Determining Computational Principles Governing Neural Circuits Responsible for Feedback and Movement Control of D. Melanogaster Flight

项目摘要 NINDS的主要目的是确定如何通过以下方式成功地实现电机控制： 神经系统运动和平衡是复杂的运动功能， 由大脑外部的复杂微电路控制。了解如何这样 微电路功能对于能够治疗与年龄，先天性疾病， 和创伤中这些回路受损。该提案将利用一个高度 一个易于处理的模型系统，果蝇（Drosophila melanogaster），以阐明计算 控制飞行稳定性的感觉运动回路的基本原理。果蝇是一种 优秀的模型系统进行这样的研究有几个原因。首先，通过A 作为与HHMI的合作项目，PI已经帮助开发了约220种转基因果蝇品系， 果蝇腹神经索（VNC）中的稀疏神经元群体，这可能是慢性的， 沉默、光遗传学激活或光遗传学抑制。第二，在实验中， 由PI开创，我们表明苍蝇对偏航，俯仰和滚动的反射反应 扰动定量描述的比例积分滤波器-a控制策略 类似于汽车的巡航控制或复杂的恒温器。因此，苍蝇的稳定反射， 虽然复杂，但特征很好。因此，有机会系统地 询问VNC中的神经元，并确定它们对复杂运动行为的影响。 为此，在目标1中，我们将绘制驱动快速飞行的运动系统的功能图 稳定苍蝇。具体来说，我们会长期沉默或短暂操纵个人 运动神经元，支配机翼操纵肌肉和测试自由飞行中的控制性能 并且在快速的机械扰动下。在目标2中，我们将阐明特定的功能角色 控制反射中的机械感觉神经元。我们将再次使用慢性沉默或 瞬时操纵个别机械感觉神经元和测试控制性能在自由 飞行和快速机械扰动下。最后，在目标3中，我们将确定神经 连接机械感觉输入到翅膀肌肉输出的结构。我们特别 将使用顺行跨突触回路追踪（trans-Tango）和离体功能成像来 识别从遗传识别的神经元接收直接输入的运动神经元和中间神经元， 机械感觉传入这些研究将使我们能够确定 这些微电路的组织和功能的前所未有的细节。反过来，这些知识 将告知我们对动物感觉运动回路设计原理的理解。

PROJECT SUMMARY A principle aim of the NINDS is to determine how motor control is successfully implemented by the nervous system. Locomotion and balance are complex motor functions that are largely controlled by complex microcircuits that reside outside the brain. Understanding how such microcircuits function is critical to being able to treat diseases related to age, congenital disorders, and trauma in which these circuits are impaired. This proposal will leverage advantages of a highly tractable model system, the fruit fly (Drosophila melanogaster), to elucidate the computational principles underlying the sensorimotor circuits that govern flight stabilization. Fruit flies are an excellent model system for conducting such studies for several reasons. First, through a collaborative project with the HHMI, the PI has helped develop ~220 transgenic fly lines targeting sparse populations of neurons in the fly ventral nerve cord (VNC), which can be chronically silenced, optogenetically activated, or optogenetically suppressed. Second, in experiments pioneered by the PI, we showed that the reflexive responses of the fly to yaw, pitch, and roll perturbations are described quantitatively by a proportional-integral controller—a control strategy similar to a car’s cruise control or a sophisticated thermostat. Thus, the fly’s stabilization reflexes, while complex, are well characterized. Consequently, there is an opportunity to systematically interrogate neurons in the VNC and determine their effect on a sophisticated motor behavior. Towards this end, in Aim 1 we will map the function of the motor system that actuates rapid flight stabilization in flies. Specifically, we will chronically silence or transiently manipulate individual motor neurons that innervate wing steering muscles and test control performance in free flight and under rapid mechanical perturbations. In Aim 2 we will elucidate the functional role specific mechanosensory neurons in the control reflex. Once again we will use chronic silencing or transient manipulation of individual mechanosensory neurons and test control performance in free flight and under rapid mechanical perturbations. Finally, in Aim 3 we will identify the neural architecture connecting the mechanosensory inputs to the wing muscle outputs. Specifically, we will use anterograde transsynaptic circuit tracing (trans-Tango) and ex-vivo functional imaging to identify motor and interneurons that receive direct input from the genetically-identified mechanosensory afferents. Together, these studies will enable us to determine with unprecedented detail the organization and function of these microcircuits. In turn, this knowledge will inform our understanding of design principles for sensorimotor circuits across animals.