Cortical synaptic circuitry underlying visual processing

描述（由申请人提供）：感觉信息的皮层处理关键取决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回路的结构是理解信息处理如何在皮层中实现的关键，但以前的进展受到桥接连接和功能的技术困难的限制。近期 在小鼠中分子和遗传工具的发展使其成为系统地解剖皮层功能下的突触回路的有吸引力的模型。利用这些工具，我们将能够整合多种方法来解决小鼠初级视觉皮层神经元的基本感受野特性的突触电路机制。在这个项目中，我们将首先揭示视觉诱发的兴奋性和抑制性突触输入兴奋性神经元在体内全细胞电压钳记录的时空相互作用。具体来说，我们将确定两个基本的视觉处理特性的皮层兴奋性神经元，方向选择性和方向选择性的对比度不变性的突触机制。然后，我们将用光遗传学方法分析不同来源的兴奋性输入的功能贡献。通过用一组特定的抑制性神经元的光遗传学激活来沉默皮质，我们将 确定丘脑皮质和皮质内输入对第4层兴奋性神经元方向选择性的各自贡献。最后，通过在转基因小鼠模型中开发双光子成像引导的全细胞电压钳记录技术，我们将确定pavalbumin阳性皮层抑制性神经元所表现出的弱方向调谐的突触机制。这些拟议的研究将可能提供重要的新见解，功能性皮层突触回路是如何组织的，以及皮层处理和感觉知觉如何在神经系统疾病条件下出错，导致兴奋-抑制平衡被破坏。

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.