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: 10668275
• 负责人: David Masao Zimmerman
• 金额: $ 3.38万
• 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/10668275
• 关键词: Ablation; Address; Adult; Animals; Architecture; Association Learning; Behavior; Behavioral; Bilateral; Biological Assay; Biological Models; Brain; Brain Diseases; Brain Injuries; Brain region; Calcium; Cells; Cerebral hemisphere; Chemotaxis; Complex; 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; Neurobehavioral Manifestations; Neurons; Odors; Olfactory Pathways; Olfactory Receptor Neurons; Optics; Output; Peripheral; Physiological; Population; Positioning Attribute; Recurrence; Research; Sensory; Side; Signal Transduction; Smell Perception; Stimulus; Stream; Synapses; Syndrome; System; Work; behavioral response; cell type; experimental study; fly; insight; interest; nervous system disorder; neural; neural circuit; neurophysiology; nonhuman primate; novel; olfactory stimulus; phenomenological models; response; sensory input; sensory integration; sensory stimulus; 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.

项目摘要 所有具有双侧对称性的动物都必须从其左侧和右侧整合感官输入 为了做出连贯的感知决定。多种神经和精神病 与两个脑之间的结构和功能连通性降低有关 半球。但是，这种障碍连接性的详细原因和影响在许多人中仍然晦涩难懂 案例。努力阐明哺乳动物中敏感整合（IHI）的神经生理机制 哺乳动物大脑的压倒性数值复杂性所阻碍 足够精确的工具来剖析潜在的神经回路。我建议聘请一个小说，还原主义者 通过利用幼虫果蝇大脑的实验可及性来解决这个问题 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 在哪个问题上，由于大脑的大小很小（仅10,000个神经元），光学 其身体的透明度以及许多用于操纵单个细胞和细胞的遗传工具的可用性 类型。此外，幼虫的嗅觉系统的整体肾小球结构具有罢工 与哺乳动物嗅觉系统的相似之处：源自左右的感觉信号 头部的侧面在很大程度上保持分开，直到到达一个称为肌肉室的高阶大脑中心 身体（MB），其中各种双侧投射细胞类型似乎从动物的两侧输入了输入。 但是，尽管了解MB电路的最新进展，但迄今为止还没有任何 在此系统中协同剖析IHI底物的尝试。我项目的第一个目的是确定 单侧气味反应转化为双侧刺激表示的处理层。 第二个目的是通过单方面烧毁各种细胞类型来表征IHI的行为表现 在幼虫嗅觉系统中，主张趋化性损害。我的第三个目标，灵感来自 人类的Bistable嗅觉感知的现象是为了表征电路和行为响应 简单地向动物的左侧和右侧呈现冲突的刺激。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 大脑整合双边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关键方面 有望产生与许多人脑疾病的病因有关的基本概念见解。