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时，视觉最初会被突然明亮的光线淹没，但过一段时间后，我们又能看得清楚了。这个过程被称为光适应，涉及到眼睛视网膜神经元敏感度的变化。虽然视网膜适应更明亮的光线水平是视觉系统的一个关键功能，但视网膜发生的使这种适应的变化尚未得到很好的理解。先前的研究表明，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，由于视网膜是大脑的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，教育材料也将与学生一起开发，以解释光线适应是如何工作的，以及这个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，并通过每年的节日和网络互动来扩大公众的兴趣。光适应是一种至关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）对微弱光刺激的反应来提高视觉敏锐度。抑制双极细胞，传递信息到神经节细胞，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。抑制的调节可能对响应光偏移（OFF）的视网膜通路的适应特别重要，因为对OFF-bipolar细胞的抑制输入在昏暗的光杆和明亮的光锥源之间切换，光适应降低了对OFF-bipolar细胞的抑制的空间范围。这表明双极细胞抑制的光适应变窄是神经节细胞空间信号变化的基础。目前尚不清楚off -双极细胞抑制的变窄如何影响off神经节细胞信号传导，也不清楚off -双极细胞变化背后的机制。多巴胺是视网膜光适应的关键神经调节剂。多巴胺介导的间隙连接解偶联和/或上游神经元之间抑制性连接的增加可能会缩小off双极细胞的抑制。然而，多巴胺调节生理抑制的作用尚不清楚。这些被提出的OFF通路抑制的光适应机制及其对视网膜敏度的影响将通过单细胞电生理学、形态学、小鼠遗传模型和光遗传学激活视网膜神经元的组合进行测试。

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.