Optogenetic manipulation of cortical feedback for controlling network coding and behavior

项目摘要/摘要 神经元信号通过局部、前馈和反馈投射传递到大脑皮层。虽然很多人 研究已经检查了本地和前馈连接的功能，反馈连接的作用 人们对此仍然知之甚少。以前的工作利用了各种方法，包括药理学 失活、电微刺激、皮质降温和经颅磁刺激研究反馈 投射。然而，这些技术是有限的，因为它们不能具体地抑制反馈终端 而不改变前馈处理。例如，使用药理学方法的研究将一种药物注射到 较高的皮质区域，以抑制对较低皮质区域的反馈。然而，这种药物本身就是 抑制离开较高皮质区域的前馈信号。除了在空间上不精确之外， 这些方法在时间上也是不精确的--这些技术的工作时间在几分钟到几小时之间，而 神经元信号在毫秒量级上被调制。此外，以往的研究主要集中在单个单元上 分析，而不检查反馈的网络级别的影响或反馈投影的层状位置。 为了解决这些限制，我们将使用光遗传构建体(AAV8-hSyn-Jaws-GFP)来选择性地 抑制反馈信号，因为光遗传方法允许在时间和空间上进行精确的操作。我们 将在非人类灵长类动物中以前所未有的方式结合光遗传学和电生理学，以 检查反馈在视觉系统中的功能作用。中层视皮层(V4)，已被 牵涉到认知需求的过程(如注意力)，向肤浅的人发送反馈预测 初级视皮层各层(V1)。注射的病毒将在V4神经元的所有部分表达，包括 投射到V1的轴突。这允许我们在V1中光刺激被转染的V4反馈终端， 而不会干扰V4中的前馈处理。我们的工作假设是反馈联系表现为 功能特异性，并增加群体编码的准确性和皮质神经元之间的沟通。 我们将确定抑制V1中的V4反馈终端如何影响单个小区和网络级别的刺激 编码(目标1)、行为表现(目标2)和注意力调节(目标3)。具体地说，我们预计 抑制V1中的V4反馈端子将(I)降低增益和调谐强度，并增加噪声 相关性(目标1)、(2)方位辨别任务成绩下降(目标2)和(3)减少 与无人参与的试验相比，在有人参与的试验中获得和增加噪声相关性(目标3)。我们还预计， 以反馈投影为目标的颗粒上层将显示出比颗粒层和 颗粒层以下，通过反馈投影来避免。该方案中的实验将确定单个 视觉系统中反馈的神经元和网络水平效应，并进一步研究反馈如何影响 行为和注意力调节。这些发现将对我们对大脑皮层的基本理解产生持久的影响 沟通，对视觉假肢等临床应用产生长期影响。

Project Summary/Abstract Neuronal signals travel the cerebral cortex through local, feedforward and feedback projections. Although many studies have examined the function of local and feedforward connections, the role of feedback connections remains poorly understood. Previous work has utilized a variety of methodologies, including pharmacological inactivation, electrical microstimulation, cortical cooling and transcranial magnetic stimulation to study feedback projections. However, these techniques are limited, as they cannot specifically suppress feedback terminals without altering feedforward processing. For example, studies using pharmacological methods inject a drug into a higher cortical area in order to suppress feedback to lower cortical areas. The drug, however, inherently suppresses the feedforward signals leaving the higher cortical area. In addition to being spatially imprecise, these methods are also temporally imprecise – these techniques work on the order of minutes to hours whereas neuronal signals are modulated on the order of milliseconds. Furthermore, previous studies focus on single unit analysis, without examining the network-level effects of feedback or laminar location of the feedback projections. In order to address these limitations, we will use an optogenetic construct (AAV8-hSyn-Jaws-GFP) to selectively suppress feedback signals, as optogenetic methods allow for temporally and spatially precise manipulations. We will combine optogenetics and electrophysiology in an unprecedented manner in the nonhuman primate to examine the functional role of feedback in the visual system. Mid-level visual cortex (V4), which has been implicated in cognitively demanding processes (like attention), sends feedback projections to the superficial layers of the primary visual cortex (V1). The injected virus will express in all parts of the V4 neurons, including their axons which project to V1. This allows us to optically stimulate the transfected V4 feedback terminals in V1, without perturbing the feedforward processing in V4. Our working hypothesis is that feedback connections exhibit functional specificity, and increase the population coding accuracy and communication among cortical neurons. We will determine how suppressing V4 feedback terminals in V1 influences single cell and network level stimulus encoding (Aim 1), behavioral performance (Aim 2), and attentional modulation (Aim 3). Specifically, we expect that suppressing V4 feedback terminals in V1 will (i) decrease gain and strength of tuning, and increase noise correlations (Aim 1), (ii) decrease performance in an orientation discrimination task (Aim 2) and, (iii) decrease gain and increase noise correlations in attended compared to unattended trials (Aim 3). We also expect that the supragranular layer, targeted by feedback projections, will show larger effects compared to the granular and infragranular layers, avoided by feedback projections. The experiments in this proposal will determine the single neuron and network-level effects of feedback in the visual system, and further, examine how feedback influences behavior and attentional modulation. The findings will have a lasting impact on our basic understanding of cortical communication, with long-term influences on clinical applications like visual prosthetics.