Mechanisms Underlying Large-Scale Coordination of Cortical Activity During Perceptual Decisions

越来越清楚的是，自发行为和训练行为都涉及整个大脑皮层的活动。然而，至少在感知决策的情况下，任务复杂性关键地调节底层的大尺度和中尺度皮层动力学。当决策是简单的感觉运动映射时，皮层活动是相关的，失活的行为效应基本上限于相关的感觉区域。相反，当决策是复杂和苛刻的，例如，当积累证据超过几秒钟，皮层活动变得去相关和失活的行为影响是广泛的，表明分布式过程。本提案试图理解与这些观察有关的两个重要问题。在博士后（K99）阶段，我将结合使用基于虚拟现实的行为，来自许多皮层区域的时间特异性光遗传学失活，来自具有细胞分辨率的皮层区域组的同步双光子钙成像，以及大规模皮层活动的动力学模型，以了解分布式过程如何支持复杂的感知决策，特别是证据积累。在独立研究（R00）阶段，我将试图了解大规模皮层动力学的任务引起的变化的机制。特别是，我将使用任务切换在虚拟现实中，大规模的钙成像在中尺度或细胞分辨率，药物遗传学，光遗传学和建模，在隔离或组合，以测试的假设，即基底前脑胆碱能系统的一部分，诱导大规模的去相关与任务复杂性增加的机制。因此，我的目标是使用一个独特的结合国家的最先进的技术，以提供一个详细的和因果关系的帐户，如何分布式皮层过程的基础复杂的决策，以及如何任务特定的皮层状态的影响神经调节。除了对基础研究的重要性之外，阐明这些过程对于理解和治疗决策缺陷至关重要，决策缺陷是许多大脑疾病的标志，如强迫症，注意力缺陷多动障碍和药物滥用。

It has become increasingly clear that both spontaneous and trained behaviors engage activity throughout the cortex. However, at least in the case of perceptual decisions, task complexity critically modulates the underlying large- and mesoscale cortical dynamics. When decisions are simple sensorimotor mappings, cortical activity is correlated, and behavioral effects of inactivation are essentially restricted to the relevant sensory areas. Conversely, when decisions are complex and demanding, e.g. when accumulating evidence over seconds, cortical activity becomes decorrelated and behavioral effects of inactivation are widespread, indicating distributed processes. The present proposal seeks to understand two important problems related to these observations. In the postdoctoral (K99) stage, I will use a combination of virtual-reality based behavior, temporally-specific optogenetic inactivations from many cortical regions, simultaneous two-photon calcium imaging from groups of cortical areas with cellular resolution, and a dynamical model of large-scale cortical activity to understand how distributed processes support complex perceptual decisions, particularly evidence accumulation. In the independent research (R00) phase, I will seek to understand the mechanisms underlying task-induced changes in large-scale cortical dynamics. In particular, I will use task switching in virtual reality, large-scale calcium imaging at mesoscale or cellular resolution, pharmacogenetics, optogenetics and modeling, in isolation or combined, to test the hypothesis that the basal forebrain cholinergic system is part of the mechanism that induces large-scale decorrelations with increased task complexity. I thus aim to use a unique combination of state-of-the-art techniques to provide a detailed and causal account of how distributed cortical process underlie complex decision-making, and how task-specific cortical states are influenced by neuromodulation. Beyond its importance for basic research, elucidating these processes will be crucial for understanding and treating the deficits in decision-making that are a hallmark of many brain disorders such as obsessive-compulsive disorder, attention deficit hyperactivity disorder and drug abuse.