Inhibitory regulation of neural circuit plasticity in visual cortex

摘要 在青春期早期的关键时期，视觉皮层中的电路线路受到以下因素的强烈影响： 感官体验在此期间，由于白内障或斜视而发生的视觉体验下降， 关键期损害立体视觉和高空间频率视觉的发育，从而有助于 弱视的病因。这项提案的长期目标是了解感官如何 经验在关键时期对皮层回路产生影响，特别强调 抑制性神经元的作用。为了确定感觉经验如何作用于抑制神经元以门电路 可塑性，我们提出了三个具体的目标，利用国家的最先进的技术，已经工作 in our laboratories实验室.为了验证视觉改变会导致抑制反应迅速丧失的假设， 然后门兴奋可塑性，我们使用双光子在体内成像，以可视化特定类型的 警觉小鼠视皮层兴奋性和抑制性神经元，然后用靶细胞贴附贴片记录 这些神经元之间的联系。这种方法提供了最高的时间和空间分辨率 available.通过比较随时间变化的反应，我们将揭示跨层可塑性的编排。 为了确定兴奋/抑制网络可塑性的空间和时间动力学，我们使用高速 2-光子在体内显微镜同时成像数百个神经元表达一个新的，非常 敏感的遗传编码钙指示剂（GCaMP 6）。我们追踪同样的神经元群体 在小鼠的眼优势可塑性之前和期间， 用基因编码的红色荧光团双重标记。在第三个目标中，我们检验假设， 单眼剥夺首先将突触连接改变为快速尖峰的中间神经元。为此，我们使用 激光扫描谷氨酸开笼和通道视紫红质辅助电路映射。这项工作将 显著推进我们对抑制可塑性的理解，并解决斜视的目标， 弱视和NEI的视觉处理程序，以“增加对 以确定经验如何改变正在发育的视觉系统中的连接性”

ABSTRACT During critical periods of early adolescence, the wiring of circuitry in visual cortex is strongly influenced by sensory experience. Degraded visual experience, as occurs from cataracts or strabismus, during this critical period impairs the development of steopsis and high sptial frequency vision, thereby contributing to the etiology of amblyopia. The long term objectives of this proposal are to understand how sensory experience exerts its influence on cortical circuitry during the critical period, with particular emphasis on the role of inhibitory neurons. To determine how sensory experience acts on inhibitory neurons to gate circuit plasticity we propose three specific aims that leverage state-of-the-art techniques that are already working in our laboratories. To test the hypothesis that altered vision induces a rapid loss of inhibitory responses, which then gates excitatory plasticity, we use 2-photon in vivo imaging to visualize specific types of excitatory and inhibitory neurons in visual cortex of alert mice and then target cell attached patch recordings to these neurons across cortical layers. This approach provides the highest temporal and spatial resolution available. By comparing responses over time, we will reveal the choreography of plasticity across layers. To determine the spatial and temporal kinetics of excitatory/inhibitory network plasticity, we use high-speed 2-photon in vivo microscopy to simultaneously image hundreds of neurons expressing a new, extremely sensitive genetically encoded calcium indicator (GCaMP6). We follow the same populations of neurons before and during ocular dominance plasticity in mice where specific populations of inhibitory neurons are double labeled with a genetically encoded red fluorophore. In the third aim we test the hypothesis that monocular deprivation first changes the synaptic connectivity to fast-spiking interneurons. To do so we use laser scanning glutamate uncaging and channelrhodopsin-assisted circuit mapping. This work will significantly advance our understanding of inhibitory plasticity and address objectives of the Strabismus, Amblyopia, and Visual Processing Program of the NEI to "increase understanding of the critical period in order to determine how experience alters connectivity in the developing visual system"