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

当从黑暗的电影院进入明亮的阳光下时，视觉最初会被突然明亮的光线淹没，但过了一段时间，我们又能看得很清楚了。这个过程称为光适应，涉及眼睛视网膜神经元敏感性的变化。虽然视网膜对更明亮的光水平的适应是视觉系统的一个重要功能，但视网膜中发生的使这种适应成为可能的变化还没有得到很好的理解。以前的研究表明，视网膜神经元释放的化学物质多巴胺是光适应的原因，但其工作原理的细节尚不清楚。这项研究将确定视网膜发生了什么变化，以适应不断增加的光照水平，并确定多巴胺如何改变视觉信号。此外，由于视网膜是大脑的一个容易接近的部分，这些实验可以用作多巴胺如何改变神经元群反应的模型。多巴胺信号在整个大脑和帕金森病等疾病中都很重要。作为这项研究的一部分，还将与学生一起开发教育材料，以解释光适应如何工作以及这一过程对正常视力的重要性。这些材料将用于提高高中生对科学的兴趣，其中许多人在科学方面的代表性不足，并通过在年度节日和网络互动中进行宣传来提高公众对科学的兴趣。光适应是一种至关重要的视网膜信号传导机制，它允许视觉系统通过重置神经元信号传导的增益来避免饱和。光适应还通过增加视网膜的输出神经元神经节细胞对微弱光刺激的反应来增加视敏度。抑制双极细胞，中继信息的神经节细胞，影响神经节细胞的空间分辨率。因此，双极细胞抑制的光适应调节可以提高视力。然而，抑制在光适应中的作用尚不清楚。抑制的调节对于响应于光偏移（OFF）的视网膜通路的适应可能特别重要，因为对OFF双极细胞的抑制性输入在昏暗的光棒和明亮的光锥源之间切换，并且光适应降低了对OFF双极细胞的抑制的空间范围。这表明了一个模型，其中双极细胞抑制的光适应变窄是神经节细胞空间信号传导变化的基础。目前尚不清楚关闭双极细胞抑制的缩小将如何影响关闭神经节细胞信号传导或关闭双极细胞变化的机制。多巴胺是视网膜光适应的关键神经调质。多巴胺介导的间隙连接的解偶联和/或上游神经元之间的抑制性连接的增加可能会缩小OFF双极细胞抑制。然而，多巴胺调节生理抑制的作用尚不清楚。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学激活的组合来测试这些提出的OFF通路抑制的光适应机制及其对视网膜敏锐度的影响。

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.