Developmental and functional analysis of neural circuits controlling navigation in Drosophila

总结 神经生物学最紧迫的研究目标之一是了解大脑回路如何发展，以及如何 这些回路控制着动物的行为这个问题具有普遍的重要性， 理解，并（治疗）操纵，在医疗环境中的大脑回路。实现这一点的先决条件是 目标是（1）详细映射包含特定电路的完整神经元组件，以及（2） 功能研究的精确工具的可用性。这两个条件现在都满足了果蝇。 完整的连接组（包含所有大脑神经元及其突触连接的数字地图）存在于 幼虫阶段（前几年部分由该赠款资助）和成虫阶段。此外，基因工具 已经开发出允许人们操纵（即，沉默或激活）几乎每个神经元，或 最少的神经元类，并测试对感兴趣的特定行为的影响。因此，战略是 从连接体中提取出特定回路的接线图，发展出不同的 电路中的元素相互作用，并使用遗传工具来测试这些假设。 对这一提议的研究集中在果蝇参与导航的脑回路上。动物导航 对感官刺激的反应，以寻找食物和交配伙伴，或避免危险。大脑中枢控制 导航需要经过处理的多模态感觉输入（气味、视觉提示），这些输入与 本体感受输入（来自肌肉、关节等的反馈）来计算操纵所需的命令。 动物在正确的方向。我们对幼虫连接体的分析突出了一个叫做外侧的大脑中心 副叶（LAL）作为感兴趣的焦点。我们已经确定了相关的LAL神经元类别及其 连接，并正在系统地筛选我们可以靶向的遗传结构， 这些神经元类来做功能研究。Laravel具有简单的、高度可量化的导航行为 使它们能够找到食物来源（通过气味）或避免光照。我们将分析LAL如何控制电机 执行这种行为的电路。 该提案的第二和第三个目标是研究幼虫LAL神经元如何成为 修改并纳入成人的LAL中。成年果蝇有一套新的器官（例如，翅膀，腿）， 移动的神经元和感知的受体;但根据我们最初的数据，幼虫的神经元仍然存在。 并且必须适应新的输入和输出。利用成人大脑的连接体和我们的 遗传工具，我们打算确定在LAL幼虫神经元的后代，并解决他们的功能， 成人导航。

Summary One of the most pressing research goals in neurobiology is to understand how brain circuits develop, and how these circuits control the behavior of an animal. This problem is of general importance if one wants to understand, and (therapeutically) manipulate, brain circuitry in a medical setting. A prerequisite to attain this goal is (1) the detailed mapping of complete neuron assemblies that embody specific circuits, and (2) the availability of precision tools for functional studies. Both of these conditions are now met for Drosophila. Complete connectomes (digital maps that contain all brain neurons and their synaptic connections) exist for both the larval stage (funded in part by this grant in previous years) and the adult. And in addition, genetic tools have been developed that allow one to manipulate (that is, silence, or activate) virtually every neuron, or at least neuron class, and test for the effect on specific behaviors that one is interested in. The strategy then is to extract from the connectome a wiring diagram of a specific circuit, develop hypotheses of how the different elements in the circuit interact, and use genetic tools to test these hypotheses. Studies of this proposal focus on a Drosophila brain circuit involved in navigation. Animals navigate in response to sensory stimuli in order to find food and mating partners, or avoid danger. Brain centers controlling navigation require processed, multimodal sensory input (smells, visual cues) which are integrated with proprioceptive input (feed back from muscles, joints etc) to calculate the commands required to steer the animal in the right direction. Our analysis of the larval connectome highlights a brain center called the lateral accessory lobe (LAL) as a focus of interest. We have identified the relevant LAL neuron classes and their connections, and are in the process to systematically screen for genetic constructs with which we can target these neuron classes to do functional studies. Larvae have a simple, highly quantifiable navigation behavior that allows them to find a food source (by odor) or avoid light. We will analyze how the LAL controls motor circuits that carry out this behavior. The second and third objective of the proposal is to study how the larval LAL neurons become modified and incorporated in the LAL of the adult. Adult flies have a new set of organs (e.g., wings, legs) with which to move, and receptors with which to sense; but according to our initial data, the larval neurons remain and have to adapt to cope with their new input and output. Using the connectome of the adult brain and our genetic tools we intend to identify the descendants of larval neurons in the LAL, and to address their function in adult navigation.