Project 3: Modeling and Theory

项目3 -建模和理论-摘要 大脑功能理论面临的最大挑战之一是我们关于大脑功能的实验知识的破碎性。 神经回路斑马鱼幼虫提供了一个独特的机会，以减轻这一障碍，由于有能力询问 在行为学相关行为期间，单个神经元分辨率下的全脑活动， 基因工具和长期监控动物行为的能力。为了利用这些好处，整个项目 他将研究一组鱼类幼体的感觉运动功能，记录其行为反应，大脑结构， 参与，和单细胞分辨率的神经元活动。项目3的主要目标是整合 将不同的实验条件转化为连贯的定量脑宽电路模型，指导进一步验证， 细化和假设检验实验。我们将建立一个长达十年的实验理论数据处理 合作，在我们对动物整个大脑功能的理解方面取得了前所未有的进展， 复杂的神经元结构和功能。 我们将采用多尺度方法，总结如下：行为模型-能够准确的概率 根据动物的环境和最近的行为历史预测动物的行为。 概念电路模型-初始 识别参与特定感觉运动任务的大脑结构及其潜在投射的图表。 功能 电路模型-系统的定量网络模型，其功能单元是通过以下方式确定的局部群体： 脑宽活动轨迹的维度缩减。重要的是，这种全脑模型将不断整合 随着特定任务实验的进展，增加了额外的结构和电路。 神经元回路模型-数据来自 在单个神经元/突触水平上的扰动和EM验证研究将被整合到单个神经元水平上 特定本地电路的模型。我们还将纳入有关动作选择、多感官整合和 在总体项目目标2的实验中收集的决策。模型电路将被集成到 多尺度虚拟鱼软件平台，允许可视化和查询实验和建模数据， 共同框架。我们的多尺度方法将扩展到时域。为了模拟大脑状态依赖性， 行为和神经元功能（总体目标3），我们将建立一个分层可切换模型，大脑状态缓慢 在顶层的动态，其调节较低层，正在进行的快速行为和神经元模型（如上所述）。 我们将试图从我们的鱼脑模型和行为模型中提取出可能普遍适用的一般原则。 物种这将通过使用我们的建模方法在大鼠和果蝇幼虫中进行相关实验来验证（项目 4），特别是在脑状态动力学和行为和感觉运动的神经调节控制领域 处理.

Project 3 - Modeling and theory-Abstract One of the greatest challenges for a theory of brain function is the fractured nature of our experimental knowledge about neuronal circuits. The zebrafish larva offers a unique opportunity to mitigate this barrier due to the ability to interrogate whole brain activity at single neuron resolution during ethologically relevant behaviors, the availability of exhaustive genetic tools and the ability to monitor the animal’s behavior over long times. To utilize these benefits the overall project will study a battery of sensorimotor functions in the fish larva, recording its behavioral responses, the brain structures involved, and the neuronal activity at single cell resolution. The primary goal of Project 3 is to integrate findings from the disparate experimental conditions into a coherent quantitative brain wide circuit model, guiding further validation, refinement and hypothesis testing experiments. We will establish a decade long experimental-theoretical-data-processing collaboration, yielding unprecedented advances in our understanding of the functioning of whole brains in animals with complex neuronal structure and function. We will adopt a multiscale approach, summarized as follows: ​Behavioral models - ​capable of an accurate probabilistic prediction of the animal’s actions given its environment and recent behavioral history. ​Conceptual circuit models ​- initial charts identifying the brain structures involved in a given sensorimotor task and their potential projections. ​Functional circuit models ​- systematic quantitative network models, whose functional units are local populations identified through dimensionality reduction of brain wide activity traces. Importantly, this brain wide model will continuously integrate additional structures and circuits as experiments on specific tasks progress. ​Neuronal circuit models – data from perturbation and EM validation studies at the single neuron/synaptic level will be integrated into single neuron level models for specific local circuits. We will also incorporate data on action selection, multi-sensory integration, and decision making gathered in experiments of Aim 2 of the Overall Project. Model circuits will be integrated into the Multiscale Virtual Fish software platform to allow visualization and interrogation of experimental and modeling data in a common framework. Our multiscale approach will extend to the time domain. To model the brain state dependence of behavioral and neuronal functions (Overall Aim 3) we will build a hierarchical switchable model, with brain state slow dynamics at the top tier, which modulate the lower tier, ongoing fast behavioral and neuronal models (described above). We will seek to extract from our models of the fish brain and behavior general principles likely to generalize across species. This will be tested by using our modeling approach to related experiments in the rat and the fruit fly larva (Project 4), especially in the domain of brain state dynamics and the neuromodulatory control of behavior and sensorimotor processing.