Mechanisms of neural circuit dynamics in working memory and decision-making

项目摘要/摘要：总体 这个U19程序的首要目标是确定跨大脑区域的神经计算如何 产生两个核心认知过程，工作记忆和决策，从而得出基本的 大脑功能原理。这一续订应用程序提议追求出现的强大的新主题 从我们以前的工作中，并大幅扩大我们的范围。为了做到这一点，八个PI计划紧密整合 一组实验和计算研究，让小鼠完成蓄积塔的任务--它们必须 记住，在虚拟现实和相关任务中，当它们在迷宫中运行时，两侧有多少塔闪烁。 第一个主题源于发现大脑中的神经元编码任务变量，并 对于任务执行来说是必要的。几乎所有这些区域都表现出顺序活动，其中神经元 在任务中的不同时间处于活动状态，并一起平铺试用期。项目1将确定任务功能 它驱动顺序活动，使用冷却来识别产生顺序活动的神经电路，以及 通过结合透射电子显微镜和计算模型阐明其解剖学基础。 第二个主题是多种推理方法，应用于大规模的海马体记录 我们的任务是揭示外部变量(位置)和内部变量的联合神经表示的几何形状， 认知变量(累积证据)。项目2将扩展我们在神经几何学方面的工作 到其他大脑区域的表达。我们将研究这些区域中的几何图形和表示 相互作用，我们将开发模型来解释观察到的神经流形是如何产生的。 第三个主题，由我们开发的推断大脑内部状态的统计方法推动的，是 在同一任务块中，动物的大脑在一次又一次的试验中处于不同的状态。我们的数据 表明每种状态下的行为需要不同的神经结构和神经回路--在相同的动物和 同样的试验区。项目3将使用多区域记录和扰动来调查状态 是局部对子电路而不是整个大脑的全局，将我们的行为推理方法扩展到神经数据， 并检查我们推断的状态在多大程度上与唤醒、口渴和饥饿的内在状态有关。 为了阐明执行局部计算的多个电路如何组合成一个活动的大脑， 项目4和项目5的目标。项目4将探索多区域录音中的功能相互作用，包括非常 使用下一代硅探针进行大规模同步电生理记录；并通过 有针对性的实验将测试关于皮质下区域如何与新皮质相互作用的两个假说。 项目5将生成一组机械性模型，这些模型实例化 不同的大脑区域。这些本地模型将被合并为单一的多区域模型，由 来自所有项目的数据，这将使我们能够剖析各个区域的作用及其在 执行我们决策任务的许多变种。

Project Summary/Abstract: Overall The overarching goal of this U19 program is to determine how neural computations across brain regions produce two core cognitive processes, working memory and decision-making, and thus to derive fundamental principles of brain function. This renewal application proposes to pursue powerful new themes that emerged from our previous work and to broaden our scope substantially. To do so, the eight PIs plan a tightly integrated set of experimental and computational studies of mice doing the accumulating towers task—in which they must remember how many towers flash on each side as they run down a maze in virtual reality—and related tasks. The first theme arises from the finding that neurons across the brain encode task variables and are necessary for task performance. Almost all of these areas exhibit sequential activity, in which neurons are active at different times in the task and, together, tile the trial duration. Project 1 will identify the task features that drive sequential activity, use cooling to identify neural circuits that generate sequential activity, and elucidate its anatomical basis by combining transmission electron microscopy and computational modeling. A second theme is that manifold inference methods, applied to large-scale hippocampal recordings in our task, reveal the geometry of a joint neural representation for an external variable (position) and an internal, cognitive variable (accumulated evidence). Project 2 will extend our work on the geometry of neural representations to other brain regions. We will examine how geometries and representations in these regions interact with each other, and we will develop models to explain how the observed neural manifolds arise. A third theme, fueled by our development of statistical methods to infer internal brain states, is that animals’ brains occupy qualitatively different states from trial to trial during the same task block. Our data suggests that behavior in each state requires different neural structures and circuits—in the same animal and the same trial block. Project 3 will use multi-region recordings and perturbations to investigate whether states are local to subcircuits versus global across the brain, extend our behavioral inference methods to neural data, and examine to what extent our inferred states are linked to internal states of arousal, thirst, and hunger. Elucidating how multiple circuits performing local computations combine into a brain in action is the goal of Projects 4 and 5. Project 4 will probe functional interactions in multi-region recordings, including very large-scale simultaneous electrophysiological recordings with next-generation silicon probes; and through targeted experiments will test two hypotheses of how subcortical regions interact with neocortex. Project 5 will generate a set of mechanistic models that instantiate specific hypothesized roles of different brain regions. These local models will be combined into a single multi-regional model, informed by data from all projects, that will enable us to dissect the roles of individual regions and their interactions in performance of the many variants of our decision-making task.