Toward causal neuroscience: capture and manipulate emergent neuronal ensembles

走向因果神经科学：捕获和操纵新兴神经元群

基本信息

批准号：
8743303
负责人：
Fan Wang
金额：
$ 78.5万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-26 至 2018-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): It is hypothesized that animals' perceptual, emotional, or behavioral processes are governed/caused by specific patterns of brain activities, or firings of selected populations (ensembles) of neurons across multiple regions in the nervous system. Indeed recent advancements in optic imaging and multi-electrode recording technology have begun to reveal the inordinately complex dynamics of large populations of neurons in awake, behaving vertebrates such as larval zebrafish and rodents. However, these visualization/recording experiments could not definitively establish the causal relationships between the activities of neuronal ensembles and their functions. A toolkit that enables neuroscientists to be not only observers, but also actuators of the observed ensembles is critically needed for "causal neuroscience". The difficulty to developing such a toolkit lies in th complexity of the mammalian brain, which contains billions of neurons and trillions of synapses. Thus, individual neurons are likely to participate in different active ensembles at different time points. Hence the ensembles associated with a given behavioral or perceptual process are emergent properties arising out of the complicated interactions among millions of neurons. Therefore, ensembles are unlikely to be genetically pre-determined, and molecule or cell-type based methods are not useful for "labeling and manipulating" them. To overcome this difficulty, we will develop a novel toolkit consisting of two key components: (1) a mouse line designed to express, transiently and selectively, a very unstable foreign receptor only in activated neurons, and (2) engineered non-toxic, pseudo-typed viruses that can only infect neurons expressing this foreign receptor. In this way, timed-injection of the pseudo-typed viruses will allow us to specifically and permanently “capture” the recently activated ensembles (which are the ones expressing the viral receptor). The engineered viruses can introduce any desired genes, including optogenetic, chemical-genetic and other molecular tools into the ensembles for subsequent functional studies and manipulations. We plan to carry out proof-of-principle experiments to test the broad applicability of this toolkit for examining the emergence and evolution of neuronal ensembles, and for dissecting the connectivity, electrophysiological properties, learning-induced changes, and causal functions of the emergent ensembles using selected mouse behavioral paradigms. Successful development of this toolkit should transform “causal neuroscience” and open the gateways for understanding the true functional underpinnings of learning, memory, perception, emotion, and many subconscious processes.

描述（由适用提供）：假设动物的感知，情感或行为过程是由大脑活动的特定模式或发火来控制/引起的。神经系统中多个区域的神经元的选定人群（合奏）。确实，视觉成像和多电极记录技术的最新进步已经开始揭示出醒着的神经元种群中不复杂的动力学，表现出脊椎动物，例如幼虫斑马鱼和啮齿动物。但是，这些可视化/记录实验无法确定建立神经元合奏活动及其功能之间的因果关系。一种使神经科学家不仅成为观察者，而且对观察到的合奏的执行者的工具包至关重要。很难开发这样的工具包在于哺乳动物大脑的复杂性，其中包含数十亿个神经元和数万亿个突触。这是，单个神经元可能在不同时间点参与不同的主动集合。因此，与给定的行为或感知过程相关的集合是数百万神经元之间复杂相互作用引起的新兴特性。因此，不太可能先预先确定集合，而基于分子或细胞类型的方法对于“标记和操纵”它们没有用。为了克服这一困难，我们将开发一个由两个关键组成部分组成的新型工具包：（1）旨在瞬时和有选择性地表达仅在活化神经元中表达非常不稳定的外国受体的小鼠系，（2）（2）工程性的无毒，伪造的型病毒只能感染这种外国受体的神经元。这样，伪型病毒的定时注射将允许我们专门，永久地“捕获”最近激活的合奏（这是表达病毒接收器）。工程病毒可以引入任何所需的基因，包括在合奏中进行光遗传学，化学遗传和其他分子工具，以进行随后的功能研究和操纵。我们计划进行原则证明实验以测试广泛的适用性该工具包检查神经元合奏的出现和演变，并剖析连通性，电生理特性，学习引起的变化和因果功能使用选定的鼠标行为范式的新兴合奏。该工具包的成功开发应该改变“因果神经科学”，并为理解真正功能的门户打开门户学习，记忆，感知，情感和许多潜意识过程的基础。