Targeted circuit modulation to delineate the causal role of oscillatory interactions in top-down networks of cognitive control

项目摘要-北卡罗来纳大学-查佩尔山，弗罗里希 持续的注意力代表了认知控制的一个基本维度，指的是分配的过程。 认知资源，以适当地应对不常见的，但任务相关的刺激。持续的注意力不同于 更常见的研究转移或分散注意力，因为它缺乏能力限制的定义特征， 竞争持续注意力缺陷在精神疾病中很常见，包括注意力缺陷多动症 躁郁症和精神分裂症。因此，了解持续注意力的网络基底， 显著提高我们开发基于回路的治疗方法的能力， 这些模式可以驱动持续的注意力。两个高阶网络中的同步已成为神经子网络 持续注意力和认知控制的策略。首先，额顶骨网络充当生成器 自上而下的控制信号。第二，后丘脑-皮层网络门控输入和展示任务的处理- 持续注意力的调节。然而，目前还不清楚这两个系统是否通过振荡实现同步， 网络在持续注意力和更广泛的认知控制中起着因果作用。靶向脑刺激 具有节律模式刺激的单个网络节点提供了操纵特定网络的机会 振荡模式，并检查由此产生的行为表现的变化，以建立一个因果关系的作用， 有针对性的活动模式。这种高阶大脑功能的因果神经科学将从根本上推进我们的研究。 理解认知如何从大脑中的大规模电活动模式中产生。总体目标是 通过节律性光遗传刺激确定振荡功能相互作用在持续注意中的因果作用， 是的。我们将采用一个广泛使用的动物持续注意力的范例，五选择系列反应时间 任务（5-CSRTT），结合雪貂中的节律性光遗传学刺激和多位点电生理学。我们 使用雪貂（而不是更常用的啮齿动物）来研究认知的振荡基质 因为我们之前发现雪貂与人类有两种基本的自上而下的大脑节律： 额叶θ振荡提供对后顶叶皮层的控制，而后α振荡则控制 视觉感知建议的项目建立在我们发表的工作振荡相互作用在这两个网络 作为与雪貂的5-CSRTT和感觉输入的接合的函数，以及我们的初步数据， 在5-CSRTT中，通过fre对神经元尖峰发放、功能连接和行为表现的显著调节， 频率特异性节律性光遗传学刺激。我们假设，振荡功能的相互作用，在这两个 网络是动态调节的，以驱动持续的注意力在这项任务中。这三个目标的实现，将有利于 深入了解额顶叶和后丘脑-皮质网络在持续性脑缺血中的因果作用， 关注该项目的基本原理是推进高阶同步的因果研究 认知控制中的大脑结构将为开发新的诊断和治疗方法开辟新的途径。 认知控制缺陷的策略。因此，建议的工作具有很高的翻译意义和广泛的 影响，因为持续的注意力在许多精神疾病中受到损害。

PROJECT SUMMARY – UNIVERSITY OF NORTH CAROLINA-CHAPEL HILL, FROHLICH Sustained attention represents a fundamental dimension of cognitive control and refers to the process of allocating cognitive resources to appropriately respond to infrequent but task-relevant stimuli. Sustained attention differs from the more commonly studied shifting or dividing attention since it lacks the defining features of capacity limitation and competition. Deficits in sustained attention are common in psychiatric illnesses including attention deficit hyperactivity disorder, bipolar disorder, and schizophrenia. Understanding the network substrate of sustained attention will thus significantly advance our ability to develop circuit-based therapeutics that selectively engage and restore the activity patterns that drive sustained attention. Synchronization in two higher-order networks have emerged as neural sub- strate of sustained attention and cognitive control in general. First, the frontoparietal network acts as a generator of top-down control signals. Second, the posterior thalamo-cortical network gates processing of input and exhibits task- modulation during sustained attention. Yet, it remains unclear if the synchronization through oscillations in these two networks plays a causal in sustained attention and more broadly in cognitive control. Targeted brain stimulation of individual network nodes with rhythmically patterned stimulation offers the opportunity to manipulate specific network oscillatory patterns and examine the resulting change in behavioral performance to establish a causal role of the targeted activity pattern. Such causal neuroscience of higher-order brain function will fundamentally advance our understanding of how cognition arises from large-scale electrical activity patterns in the brain. The overall objective is to identify the causal role of oscillatory functional interactions in sustained attention by rhythmic optogenetic stimula- tion. We will employ a widely used paradigm of sustained attention in animals, the five-choice serial reaction time task (5-CSRTT), in combination with rhythmic optogenetic stimulation and multisite electrophysiology in ferrets. We use the ferret (instead of more commonly used rodent species) for the study of the oscillatory substrate of cognitive function since we previously found that the ferret shares two fundamental top-down brain rhythms with humans: frontal theta oscillations that provide control of posterior parietal cortex and posterior alpha oscillations that gate visual perception. The proposed project builds on our published work of oscillatory interactions in these two networks as a function of engagement with both the 5-CSRTT and sensory input in ferrets, and our preliminary data of suc- cessful modulation of neuronal spiking, functional connectivity, and behavioral performance in the 5-CSRTT by fre- quency-specific rhythmic optogenetic stimulation. We hypothesize that oscillatory functional interaction in these two networks is dynamically regulated to drive sustained attention in this task. Completion of these three aims will pro- vide an in-depth understanding of the causal role of frontoparietal and posterior thalamo-cortical network in sustained attention. The rationale of this project is that advancing the causal investigation of synchronization in higher-order brain structures in cognitive control will open new avenues for the development of novel diagnostic and therapeutic strategies for deficits in cognitive control. The proposed work is thus of high translational significance and broad impact since sustained attention is impaired in numerous psychiatric illnesses.