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

项目摘要 所有具有双侧对称性的动物都必须整合来自其左右两侧的感觉输入 为了做出连贯的感官决定，身体需要更多的知识和技能。广泛的神经和精神障碍 与两个大脑之间结构和功能连接的减少有关 半个半球。然而，在许多情况下，这种连接受损的详细原因和影响仍然不清楚 案子。哺乳动物大脑半球间整合(IHI)的神经生理机制研究进展 都受到哺乳动物大脑数量的压倒性复杂性和缺乏 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，简化论者 利用果蝇幼虫大脑的实验可及性来探讨这一问题 在嗅觉加工的背景下IHI的电路基础。果蝇幼虫是理想的系统 由于它的大脑很小(只有大约10,000个神经元)，光学的 其身体的透明度，以及可用来操纵单个细胞和细胞的众多基因工具 类型。此外，幼虫嗅觉系统的整体肾小球结构具有显著的 与哺乳动物嗅觉系统的相似之处：来自左侧和右侧的感觉信号 头部的两侧基本保持分离，直到到达更高级的大脑中枢，称为蘑菇 身体(MB)，其中各种双向投射细胞类型似乎汇集了动物两侧的输入。 然而，尽管最近在理解MB回路方面取得了一系列进展，但到目前为止还没有任何 同心协力地剖析这一系统中的IHI底物。我的项目的第一个目标是确定 单侧气味反应转化为双侧刺激表征的加工层。 第二个目标是通过单侧消融不同类型的细胞来表征IHI的行为表现 在幼虫嗅觉系统和分析对趋化性的损害。我的第三个目标，灵感来自 人类的双稳态嗅觉现象，是表征人的神经回路和行为反应 将相互冲突的刺激同时呈现在动物的左右两侧。这部作品， 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一个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和 承诺产生基本的概念性见解，与许多人类大脑疾病的病因有关。

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.