Dissecting the neural substrates of interhemispheric integration in the larval Drosophila olfactory system

项目摘要 所有两侧对称的动物都必须整合来自其左右两侧的感觉输入。 以做出连贯的感知决策。广泛的神经和精神疾病 与两个大脑之间的结构和功能连接减少有关 半球然而，在许多国家，这种连接受损的详细原因和影响仍然模糊不清。 例哺乳动物大脑半球间整合的神经生理学机制 已经被哺乳动物大脑压倒性的数字复杂性和缺乏 足够精确的工具来解剖潜在的神经回路。我建议用一本小说，一个还原论者 通过利用果蝇幼虫大脑的实验可及性来解剖 在嗅觉感觉处理的背景下，IHI的电路基础。果蝇幼虫是理想的系统 由于它的大脑体积很小（只有~ 10，000个神经元）， 它的身体的透明度，以及许多遗传工具的可用性，用于操纵单个细胞和细胞 类型此外，幼虫嗅觉系统的整体肾小球结构具有惊人的 类似于哺乳动物的嗅觉系统：感觉信号来自左侧和右侧 头部的两侧在到达一个叫做蘑菇的高级大脑中心之前， 身体（MB），其中各种双侧投射的细胞类型似乎汇集了来自动物两侧的输入。 然而，尽管最近在理解MB电路方面取得了一系列进展，但迄今为止还没有任何进展。 一致的尝试，剖析在这个系统中的IHI的基板。我的项目的第一个目标是确定 处理层，在此将单侧气味反应转化为双侧刺激表征。 第二个目的是通过单侧消融各种细胞类型来表征IHI的行为表现 在幼虫的嗅觉系统和测定趋化性的损害。我的第三个目标， 人类的嗅觉感知现象，是表征回路和行为反应的 同时向动物的左侧和右侧呈现相互冲突的刺激。这项工作， 利用塞缪尔实验室在功能成像和行为分析方面的专业知识，将开始解决 大脑整合双侧感觉刺激以形成统一的内部模型的机制。 世界阐明知觉统一的出现是我长期研究兴趣的一个关键方面， 有望产生对许多人类大脑疾病病因学的基本概念性见解。

Project Summary All animals with bilateral symmetry must integrate the sensory input from the left and right sides of their bodies in order to make coherent perceptual decisions. A wide range of neurological and psychiatric disorders have been associated with reduced structural and functional connectivity between the two cerebral hemispheres. However, the detailed causes and effects of this impaired connectivity remain obscure in many cases. Efforts to unravel the neurophysiological mechanisms of interhemispheric integration (IHI) in mammals have been hindered by the overwhelming numerical complexity of the mammalian brain and the lack of sufficiently precise tools for dissecting the underlying neural circuits. I propose to take a novel, reductionist approach to this problem by leveraging the experimental accessibility of the larval Drosophila brain to dissect the circuit basis for IHI in the context of olfactory sensory processing. The Drosophila larva is the ideal system in which to approach this problem owing to the small size of its brain (just ~10,000 neurons), the optical transparency of its body, and the availability of numerous genetic tools for manipulating individual cells and cell types. Furthermore, the overall glomerular architecture of the larva’s olfactory system bears a striking resemblance to that of the mammalian olfactory system: sensory signals originating from the left and right sides of the head are kept largely separate until reaching a higher-order brain center called the mushroom body (MB), where various bilaterally projecting cell types seem to pool input from the two sides of the animal. However, despite a flurry of recent progress in understanding the MB circuit, to date there has not been any concerted attempt to dissect the substrate of IHI in this system. The first aim of my project is to identify the processing layer at which unilateral odor responses are transformed into bilateral stimulus representations. The second aim is to characterize the behavioral manifestation of IHI by unilaterally ablating various cell types in the larval olfactory system and assaying for impairments to chemotaxis. My third aim, inspired by the phenomenon of bistable olfactory perception in humans, is to characterize the circuit and behavioral response to the presentation of conflicting stimuli to the left and right sides of the animal simultaneously. This work, which leverages the Samuel lab’s expertise in functional imaging and behavioral analysis, will begin to address the mechanism by which the brain integrates bilateral sensory stimuli to form a unified internal model of the world. Elucidating the emergence of perceptual unity is a key aspect of my long-term research interests and promises to yield basic conceptual insights bearing on the etiology of many human brain disorders.