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

解剖果蝇幼虫嗅觉系统半球间整合的神经基础

• 批准号: 10536196
• 负责人: David Masao Zimmerman
• 金额: $ 3.28万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536196
• 关键词: Ablation; Address; Adult; Animals; Architecture; Behavior; Behavioral; Bilateral; Biological Assay; Biological Models; Brain; Brain Diseases; Brain Injuries; Brain region; Calcium; Cerebral hemisphere; Chemotaxis; Complex; Conflict (Psychology); Conscious; Corpus Callosum; Cues; Drosophila genus; Drosophila melanogaster; Etiology; Exhibits; Experimental Models; Foundations; Functional Imaging; Genetic; Head; Higher Order Chromatin Structure; Human; Image; Impairment; Individual; Infrastructure; Insecta; Ipsilateral; Knowledge; Larva; Left; Link; Mammals; Mediating; Mental disorders; Modeling; Morphology; Motor output; Muscle; Mushroom Bodies; Nervous system structure; Neurobehavioral Manifestations; Neurons; Odors; Olfactory Pathways; Olfactory Receptor Neurons; Optics; Organism; Output; Peripheral; Physiological; Population; Positioning Attribute; Research; Sensory; Side; Signal Transduction; Smell Perception; Stimulus; Stream; Suggestion; Synapses; Syndrome; System; Ursidae Family; Work; behavioral response; cell type; classical conditioning; experimental study; fly; insight; interest; nervous system disorder; neural circuit; neurophysiology; nonhuman primate; novel; olfactory stimulus; phenomenological models; relating to nervous system; response; sensory input; sensory integration; sensory stimulus; sensory system; split brain; tool

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.

项目概要 所有双侧对称的动物都必须整合来自其左右两侧的感觉输入 身体以便做出一致的感知决策。多种神经和精神疾病 与两个大脑之间的结构和功能连接减少有关 半球。然而，这种连通性受损的详细原因和影响在许多方面仍然不清楚。 案例。努力揭示哺乳动物半球间整合（IHI）的神经生理学机制 哺乳动物大脑的巨大数字复杂性和缺乏 足够精确的工具来剖析底层神经回路。我建议采取小说，还原论 通过利用幼虫果蝇大脑的实验可及性来解剖来解决这个问题 嗅觉感官处理背景下 IHI 的电路基础。果蝇幼虫是理想的系统 由于其大脑尺寸很小（只有约 10,000 个神经元），因此要解决这个问题，光学 其身体的透明度，以及操纵单个细胞和细胞的众多遗传工具的可用性 类型。此外，幼虫嗅觉系统的整体肾小球结构具有惊人的 与哺乳动物嗅觉系统相似：来自左侧和右侧的感觉信号 头部的两侧基本上保持分离，直到到达称为蘑菇的高级大脑中心 身体（MB），其中各种双边突出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。 一致尝试剖析该系统中 IHI 的底物。我的项目的首要目标是确定 处理层，将单侧气味反应转化为双边刺激表征。 第二个目标是通过单方面消融各种细胞类型来表征 IHI 的行为表现 在幼虫嗅觉系统中检测趋化性损伤。我的第三个目标的灵感来自于 人类双稳态嗅觉感知现象，是为了表征电路和行为反应 同时向动物的左侧和右侧呈现相互冲突的刺激。这个作品， 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， 有望产生与许多人类大脑疾病的病因学相关的基本概念见解。