Sensorimotor processing, decision making, and internal states: towards a realistic multiscale circuit model of the larval zebrafish brain

感觉运动处理、决策和内部状态：建立幼虫斑马鱼大脑的真实多尺度电路模型

• 批准号: 9570757
• 负责人: Florian Engert
• 金额: $ 366.55万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9570757
• 关键词: Acetylcholine; Address; Affect; Algorithms; Animals; Area; Automobile Driving; BRAIN initiative; Behavior; Behavioral; Behavioral Assay; Behavioral Model; Biological; Biological Models; Brain; Brain imaging; Cellular Structures; Cognition; Complement; Complex; Conflict (Psychology); Decision Making; Disease; Dopamine; Dorsal; Drosophila genus; Electron Microscopy; Elements; Epinephrine; Event; Fishes; Foundations; Goals; Guidelines; Health; Human; Hunger; Hypothalamic structure; Individual; Intervention; Knowledge; Larva; Left; Link; Loneliness; Measures; Medical; Mind; Modeling; Motion; Nature; Neurons; Neurophysiology - biologic function; Neurotransmitters; Organism; Output; Pattern; Pilot Projects; Process; Property; Rattus; Research; Research Infrastructure; Series; Serotonin; Side; Son; Starvation; Stimulus; Stress; Swimming; Synapses; System; Testing; Transcend; Vision; Visual Fields; Work; Zebrafish; base; design; experimental study; in vivo; information processing; insight; multimodality; nanoscale; neural circuit; neurochemistry; neuroregulation; nutrient deprivation; optogenetics; relating to nervous system; repaired; response; sensory input; simulation; social deprivation; theories; ultraviolet irradiation; virtual; visual stimulus; working group

Project Summary - A realistic multiscale circuit model of the larval zebrafish brain The working group of the BRAIN initiative (BRAIN 2025, a Scientific Vision) identified “the analysis of circuits of interacting neurons as being particularly rich in opportunity, with potential for revolutionary advances”. They further pointed out that “truly understanding a circuit requires identifying and characterizing the component cells, defining their synaptic connections with one another, observing their dynamic patterns of activity as their circuit functions in vivo during behavior, and perturbing these patterns to test their significance. It also requires an understanding of the algorithms that govern information processing within a circuit and between interacting circuits in the brain as a whole”. We propose to generate a realistic multiscale circuit model of the larval zebrafish brain – the multiscale virtual fish (MVF), which is well aligned with the BRAIN initiative's guidelines. The model will be based on algorithms inferred from behavioral assays and it will span spatial ranges across three levels: from the nanoscale at the synaptic level, to the microscale describing local circuits, to the macroscale brain-wide activity patterns distributed across many regions. The model will be constrained and validated by optogenetic interrogation and sparse connectomics of identified circuit elements 1​ ,2​. The ultimate purpose is to explain and simulate the quantitative and qualitative nature of behavioral outputs in response to sensory inputs across various timescales, and to explore how these findings might integrate with parallel work in two other important behavioral model systems, ​ the ​Drosophila larva and the rat. Our prior U01 project achieved the first instantiation of this model, whereby we successfully dissected the optomotor response (OMR)1​ ​, where a larval zebrafish will turn and swim to match the direction of a whole-field visual stimulus ​3–5.​ We will build on this model by achieving three further aims: First, we will expand the OMR project with four additional ethologically relevant behaviors: phototaxis, rheotaxis, escape, and hunting. We will extract the precise algorithms underlying each behavior and develop a version of the circuit model to understand their neural implementation. Second, we will further refine the model to account for multimodal integration and decision making, events that naturally happen when conflicting stimuli driving different behaviors are presented simultaneously. For example, a fish might be driven to execute a left turn by whole field motion moving to the left (OMR), while simultaneously being induced to turn right by increased brightness on its right side (phototaxis). Third, we will examine how internal brain states, such as hunger or stress, influence and modulate the specific behaviors (Aim 1) or behavioral interactions (Aim 2). Implementation of neurochemical modulation into the framework of the MVF will be achieved through simulation of highly conserved neuromodulatory neurotransmitter systems such as serotonin, acetylcholine, epinephrine and dopamine. To uncover generalizable principles of circuit design and function, we will compare our findings with those from two other model systems, the fruit fly larva and the rat. This will serve to elucidate the rules, motifs and algorithms of neural circuit function that transcend the potential idiosyncrasies of any given model.

项目摘要 - 斑马鱼幼体大脑的真实多尺度电路模型 BRAIN 计划（BRAIN 2025，科学愿景）工作组确定了“对大脑电路的分析” 相互作用的神经元机会特别丰富，具有革命性进步的潜力”。他们进一步 指出“真正理解电路需要识别和表征元件单元，定义它们的 突触之间的连接，观察它们在体内电路功能时的动态活动模式 行为期间，并扰乱这些模式以测试它们的重要性。还需要对算法有一定的了解 控制电路内以及整个大脑中相互作用的电路之间的信息处理”。 我们建议生成斑马鱼幼虫大脑的真实多尺度电路模型——多尺度虚拟鱼 (MVF)，这与 BRAIN 计划的指导方针非常一致。该模型将基于算法推断 从行为分析中，它将跨越三个层次的空间范围：从突触水平的纳米级，到 从微观尺度描述局部回路，到宏观尺度分布在许多区域的全脑活动模式。这 模型将通过光遗传学询问和已识别电路的稀疏连接组学进行约束和验证 元素 1​ ,2​。最终目的是解释和模拟行为输出的定量和定性本质 响应不同时间尺度的感官输入，并探索这些发现如何与并行相结合 在另外两个重要的行为模型系统中工作，果蝇幼虫和大鼠。 我们之前的U01项目实现了该模型的首次实例化，我们成功地剖析了光电机 响应（OMR）1​​，斑马鱼幼虫将转身并游泳以匹配全场视觉刺激的方向​3-5。​ 我们将在此模型的基础上进一步实现三个目标：首先，我们将扩大 OMR 项目，新增四个目标 行为学相关行为：趋光性、趋变性、逃避和狩猎。我们将提取精确的算法 构建每个行为的基础，并开发一个版本的电路模型来理解它们的神经实现。第二， 我们将进一步完善模型，以考虑多模式集成和决策以及自然发生的事件 当驱动不同行为的冲突刺激同时出现时。例如，一条鱼可能被驱赶到 通过向左移动的整个场运动（OMR）执行左转，同时通过以下方式诱导右转 右侧的亮度增加（趋光性）。第三，我们将检查内部大脑状态，例如饥饿或 施加压力、影响和调节特定行为（目标 1）或行为互动（目标 2）。实施 MVF 框架中的神经化学调节将通过高度保守的模拟来实现 神经调节神经递质系统，如血清素、乙酰胆碱、肾上腺素和多巴胺。 为了揭示电路设计和功能的普遍原理，我们将我们的发现与来自两个方面的发现进行比较 其他模型系统，果蝇幼虫和大鼠。这将有助于阐明神经网络的规则、主题和算法 超越任何给定模型的潜在特性的电路功能。