Functional analysis of whole-brain dynamics in learning

项目摘要 学习是一个复杂的过程，可能涉及大脑中检测和处理感官信息的许多区域。 输入、整合经验和显示行为。同时，各种神经系统疾病损害 不同的大脑区域与学习方面的严重缺陷有关。因此，在不同的空间尺度之间架起桥梁， 了解不同大脑区域的动态对于理解学习是如何发生的至关重要 并可能设计策略来减轻学习不足。然而，目前还不可能 在大多数实验系统中实现这些目标，而我们对学习的理解受到 通过技术方法，局部电路和细胞特性或粗略的心理物理 测量作为学习基础的参数。在这里，我们建议解决这些基本问题， 一个简化的系统-线虫C的神经系统。优雅理由是，布线和 这个网络的基因组成是众所周知的，用单细胞分辨率探测全脑动力学 精确的时间分辨率，在技术上已经为C语言做好了准备。优雅，和基本原则， 发育和神经系统的功能在C. elegans和更多 复杂的动物模型此外，C.秀丽线虫表现出多种形式的学习，类似于 高等生物的行为特征和分子细胞基础。特别是，我们将使用 一个嗅觉学习范例，其中C。线虫学会避开病原菌的气味， 一种类似于加西亚效应的学习类型，许多动物，包括人类，通过这种学习来避免 使他们生病的食物的气味和/或味道。我们的长期目标是了解学习是如何 由整个大脑的功能编码和执行，并告知潜在的治疗设计， 战略布局该项目的中心假设是，学习涉及全球活动和学习者 信息被编码在不同的功能模块中。具体来说，我们将测试学习到的信息是否 编码在个体功能模块的活动模式中的学习依赖性变化中，和/或 模块之间的交互。为此，我们的目标是成像和分析多细胞和全脑 在幼稚和学习条件下的动力学，以表征学习如何改变大脑结构 活动;此外，我们将引入扰动全脑动力学，并研究其后果 为了学习这项工作是创新的，因为（1）它带来了概念上的进步，理解学习 （2）它介绍了全脑成像和分析的技术进步，（3）它 展示了改变具有行为后果的全脑动力学的扰动策略。 这是重要的，因为它测试了几个高度可信和可能保守的细胞和全脑 学习的动态模型，并检查其行为后果，它通知和促进学习 在其他系统中的研究，它为设计干预措施铺平了道路。

PROJECT SUMMARY Learning is a complex process, and likely involves many areas of the brain that detect and process sensory inputs, integrate experience, and display behavior. Consistently, various neurological diseases that impair different brain areas are associated with profound defects in learning. Thus, bridging different spatial scales and understanding the dynamics of different brain regions are essential to understanding how learning occurs and potentially designing strategies to mitigate learning deficiency. However, it is currently not possible to achieve these goals in most experimental systems, and our understanding of learning is limited by the technical approaches by which either local circuit and cellular properties or coarse psychophysical parameters underlying learning are measured. Here, we propose to address these fundamental questions in a reduced system – the nervous system of the nematode C. elegans. The rationale is that the wiring and genetic make-up of this network are well known, probing whole-brain dynamics with single-cell resolution with exquisite temporal resolution is technically ready for C. elegans, and the fundamental principles for the development and the function of the nervous system are well conserved between C. elegans and more complex animal models. Further, C. elegans exhibits many forms of learning, similar to those displayed by higher organisms in behavioral characteristics and molecular cellular underpinnings. Particularly, we will use an olfactory learning paradigm whereby C. elegans learns to avoid the odorants of pathogenic bacteria, a type of learning similar to the Garcia effect through which many animals, including humans, learn to avoid the smell and/or taste of a food that makes them ill. Our long-term goal is to understand how learning is encoded and executed by the function of the whole brain, and to inform the design of potential therapeutic strategies. The central hypothesis of this project is that learning engages global activity and the learned information is encoded in distinct functional modules. Specifically, we will test whether learned information is encoded in the learning-dependent changes in the activity patterns of individual functional modules and/or the interactions among the modules. To this end, we aim to image and analyze multi-cell and whole-brain dynamics under naive and learned conditions to characterize how learning alters the structure of the brain activities; further, we will introduce perturbations to the whole-brain dynamics and examine the consequences for learning. This work is innovative because (1) it brings a conceptual advance to understanding learning across scales, (2) it introduces technical advancement in whole-brain imaging and analyses, and (3) it demonstrates perturbation strategies for altering whole-brain dynamics that have behavioral consequences. It is significant, because it tests several highly plausible and likely conserved cellular and whole-brain dynamic models for learning and examine their behavioral consequences, it informs and facilitates learning studies in other systems, and it paves the way for designing interventions.