他们中的许多人在科学领域的代表性不足，并将通过在一年一度的节日上的宣传和网络互动来增加公众的兴趣。光适应是一种重要的视网膜信号机制，它允许视觉系统通过重置神经元信号的增益来避免饱和。光适应还通过增加神经节细胞(视网膜的输出神经元)对微小光刺激的反应来提高视觉敏锐度。抑制双极细胞将信息传递给神经节细胞，影响神经节细胞的空间分辨率。因此，光适应调节双极细胞抑制可以提高视觉敏感度。然而，抑制在光适应中的作用尚不清楚。抑制的调节对视网膜通路的适应可能特别重要，该通路对光的偏移(OFF)做出反应，因为到非双极细胞的抑制输入在暗淡的光棒和明亮的光锥光源之间切换，光适应降低了对非双极细胞的抑制的空间范围。这提出了一种模型，在该模型中，双极细胞抑制的光适应缩小是神经节细胞空间信号变化的基础。目前尚不清楚非双极细胞抑制的缩小将如何影响节外细胞信号转导，也不清楚非双极细胞改变的机制。多巴胺是视网膜光适应的关键神经调节剂。多巴胺介导的缝隙连接的解偶联和/或上游神经元之间抑制性连接的增加可能会缩小双极细胞的抑制。然而，多巴胺对生理抑制的调节作用尚不清楚。这些提出的光适应旁路抑制的机制及其对视网膜视力的影响将使用单细胞电生理学、形态学、遗传小鼠模型和视网膜神经元的光遗传激活相结合的方法进行测试。

When going from a dark movie theater into the bright sunshine, vision is initially overwhelmed by the suddenly bright light levels, but after time we are again able to see well. This process, called light adaptation, involves a change in the sensitivity of neurons in the retina of the eye. Although retinal adaptation to brighter light levels is a crucial function of the visual system, the changes that happen in the retina to enable this adaptation are not well understood. Previous work has suggested that release of the chemical dopamine from retinal neurons is responsible for light adaptation, but the details of how this works are not clear. This study will determine what changes are occurring in the retina to allow adaptation to increasing light levels and determine how dopamine is changing visual signaling. Additionally, since the retina is an easily accessible part of the brain, these experiments can be used as a model for how dopamine changes the responses of groups of neurons. Dopamine signaling is important throughout the brain and in disorders such as Parkinson's disease. As part of this research, educational materials will also be developed with students to explain how light adaptation works and the importance of this process for normal vision. These materials will be used to increase interest in science for high school students, many of whom are underrepresented in science, and the public through outreach at a yearly festival and web interactions. Light adaptation is a crucial retinal signaling mechanism that allows the visual system to avoid saturation by resetting the gain of neuronal signaling. Light adaptation also increases visual acuity by increasing the response of ganglion cells, the output neurons of the retina, to small light stimuli. Inhibition of bipolar cells, which relay information to ganglion cells, influences ganglion cell spatial resolution. Therefore, light adaptation modulation of bipolar cell inhibition could increase visual acuity. However, the role of inhibition in light adaptation is not known. Modulation of inhibition may be especially important to adaptation of the retinal pathway that responds to the offset of light (OFF), as inhibitory inputs to OFF-bipolar cells switch between dim light rod and bright light cone sources and light adaptation decreases the spatial extent of inhibition to OFF-bipolar cells. This suggests a model where light adaptation narrowing of bipolar cell inhibition underlies the changes in ganglion cell spatial signaling. It is unknown how narrowing of OFF-bipolar cell inhibition will affect OFF-ganglion cell signaling or what mechanisms underlie the OFF-bipolar cell changes. Dopamine is a key neuromodulator of retinal light adaptation. Dopamine-mediated uncoupling of gap junctions and/or increases in inhibitory connections between upstream neurons might narrow OFF-bipolar cell inhibition. However, the role of dopamine modulation of physiological inhibition is not known. These proposed mechanisms for light adaptation of OFF pathway inhibition and their effects on retinal acuity will be tested using a combination of single-cell electrophysiology, morphology, genetic mouse models and optogenetic activation of retinal neurons.