Toward mechanistic cognitive neuroscience: cell types, connectivity, and patterned perturbations

总结 大脑的认知功能使高等动物能够以复杂和适应性的方式与世界互动 礼节.例如，动物利用过去的经验来发展规则和背景的内部模型， 影响后续决策。这些认知过程在许多破坏性的心理健康中被破坏 紊乱认知神经科学中的传统实验已经确定了认知神经元之间的相关性。 过程和行为输出或神经事件。然而，要揭开因果关系一直是一个挑战。 认知过程从神经生物学的基本构建模块中出现的机制 计算：分子、细胞、突触和电路。原因很大程度上是因为 联合收割机结合神经科学中新兴的机械方法和范式来研究认知过程。 在这里，我们的目标是克服这些挑战，通过制定一项研究计划，以确定因果关系之间的联系， 认知过程和结构-细胞类型和连接-和功能-时空活动 神经回路的模式。我们最近为老鼠设计了一个虚拟现实系统， 开发了训练老鼠在虚拟环境中导航时执行复杂认知任务的方法， 环境.此外，我们开发了神经生理学和计算工具， 认知过程在神经元群体中的活动模式。我们将利用这一基础建立一个 机械认知神经科学的研究计划。首先，我们将开发一个认知细胞类型的图谱， 大脑区域，使用病毒工具标记这些细胞类型，然后研究这些细胞类型的功能作用 灵活的决策任务。第二，我们将建立基于单神经元光遗传学的方法 以揭示认知行为中识别出的细胞之间的连接。第三，我们将使用钙成像， 在认知任务中“读取”神经活动的模式，然后将“写入”和“擦除”这些模式， 模式化的光遗传学来测试充足性和必要性。我们将研究这些结构和功能特性 在局部神经元群体（微电路）和跨脑区域（中电路）中。这项工作将扩大 新兴的机械认知神经科学领域，并制定新的研究计划，以实现 从核心生物成分和机制的角度定义认知和心理健康。

Summary The cognitive functions of the brain allow higher animals to interact with the world in complex and adaptive manners. For example, animals use past experiences to develop internal models of rules and contexts that shape subsequent decisions. These cognitive processes are disrupted in many devastating mental health disorders. Traditional experiments in cognitive neuroscience have identified correlations between cognitive processes and behavioral outputs or neural events. However, it has been challenging to uncover the causal mechanisms by which cognitive processes emerge from the basic building blocks of neurobiological computations: molecules, cells, synapses, and circuits. The reason is, in large part, because it has been difficult to combine emerging mechanistic approaches in neuroscience with paradigms to study cognitive processes. Here we aim to overcome these challenges by developing a research program to identify causal links between cognitive processes and the structure – cell types and connectivity – and function – spatiotemporal activity patterns in neural populations – of neural circuits. We recently devised a virtual reality system for mice and developed methods to train mice to perform complex, cognitive tasks as they navigate through virtual environments. Further, we developed neurophysiological and computational tools that have identified correlates of cognitive processes in the activity patterns in population of neurons. We will use this foundation to establish a research program for mechanistic cognitive neuroscience. First, we will develop an atlas of cell types in cognitive brain regions, use viral tools to label these cell types, and then study the functional roles of these cell types during flexible decision-making tasks. Second, we will establish methods based on single-neuron optogenetics to reveal connectivity between identified cells during cognitive behaviors. Third, we will use calcium imaging to ‘read’ patterns of neural activity during cognitive tasks and will then ‘write’ and ‘erase’ these patterns using patterned optogenetics to test sufficiency and necessity. We will study these structural and functional properties in local populations of neurons (microcircuits) and across brain areas (mesocircuits). This work will expand the emerging field of mechanistic cognitive neuroscience and develop a new research program toward the goal of defining cognition and mental health in terms of core biological components and mechanisms.