INHIBITORY SYNAPTIC MECHANISMS UNDERLYING VISUAL CORTICAL PROCESSING

产品描述：（申请人提供）：感觉皮层神经元的功能特性，反映在它们对刺激属性的反应选择性，主要是由感觉诱发的兴奋性和抑制性突触输入到细胞的时空整合决定的。本项目的目的是提供一个了解兴奋性和抑制性突触机制的皮质细胞的功能特性。突触抑制在形成视觉皮层处理中的作用仍然存在争议。此外，由于在体内识别和靶向皮层抑制性神经元的困难，这些神经元的感受野（RF）特性，这是至关重要的突触抑制的功能，仍然在很大程度上难以捉摸。本研究拟将在体全细胞记录技术与双光子成像技术联合收割机相结合，利用小鼠遗传模型，研究视觉皮层神经元对兴奋性和抑制性输入的反应特性。在目标1中，使用“盲”全细胞电压钳记录结合组织学，我们将解剖稀疏闪光刺激引起的皮层兴奋性神经元的兴奋性和抑制性突触电导。我们将确定简单和复杂的感受野结构是如何由突触输入的空间分布决定的。通过重构这些突触输入导致的膜电位变化，我们将测试抑制性输入在锐化尖峰开和关感受野的空间离散性中起着至关重要的作用的假设。在目标2中，我们将在转基因小鼠系中进行双光子成像引导的松散斑记录，其中用绿色荧光蛋白标记抑制性神经元。我们将研究荧光抑制性神经元和非荧光兴奋性神经元的视觉诱发尖峰响应，并测试这两组神经元之间存在功能差异的假设，即抑制性神经元对刺激属性（如空间相位和方向）的选择性较低。在目标3中，通过应用成像引导的全细胞电流钳和电压钳记录，我们将测试兴奋性和抑制性神经元之间的功能差异可以归因于它们接收的突触输入强度的差异，而不是突触输入电路的结构。这些研究将为功能性皮层回路提供新的见解。在中枢神经系统中，抑制性突触输入控制网络活动的获得，并在信息处理中起关键作用。突触抑制的异常与几种认知障碍和与年龄相关的感知功能下降有关。该项目将促进我们对抑制性回路在视觉处理中的作用的理解，并可能为抑制性神经元的功能变化如何导致认知功能的恶化提供重要的见解。

Description: (provided by applicant): The functional properties of sensory cortical neurons, as reflected in their response selectivity to stimulus attributes, are primarily determined by the spatiotemporal integration of sensory-evoked excitatory and inhibitory synaptic inputs to the cell. The objective of this project is to provide an understanding of excitatory and inhibitory synaptic mechanisms underlying the cortical cells' functional properties. The role of synaptic inhibition in shaping visual cortical processing has remained controversial. In addition, due to the difficulties in identifying and targeting cortical inhibitory neurons in vivo, the receptive field (RF) properties of these neurons, which are crucial to the function of synaptic inhibition, remain largely elusive. We propose to combine the in vivo whole-cell recording and two-photon imaging techniques, and exploit mouse genetic models, to determine the response properties of excitatory and inhibitory inputs in visual cortical neurons. In Aim 1, using "blind" whole-cell voltage-clamp recording coupled with histology, we will dissect the excitatory and inhibitory synaptic conductances of cortical excitatory neurons evoked by sparse flash stimuli. We will determine how simple and complex receptive field structures are determined by the spatial distribution of synaptic inputs. By reconstituting the membrane potential changes that result from these synaptic inputs, we will test the hypothesis that inhibitory inputs play a crucial role in sharpening the spatial discreteness of spike On and Off receptive fields. In Aim 2, we will perform two-photon imaging guided loose patch recording in a transgenic mouse line where inhibitory neurons are labeled with green fluorescence protein. We will examine visually evoked spike responses of both fluorescent inhibitory neurons and non-fluorescent excitatory neurons, and test the hypothesis that there are functional differences between these two groups of neurons, i.e. inhibitory neurons are less selective to stimulus attributes such as spatial phase and orientation. In Aim 3, by applying imaging guided whole-cell current-clamp and voltage-clamp recordings, we will test the hypothesis that the functional differences between excitatory and inhibitory neurons can be attributed to the difference in the strength of synaptic inputs they receive, rather than in the structure of synaptic input circuitry. These studies will provide novel insights into functional cortical circuitry. PUBLIC HEALTH RELEVANCE In the central nervous system inhibitory synaptic inputs control the gain of network activity and play a critical role in information processing. Abnormality in synaptic inhibition has been implicated in several cognitive disorders and age-related reduction in perceptual functions. The proposed project will advance our understanding of the role of inhibitory circuits in visual processing, and may provide important insights into how functional changes of inhibitory neurons can lead to deterioration of cognitive functions.