Cortical synaptic circuitry underlying visual processing

描述(由申请人提供)：感觉信息的皮质处理在很大程度上依赖于相互连接的兴奋性和抑制性神经元的协调活动。了解这些兴奋性和抑制性突触电路的结构是理解大脑皮质如何实现信息处理的关键，但之前的进展受到桥接连接和功能方面的技术困难的限制。最近的 小鼠的分子和遗传工具的发展使其成为系统剖析皮层功能基础上的突触电路的一个有吸引力的模型。利用这些工具，我们将能够集成多种方法来解决小鼠初级视觉皮质神经元的基本感受野特性的突触电路机制。在这个项目中，我们将首先通过活体全细胞电压钳记录揭示视觉诱发的兴奋性和抑制性突触输入到兴奋性神经元的时空相互作用。具体地说，我们将确定皮层兴奋性神经元两个基本视觉处理特性的突触机制，即方向选择性和方向选择性的对比度不变性。然后，我们将用光遗传学方法剖析来自不同来源的兴奋性输入的功能贡献。通过用特定组抑制性神经元的光遗传激活来沉默大脑皮层，我们将 确定丘脑皮质和皮质内输入对第四层兴奋性神经元定向选择性的各自贡献。最后，通过在转基因小鼠模型中发展双光子成像引导的全细胞电压钳记录技术，我们将确定帕白蛋白阳性的皮质抑制神经元表现出弱定向调节的突触机制。这些拟议的研究可能为以下方面提供重要的新见解：功能性皮质突触回路是如何组织的，以及在导致兴奋-抑制平衡中断的神经疾病条件下，皮质处理和感觉感知可能会如何出错。

DESCRIPTION (provided by applicant): The cortical processing of sensory information depends critically on the orchestrated activity of interconnected excitatory and inhibitory neurons. Understanding the structure of these excitatory and inhibitory synaptic circuits is key for comprehending how information processing is achieved in the cortex, but the progress has been limited previously by technical difficulties in bridging connectivity and function. The recent development of molecular and genetic tools in the mouse makes it an attractive model for systematically dissecting synaptic circuitry underlying cortical functions. Taking advantage of these tools, we will be able to integrate multiple approaches to address synaptic circuitry mechanisms for the fundamental receptive field properties of mouse primary visual cortical neurons. In this project, we will first reveal the spatiotemporal interplays of visually evoked excitatory and inhibitory synaptic inputs to excitatory neurons with in vivo whole-cell voltage-clamp recordings. Specifically, we will determine the synaptic mechanisms underlying two fundamental visual processing properties of cortical excitatory neurons, the directional selectivity and the contrast invariance of orientation selectivity. We will then dissect the functional contribution of excitatory inputs from different origins with optogenetic methods. By silencing the cortex with optogenetic activation of a specific group of inhibitory neurons, we will determine the respective contribution of thalamocortical and intracortical input to orientation selectivity of layer 4 excitatory neurons. Finally, by developing two-photon imaging guided whole-cell voltage-clamp recording techniques in transgenic mouse models, we will determine the synaptic mechanisms for the weak orientation tuning exhibited by pavalbumin-positive cortical inhibitory neurons. These proposed studies will potentially provide important new insights into how functional cortical synaptic circuits are organized and how cortical processing and sensory perception may go awry under neurological disease conditions which result in disrupted excitation-inhibition balance.