Functional Roles of Retinal Gap Junctions in Visual Processing

描述（由申请人提供）：通过间隙连接（gjs）的突触电传递是中枢神经系统中神经元通信的重要模式。一个很好的例子是视网膜，其中五种主要的神经元类型中的每一种都通过gjs电偶联。视网膜gjs的广泛分布、结构和调控表明其在视觉加工中具有多种功能作用；阐明这些角色形成了我们实验项目的长期目标。在这里，我们建议研究小鼠视网膜内部的gjs，它服务于丰富而复杂的各种电路。该提议的第一个目的是确定gjs在神经节细胞显示的稳健、相关活动中所起的作用。相关的神经节细胞活动被认为具有许多功能，包括增强信号显著性和编码有关视觉刺激的特定信息，如强度、大小和运动。目前尚不清楚神经节细胞的协同活动是否反映了通过化学突触和/或gj介导的神经节细胞及其邻近细胞之间的电偶联的共同兴奋性输入。我们提出了一种结合电生理、药理学和光遗传学技术的多学科方法，应用于转基因和敲除小鼠系，以区分负责相关神经节细胞活性的回路。第二个目标将集中在远距离分离的神经节细胞的协同活动及其在编码与感知分组和物体识别相关的全局视觉信息中的作用。我们将验证这样的假设，即这种“远距离”协同活动是由宽视场无突细胞产生的，这些细胞与神经节细胞相隔至少750¿m。我们将测试神经节和无突细胞之间gjs的缺失是否会消除由连续刺激引起的协同活动，从而产生行为功能障碍，使动物区分大的、连续的物体和两个离散的物体的能力下降。在第三个目标中，我们将研究神经节细胞通过相互连接的gjs向无突细胞发送信号来改变视网膜内活动的新想法。我们假设神经节细胞可以改变偶联的无突细胞邻居的活性，这反过来又通过传统的化学突触抑制其他神经节细胞。这种由神经节细胞发出的视网膜内信号形成了一个回路，提供了一种新的侧抑制形式。在最后的目标中，我们建议将标签与

DESCRIPTION (provided by applicant): Electrical synaptic transmission via gap junctions (gjs) is an important mode of neuronal communication in the CNS. An elegant example is the retina in which each of the five main neuronal types is electrically coupled via gjs. The broad distribution, structure, and regulation of retinal gjs suggest a diversity of functional roles in vsual processing; elucidating these roles forms the long-term goal of our experimental program. Here we propose to study the gjs in the inner mouse retina, which subserve a rich and complex variety of electrical circuits. The first aim of this proposal is to determine the role of gjs in creating the robust, correlated activity displayed by ganglion cells. Correlated ganglion cell activity is believed to have a number of functions, including enhancement of signal saliency and encoding of specific information about visual stimuli such as intensity, size, and motion. It is presently unclear whether concerted ganglion cell activity reflects common excitatory inputs via chemical synapses and/or gj-mediated electrical coupling between ganglion cells and their neighbors. We propose a multidisciplinary approach combining electrophysiological, pharmacological, and optogenetic techniques applied to transgenic and knockout mouse lines to differentiate the circuits responsible for correlated ganglion cell activity. The second aim will focus on concerted activity of ganglion cells separated over long distances and its role in encoding global visual information pertinent to perceptual grouping and object recognition. We will test the hypothesis that such "long-range" concerted activity is generated by wide-field amacrine cells that form gjs with ganglion cells separated by at least 750 ¿m. We will test whether deletion of gjs between ganglion and amacrine cells abolishes the concerted activity evokes by contiguous stimuli thereby producing a behavioral dysfunction rendering animals less capable of discriminating large, contiguous objects from two discrete objects. In the third aim we will study the novel idea the ganglion cells can alter intraretinal activity by signaling back to amacrine cells through interconnecting gjs. We posit that ganglion cells can alter the activity of coupled amacrine cell neighbors, which, in turn, inhibit other ganglion cells via conventional chemical synapses. This form of intraretinal signaling by ganglion cells creates a circuit providing a novel form of lateral inhibition. In the final aim, we propose to combine labeling with the gj-permeant dyes Po-, Pro-1, and Neurobiotin to provide a complete description of the different gj-mediated electrical circuits in the inner mouse retina that help produce the responses of the >20 different ganglion cell subtypes, which are transmitted to the brain. Deficits in gj communication have been implicated in a number of brain neuropathies, including visual impairments associated with retinitis pigmentosa, glaucoma and ischemic retinopathy. The experimental program proposed here will extend our understanding of the distribution and physiological roles of gjs, which form important prerequisites for determining how gj dysfunction affects neural function so as to suggest novel targets for the treatment for human disease.