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

越来越清楚的是，自发的和训练过的行为都参与了整个大脑皮层的活动。然而，至少在知觉决策的情况下，任务复杂性关键地调节了潜在的大、中尺度皮质动力学。当决定是简单的感觉运动映射时，皮质活动是相关的，失活的行为影响基本上限于相关的感觉区域。相反，当决策复杂且要求苛刻时，例如，当在几秒钟内积累证据时，皮质活动变得不相关，失活的行为影响普遍存在，表明过程是分布式的。本提案试图了解与这些意见有关的两个重要问题。在博士后阶段(K99)，我将结合使用基于虚拟现实的行为、来自许多皮质区域的时间性特定光遗传失活、来自具有细胞分辨率的皮质区域组的同步双光子钙成像，以及大规模皮质活动的动力学模型，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，我将试图理解任务诱导的大规模皮质动力学变化背后的机制。特别是，我将使用虚拟现实中的任务切换、中尺度或细胞分辨率的大规模钙成像、药物遗传学、光遗传学和建模，单独或结合使用，以检验这一假设，即基底前脑胆碱能系统是导致大规模去关联和任务复杂性增加的机制的一部分。因此，我的目标是使用一种独特的最先进技术的组合来提供一个详细和因果的描述，说明如何在复杂的决策下进行分布式皮质过程，以及特定任务的皮质状态如何受到神经调节的影响。除了对基础研究的重要性外，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.