BRAIN EAGER: Massive-scale multi-area single neuron recordings to reveal circuits underlying short-term memory

BRAIN EAGER：大规模多区域单神经元记录揭示短期记忆背后的电路

• 批准号: 1451125
• 负责人: Mriganka Sur
• 金额: $ 30万
• 依托单位: Massachusetts Institute of Technology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1451125&HistoricalAwards=false
• 关键词: BRAIN; EAGER; Massive; scale; multi

This award is jointly made by two programs: Instrument Development for Biological Research program (IDBR), and Emerging Frontiers (EF), in the Directorate of Biological Sciences (BIO).Short-term memory is a crucial component of cognitive function and pervades nearly all aspects of our mental lives. Previous research has shown that short-term memory involves multiple cognitive components and diverse brain regions. However, it is not mechanistically understood what regions are involved when, what neuronal subsets are recruited within these regions, or how they interact to represent information relevant to behavior. This proposal aims to elucidate the role of visual, association, and motor cortex in mice performing a visually-cued short-term memory task. This will be accomplished using massive-scale two-photon calcium imaging in behaving mice to measure activity of thousands of neurons simultaneously across these multiple brain regions. Subsequently, optogenetic manipulation of brain regions and of computationally identified neuronal assemblies will be used to determine their causal role in behavior. These technologies and results will have wide impact on understanding neural circuits underlying behavior and cognition. New approaches will be introduced for massive-scale mapping of single neuron activity in relation to a quantifiable behavior. New ways to determine circuit connectivity, and novel combination computational and optogenetic technologies to manipulate critical circuit components, will be introduced. These large data sets will be made widely and freely available, enabling other research groups to avail of these data for novel analyses.The goal of this proposal is to develop novel tools and provide unprecedented information on neuronal activity patterns and circuits in order to understand the role of multiple cortical areas during short-term memory in mice. Classical electrophysiological recordings are limited to relatively small numbers of neurons with unknown identity. In addition, while microstimulation or pharmacological manipulations can be used to activate or inhibit all the neurons within a local area, it is not possible to selectively excite or inhibit specific neuronal subpopulations that are known to play a role in the behavior. The proposal addresses these issues by developing novel tools to study mice performing a visually-cued memory-guided discrimination task. First, methods for massive scale imaging (up to ten thousand neurons simultaneously) of multiple cortical regions spanning several millimeters in the mouse cortex will be developed. Second, mice will be trained on a visually cued short-term memory task with suitable behavioral richness, including separate sensory, memory and response epochs, so that activity in distributed cortical regions (such as visual, parietal, and frontal motor cortices) can be imaged and the role of individual areas in each epoch can be ascertained. Third, targeted inactivation of specific brain areas will be performed to determine their role in the behavior. Finally, computationally identified neuronal subsets in specific areas will be stimulated in order to determine if they are sufficient for altering behavior. Together, these will be the first studies in the field to link behavior, extremely large-scale multiple-area recordings, and causal manipulations of areas and identified neuronal assemblies. By introducing tools for a radically different approach from previous analyses of memory and memory-guided functions, it is expected that the project will have a significant impact on the field.

该奖项由两个项目联合颁发：生物研究仪器开发项目 (IDBR) 和生物科学理事会 (BIO) 的新兴前沿项目 (EF)。短期记忆是认知功能的重要组成部分，几乎渗透到我们心理生活的各个方面。先前的研究表明，短期记忆涉及多种认知成分和不同的大脑区域。然而，尚不清楚何时涉及哪些区域、这些区域内招募哪些神经元子集，或者它们如何相互作用以表示与行为相关的信息。该提案旨在阐明视觉、联想和运动皮层在执行视觉提示短期记忆任务的小鼠中的作用。这将通过对行为小鼠进行大规模双光子钙成像来实现，以同时测量这些多个大脑区域中数千个神经元的活动。随后，对大脑区域和计算识别的神经元组件的光遗传学操作将用于确定它们在行为中的因果作用。这些技术和结果将对理解行为和认知背后的神经回路产生广泛影响。将引入新方法来大规模绘制与可量化行为相关的单个神经元活动。将介绍确定电路连接性的新方法，以及操纵关键电路组件的新颖的组合计算和光遗传学技术。这些大型数据集将广泛免费提供，使其他研究小组能够利用这些数据进行新颖的分析。该提案的目标是开发新颖的工具并提供有关神经元活动模式和回路的前所未有的信息，以便了解多个皮质区域在小鼠短期记忆中的作用。经典的电生理记录仅限于相对少量且身份未知的神经元。此外，虽然微刺激或药理学操作可用于激活或抑制局部区域内的所有神经元，但不可能选择性地兴奋或抑制已知在行为中发挥作用的特定神经元亚群。该提案通过开发新颖的工具来研究执行视觉提示记忆引导辨别任务的小鼠来解决这些问题。首先，将开发对小鼠皮质中跨越几毫米的多个皮质区域进行大规模成像（同时多达一万个神经元）的方法。其次，小鼠将接受具有适当行为丰富度的视觉提示短期记忆任务的训练，包括单独的感觉、记忆和反应时期，以便可以对分布式皮质区域（例如视觉、顶叶和额叶运动皮质）的活动进行成像，并可以确定每个时期中各个区域的作用。第三，将对特定大脑区域进行有针对性的失活，以确定它们在行为中的作用。最后，通过计算确定的特定区域的神经元子集将受到刺激，以确定它们是否足以改变行为。总之，这些将是该领域首次将行为、超大规模多区域记录以及区域和已识别神经元组件的因果操作联系起来的研究。通过引入与之前的记忆和记忆引导功能分析完全不同的方法的工具，预计该项目将对该领域产生重大影响。