Visual system synapses and circuits

描述（由申请人提供）：我们将分析调节果蝇感光突触形成和功能的基因的作用，以及这些基因如何对果蝇视觉系统中的神经元回路做出贡献。 项目集中在第一和第二neuropils，板和髓质，视网膜的外和内丛状层的功能对应物的感光器目标中间神经元。 一个长期的目标是了解组织的多接触突触（如二分体和三分体）从苍蝇的感光四分体突触。 最近的目标是了解这些是如何形成的，然后有助于视觉系统的突触微电路。 目前的目标是研究轴突靶向感光细胞突触发生之前，和面包屑在指导生长锥轨迹的行动。 反馈光感受器突触的数量和类型将使用遗传试剂在EM水平上标记和识别参与神经元，以及Kirre和Irrec样蛋白以及Dscam细胞粘附分子在两种类型的板层反馈中间神经元L2和L4之间建立突触特异性以及调节这些之间的相互作用中的参与。 这些项目使用相应基因的突变体和敲低，以及其他遗传试剂。 突触功能将从改变光感受器的突触囊泡表型的突变体中进行检查，或其末端的靶向，以及通过β-丙氨酰缀合途径回收神经递质组胺。 从不同突变背景下的突触数量来评估感光器反馈的通路强度，以揭示突触回路的网络调节。 这些项目使用先进的连续切片和免疫EM方法以及熟练的人员来检查突变的光感受器。 将继续分析复杂髓质中的突触回路，使用串行EM来识别光谱辨别基础通路的已识别神经元之间的实际回路。 这些数据将被用来检查颜色视觉的神经基础;识别电路设计和突触电路中网络图案的频率;并检查当贡献神经元被消除或遗传转化时，这些神经元在板层和髓质中所经历的调节。 拟议的研究将确定视觉系统中突触功能和组织的细胞机制，以及这些在视网膜的功能和疾病状态中经历的重排，并将在与视网膜具有显著相似性的模型视觉系统中从其遗传基础中识别。 公共卫生相关性：这些研究旨在产生适用于多元突触（如视网膜的二分体和三分体）的突触发生的基本模型，并确定先天性或营养不良性疾病或视网膜损伤导致的变化的潜在遗传基础，以及视网膜突触网络的调节。这些项目分析了解剖学上的突触回路（其中许多在视网膜上有对应物）如何产生视觉行为模块。

DESCRIPTION (provided by applicant): We will analyze the actions of genes that regulate how photoreceptor synapses in Drosophila form and function, and how these contribute to circuits of neurons in the fly's visual system. Projects focus on the photoreceptor target interneuron in the first and second neuropils, the lamina and medulla, functional counterparts to the outer and inner plexiform layers of the retina. A long-term objective is to understand the organization of multiple-contact synapses (such as dyads and triads) from the fly's photoreceptor tetrad synapses. More recent objectives are to understand how these form and then contribute to the visual system's synaptic microcircuits. Current objectives are to study axon targeting prior to photoreceptor synaptogenesis, and the action of crumbs in directing growth cone trajectories. The numbers and types of feedback photoreceptor synapses will be studied using genetic reagents to label and identify participating neurons at EM level, and the involvement of Kirre and Irrec-like proteins as well as Dscam cell adhesion molecules in establishing the specificity of synapses between two types of lamina feedback interneuron, L2 and L4, as well as in regulating reciprocity between these. The projects use mutants and knockdowns of the corresponding genes, and other genetic reagents. Synaptic function will be examined from mutants that alter the synaptic vesicle phenotype of photoreceptors, or the targeting of their terminals, as well as the recycling of neurotransmitter, histamine, through a beta-alanyl conjugation pathway. Pathway strength for photoreceptor feedback will be evaluated from synapse numbers in different mutant backgrounds to reveal the network regulation of synaptic circuits. These projects examine mutant photoreceptors using advanced methods of serial-section and immuno-EM, and skilled personnel to implement these. Analysis of synaptic circuits in the complex medulla will continue, using serial-EM to identify actual circuits between identified neurons of the pathways underlying spectral discrimination. These data will be used to examine the neural basis of color vision; to identify circuit design and the frequencies of network motifs in synaptic circuits; and to examine the regulation that these undergo in both the lamina and medulla when contributing neurons are eliminated or genetically transformed. The proposed studies will identify the cellular mechanisms for synaptic function and organization in visual systems, and the rearrangements these undergo in functional and disease states of the retina, and will be identified from their genetic bases in a model visual system with marked similarities to the retina. PUBLIC HEALTH RELEVANCE: The studies aim to produce a basic model of synaptogenesis applicable to polyadic synapses like the retina's dyads and triads, and identify underlying genetic bases for changes that result from congenital or dystrophic diseases, or retinal damage, and the regulation of the retina's synaptic networks. The projects analyze how anatomical synaptic circuits, many with counterparts in the retina, give rise to modules of visual behavior.