CRCNS: Theory-guided studies of cortical mechanisms of multi-input integration

了解大脑、哺乳动物和人类智力的基本目标，并了解 处理在遗传和发育疾病中如何出错，是要了解的原理 大脑皮层的运作。关键一步是理解皮层执行的“规范”操作。这里 我们将在候选人的新理论指导下的实验中探索皮层回路的运作 规范电路操作。感觉皮层必须全局整合局部感觉输入来解析物体 并支持感知。在单个神经元中，这表现为通过调节对局部刺激的反应 环境或自上而下的影响，例如注意力以及驾驶中局部刺激之间的相互作用 响应（“标准化”）。这些相互作用往往会抑制较强的刺激，但会抑制较弱的刺激 抑制或促进较弱的刺激。米勒博士实验室最近的理论工作提出了一个 新颖的皮质电路主题，稳定的超线性网络（SSN），提供了一个简单的统一 解释与全球一体化相关的各种神经反应。该模型作为 Van Hooser 博士实验室的皮层回路新实验探索指南，使用两者 传统的实验记录技术和他最近开发的新颖的光学方法 以高空间和时间分辨率操纵皮质活动。 SSN 模式如果成功，将 进行详细阐述以最好地解释实验结果。在目标 1 中，光激活通道视紫红质 2 （ChR2）和光学刺激系统用于驱动精确空间和皮质回路的活动 时间模式来测试皮质回路对正常化和情境调制的贡献 包括关于他们的各种 SSN 预测。在目标 2 中，兴奋性驱动力 (E) 与抑制性驱动力的平衡 (I) 使用很大程度上限制 E 或 I 细胞 ChR2 表达的病毒将改变皮质内的细胞。 这将测试涉及通过调制输入偏置调制网络增益的 SSN 模型预测 针对 E 或 I 细胞、注意力调节机制以及“矛盾”结果的依赖性 - 向 I 细胞添加驱动力会降低稳态 I 响应——关于 I 细胞驱动力的空间模式和水平 皮质激活。 相关性（参见说明）： 我们将测试一个强大框架的预测，以了解感觉皮层在全球范围内的运作方式 整合多个输入源，自下而上和自上而下，以产生神经元反应和 最终的感知。了解导致皮质运作崩溃的电路变化可能 提供对自闭症和精神分裂症等疾病的深入了解，这些疾病在背景或全局方面表现出缺陷 处理。了解全球一体化对于创建治疗假肢装置是必要的 失明和其他疾病。

A fundamental goal for understanding the brain and mammalian and human intelligence, and to understand how processing goes awry in genetic and developmental diseases, is to understand the principles of operation of cerebral cortex. A key step is to understand "canonical" operations carried out by cortex. Here we will explore the operations of cortical circuitry in experiments guided by a new theory of a candidate canonical circuit operation. Sensory cortex must globally integrate localized sensory input to parse objects and support perception. In individual neurons, this manifests as modulation of responses to local stimuli by context or top-down influences such as attention and as interactions between local stimuli in driving responses ("normalization"). These interactions tend to be suppressive for stronger stimuli but more weakly suppressive or facilitative for weaker stimuli. Recent theoretical work in Dr. Miller's lab has proposed a novel cortical circuit motif, the stabilized supralinear network (SSN), that provides a simple unified explanation for a wide variety of neural responses related to global integration. The model serves as a guide for new experimental explorations of cortical circuitry in Dr. Van Hooser's laboratory, using both traditional experimental recording techniques and his recently developed novel optical methods for manipulating cortical activity with high spatial and temporal resolution. The SSN model, if successful, will be elaborated to best explain experimental results. In Aim 1, the light-activated channel channelrhodopsin2 (ChR2) and an optical stimulation system are used to drive activity of cortical circuits in precise spatial and temporal patterns to test the contribution of cortical circuits to normalization and contextual modulation including various SSN predictions about them. In Aim 2, the balance of drive to excitatory (E) vs. inhibitory (I) cells within the cortex will be altered using viruses that largely restrict expression of ChR2 to E or I cells. This will test SSN model predictions involving modulation of network gain by modulatory input biased toward E or I cells, mechanisms of attentional modulation, and the dependence of a "paradoxical" result -­ adding drive to I cells reduces steady-state I responses -- on the spatial pattern of drive to I cells and level of cortical activation. RELEVANCE (See instructions): We will test the predictions of a powerful framework for understanding how sensory cortex globally integrates multiple sources of input, bottom-up and top-down, to produce neuronal responses and ultimately perception. Understanding circuit changes that cause breakdown of this cortical operation may provide insight into disorders such as autism and schizophrenia, which show deficits in contextual or global processing. Understanding global integration will be necessary for the creation of prosthetic devices to treat blindness and other disorders.