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，任务复杂性严格调节潜在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，而失活的行为影响基本上局限于相关的感觉区域。相反，当决策复杂且要求很高时，例如，在几秒钟内积累证据时，皮层活动变得不相关，失活的行为影响广泛存在，表明过程是分布式的。本建议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），我将结合基于虚拟现实的行为，来自许多皮质区域的暂时特异性光遗传失活，来自皮质区域的细胞分辨率组的同时双光子钙成像，以及大规模皮质活动的动态模型来理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，我将寻求理解大规模皮层动力学中任务诱导变化的机制。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，来测试基础前脑胆碱能系统是诱导大规模去相关机制的一部分，增加任务复杂性。因此，我的目标是使用最先进技术的独特组合来提供分布式皮层过程如何成为复杂决策基础的详细和因果解释，以及任务特异性皮层状态如何受到神经调节的影响。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，决策缺陷是许多脑部疾病的标志，如强迫症、注意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.