Visual system synapses and circuits

描述（由申请人提供）：我们将分析果蝇中调节光感受器突触形成和功能的基因的作用，以及这些基因如何影响果蝇视觉系统中的神经元回路。项目集中在第一和第二神经粒，层和髓质的光感受器目标中间神经元，与视网膜的内外丛状层功能对应。一个长期的目标是了解苍蝇的光感受器四分体突触的多接触突触（如二分体和三分体）的组织。最近的目标是了解这些细胞是如何形成的，然后对视觉系统的突触微电路有何贡献。目前的目标是研究轴突在光感受器突触发生之前的靶向性，以及碎屑在指导生长锥轨迹中的作用。利用遗传试剂在EM水平上标记和识别参与神经元，研究反馈光感受器突触的数量和类型，并研究Kirre和irrec样蛋白以及Dscam细胞粘附分子在两种层反馈中间神经元L2和L4之间建立突触特异性以及调节它们之间的互易性中的作用。该项目使用相应基因的突变和敲低，以及其他遗传试剂。突触功能将从改变光感受器突触囊泡表型的突变体，或其末端的靶向，以及通过β -丙烯偶联途径神经递质，组胺的再循环来检查。我们将从不同突变背景下的突触数量来评估光感受器反馈的通路强度，以揭示突触回路的网络调控。这些项目使用先进的连续切片和免疫电镜方法检查突变的光感受器，并由熟练的人员实施这些。对复杂髓质的突触回路的分析将继续进行，使用串行em来识别已识别神经元之间的实际回路，这些神经元之间的通路是频谱区分的基础。这些数据将用于检查色觉的神经基础；识别突触回路中的电路设计和网络基序的频率；并研究当贡献神经元被消除或基因转化时，这些神经元在脑板和髓质中所经历的调节。拟开展的研究将确定视觉系统中突触功能和组织的细胞机制，以及这些突触在视网膜功能和疾病状态下的重排，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进行鉴定。

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.