Genetic mechanisms controlling the visual pathway to the central complex of the Drosophila brain

 描述(申请人提供)：这项申请的研究询问基因表达如何控制神经元的连接，从而控制大脑功能。如果一个人想要理解并(从疗法上)操纵大脑回路，这个问题具有普遍的重要性。我们使用模型系统果蝇，在那里，几乎每个基因都可以以细胞类型选择性的方式作为敲除或激活的靶点，果蝇还提供了一个优势，即它的大脑I由相对较少的刻板印象的神经元谱系组成，这些神经元是从单个胚胎干细胞衍生出来的，称为神经母细胞。在其增殖过程中，每个神经母细胞都表达一组特有的调控基因。这些基因控制着特定神经母细胞在特定时期所产生的神经元的分化 时间间隔。通过这种机制，一个谱系或一个称为亚系的较小分支发展成一类特定的神经元，这些神经元共享共同的连接属性，包括轴突的投射、分支模式和突触的位置。几个离散的神经元类别/谱系被放在一起组成一个神经元电路。我们已经确定了一种名为前视觉通路(AVP)的电路，它将眼睛的输入传导到大脑中心，大脑中心是已知的处理和存储视觉信息的中央复合体，以控制苍蝇的运动(行走、飞行)。这个电路的中央部分由三个谱系组成，它们的神经元形成几类高度有序的平行和顺序元件。在我们的第一个目标中，我们将通过记录AVP的活动来研究AVP的神经元类别的功能。 对特定视觉刺激的反应。我们还将通过实验证明，这些类型的神经元通过突触直接相连。第二个目的是解决神经元的发育历史(出生时间、在发育中的大脑的空间框架内的位置)如何与其在AVP回路中后来的连接有关的问题。此外，通过基因消融特定类别的AVP神经元并监测它们正常突触伙伴的反应，我们将获得关于特定细胞相互作用对连接性的作用的重要线索。第三，利用高通量RNAseq，我们将分析在两个特定的AVP亚系R3和R2中差异表达的基因(转录组)的完整分类。这两个类别在结构标准上相互区别很少，我们将筛选并分析导致它们连接的差异的基因。我们希望找出在神经系统中控制路径选择和连通性的基因。

 DESCRIPTION (provided by applicant): The studies of this application ask how gene expression controls neuronal connectivity and, thereby, brain function. This question is of general importance if one wants to understand, and (therapeutically) manipulate brain circuitry. We use the model system Drosophila, where virtually every gene can be targeted for knock-out or activation in a cell type selective manner Drosophila also offers the advantage that its brain i composed of a relatively small number of stereotyped neuronal lineages, groups of neurons descended from individual embryonic stem cells, called neuroblasts. During the course of its proliferation, each neuroblast expresses characteristic sets of regulatory genes. These genes control the differentiation of the neurons born from that particular neuroblast during a particular time interval. Through this mechanism, a lineage, or smaller subdivision of a lineage called sublineage, develops into a specific class of neurons which share common wiring properties, including the projection of their axons, branching pattern, and placement of synapses. Several discrete neuronal classes/lineages are put together into a neuronal circuit. We have identified a circuit, called the anterior visual pathway (AVP), which conducts input form the eye to a brain center, the central complex, known to process and store visual information in order to control fly locomotion (walking, flight). The central part of this circuit is formed by three lineages, whose neurons form several classes of highly ordered parallel and sequential elements. In our first aim we will investigate the function of the neuronal classes of the AVP, by recording their activity in response to defined visual stimuli. We will also demonstrate experimentally that these classes of neurons are directly connected by synapses. The second aim addresses the question how the developmental history of a neuron (time of birth, placement within the spatial framework of the developing brain) relates to its later connectivity within the AVP circuit. Furthermore, by genetically ablating specific classes of AVP neurons and monitoring the response of their normal synaptic partners, we will obtain important clues towards the role of specific cell interactions ordering connectivity. Thirdly, using high throughput RNAseq, we will analyze the complete assortment of genes (transcriptome) expressed differentially in two particular AVP sublineages, R3 and R2. These two classes are distinguished from each other by very few structural criteria, and we will screen for and then analyze genes responsible for their differences in wiring. We expect to identify genes which play a general role in controlling pathway choices and connectivity in the nervous system.