Olfactory navigation in Drosophila as a model for multi-sensory integration

描述(申请人提供)：被风吹散的气味形成湍流羽流，其中只包含关于污染源位置的随机信息。因此，一只飞向诱人气味的苍蝇必须将嗅觉线索与有关风向和自我运动的信息结合起来，才能正确定位其来源。我建议用果蝇的嗅觉导航作为研究一般问题的模型系统，这些问题包括神经元如何代表嘈杂的现实世界刺激，动物如何使它们的行为适应不断变化的环境条件，以及神经电路如何整合来自多个感官的信息来指导行为。我的希望是，果蝇身上可用的遗传工具最终将允许我们在机械生物物理水平上回答这些问题。在我的博士后论文的第一部分，我研究了动态刺激，包括羽毛，是如何由果蝇嗅觉外周的嗅觉感受器神经元(ON)编码的(Nagel和Wilson，2011)。以前的研究已经观察到，鸟嘴鸟显示出依赖气味和细胞的动力学，这似乎使它们不太适合对天然羽流中看到的快速波动进行编码。我发现我可以用两个生物物理过程来解释这些动力学，气味转导和尖峰作用。气味转导导致ORN动力学的气味和细胞依赖性，而尖峰反应既增加了反应的复杂性，也增加了反应的速度。这项工作利用了我的研究生培训，量化了鸣禽听觉神经元的反应特性(Nagel和Doupe，2006,2008)。然而，它也依赖于我在博士后期间学到的基因技术。对于我博士后的第二部分，我建议将这种类型的分析扩展到二阶嗅觉神经元。具体地说，我建议问二阶神经元如何编码动态羽流刺激，以及什么电路和突触机制对它们的反应做出贡献。该项目形成了本提案的第一个目标。在这个项目的工作中，我将学习新的技术，例如中央苍蝇神经元的细胞内记录。我还将学习操作神经回路的不同部分，并批判性地分析这些实验的结果。连同我博士后的第一部分，这项研究将形成一个如何将感觉刺激的神经表征与生物物理机制联系起来的模板。作为一名独立研究员，我计划扩大我的关注点，看看苍蝇用来定位气味来源的算法(目标2)和参与这种行为的中央回路(目标3)。这将使我能够将我的研究项目与我的博士后导师雷切尔·威尔逊的研究项目区分开来，并开始解决关于多感觉整合和行为选择的更大问题。在具体目标#2中，我提出了三种研究嗅觉导航行为的新方法。这些方法将使我能够量化苍蝇如何整合来自多种模式的线索，以决定何时转弯、停止和前进。在具体目标#3中，我建议研究候选大脑区域--中央复合体--如何影响这些行为。利用细胞内的记录，我会问这个区域的神经元是否携带导航所需的那种空间或方向信息。利用遗传损伤，我会问这个区域的突变是否会以可预测的方式扰乱感觉整合或行为选择。这些实验将使我能够确定苍蝇神经系统必须执行的主要计算，才能成功定位诱人的气味，并测试特定的大脑区域是否可能在这些计算中发挥重要作用。最重要的是，这些实验将为提出机械问题提供基础，这些问题是如何整合感觉输入来指导正在进行的行为的。回答这些问题是我长期的研究目标。

DESCRIPTION (provided by applicant): Odors dispersed by the wind form turbulent plumes that contain only stochastic information about source location. A fly navigating towards an attractive odor must therefore combine olfactory cues with information about wind direction and self-motion to correctly locate its source. I propose to use olfactory navigation in the fruit-fly Drosophila as a model system for studying general questions about how neurons represent noisy real-world stimuli, how animals adapt their behavior to changing environmental conditions, and how neural circuits integrate information from multiple senses to guide behavior. My hope is that the genetic tools available in Drosophila will ultimately allow us to answer these questions at a mechanistic biophysical level. In the first part of my post-doc I examined how dynamic stimuli, including plumes, are encoded by olfactory receptor neurons (ORNs) in the Drosophila olfactory periphery (Nagel and Wilson, 2011). Previous studies had observed that ORNs show odor- and cell-dependent dynamics that would seem to make them poorly suited for encoding the rapid fluctuations seen in natural plumes. I found that I could explain these dynamics in terms of two biophysical processes, odor transduction and spiking. Odor transduction gives rise to the odor- and cell-dependence of ORN dynamics, while spiking increases both the complexity of responses, and their speed. This work drew on my graduate training quantifying the response properties of auditory neurons in the songbird (Nagel and Doupe, 2006, 2008). However, it also relied on genetic techniques that I learned during my post-doc. For the second part of my post-doc, I propose to extend this type of analysis to second order olfactory neurons. Specifically I propose to ask how second order neurons encode dynamic plume stimuli, and what circuit and synaptic mechanisms contribute to their responses. This project forms Aim #1 of this proposal. In working on this project I will learn new techniques, such as intracellular recording from central fly neurons. I will also learn to manipulate different parts of a neural circuit and to analyze the results of these experiments critically. Together with the first part of my post-doc, this study will form a template for how to link neural representations of sensory stimuli to biophysical mechanisms. As an independent investigator, I plan to expand my focus to look at the algorithms flies use to localize odor sources (Aim #2) and the central circuits involved in this behavior (Aim #3). This will allow me to differentiate my research program from that of my post-doctoral advisor, Rachel Wilson, and to begin to address larger questions about multi-sensory integration and behavioral choice. In Specific Aim #2, I propose three novel methodologies for studying olfactory navigation behavior. These approaches will allow me to quantify how flies integrate cues from multiple modalities to decide when to turn, stop, and advance. In Specific Aim #3, I propose to study how a candidate brain area, the central complex, contributes to these behaviors. Using intracellular recordings, I will ask whether neurons in this area carry the sort of spatial or directional information necessary for navigation. Using genetic lesions I will ask whether mutations of this area disrupt sensory integration or behavioral choice in predictable ways. Together these experiments will allow me to identify the main computations that the fly nervous system must perform in order to successfully localize an attractive odor and to test whether a particular brain area is likely to play an important role in these computations. Most importantly, these experiments will provide a basis for asking mechanistic questions about how sensory input is integrated to guide on-going behavior. Answering these questions is my long-term research goal.