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Understanding synaptic complexity: Parallel feedback mechanisms in the mouse retina

了解突触复杂性：小鼠视网膜中的并行反馈机制

基本信息

批准号：
253528872
负责人：
Dr. Timm Schubert
金额：
--
依托单位：
Ophthalmic Research
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/253528872?language=en
关键词：
Understanding synaptic complexity Parallel feedback

项目摘要

The first synapse of the visual system plays a fundamental role for all subsequent processing steps: It must provide a reliable, high-fidelity signal flow from the cone photoreceptors to second order neurons of the retina under a wide range of illumination conditions. Here, cone photoreceptors form complex synapses with dendrites of both horizontal cells and bipolar cells. Different types of bipolar cells relay the cone output to signal pathways with different functional properties. Horizontal cells form a single electrically-coupled lateral interneuron network and modulate cone output via feedback synapses, and thus, adjust the cone output gain as a function of background illumination as sensed by the network. The connections from horizontal cells to cones have been intensively studied for several decades but to date we still lack a comprehensive and coherent picture of the mechanisms underlying the modulation of cone output by HCs and their role in retinal light adaptation. Three different synaptic mechanisms have been described to mediate feedback: GABA-mediated feedback, hemichannel-mediated ephaptic feedback, and proton- (pH-) mediated feedback. Contradictory findings with respect to multiple feedback mechanisms within a single species may result from different adaptation states and/or the different experimental conditions. Thus, it is still unclear if the different feedback mechanisms act in parallel or if they part of a multifaceted feedback network as proposed recent studies. Furthermore, it is not clear whether/how the pathways might be functionally connected. By combining three genetic approaches - (i) a transgenic mouse line, in which cones selectively express a genetically encoded calcium biosensor, (ii) horizontal cells transfected with viruses encoding calcium and chloride biosensors, and (iii) gene-silencing techniques to knockdown hemichannels in horizontal cells - with two-photon calcium imaging we want to unravel the synaptic mechanisms that underlie light adaptation in the mouse outer retina. In particular, we aim at probing the HC feedback mechanisms present at different background light levels first directly in the cone axon terminals (as an effect on cone output), and then in HC dendrites (as the presynaptic signal that generates feedback). To gain insight into the spatio-temporal aspects of different feedback mechanisms, we will analyze how chromatic input from spectrally different (green and blue) cone types is integrated in HCs both at the anatomical and the functional level, and then study how this input is translated into (local and/or global network) feedback. We think that a comprehensive outer retina feedback model system may provide new impulses for studies of parallel synaptic mechanisms in other neuronal circuits of the brain.

视觉系统的第一个突触在所有后续处理步骤中起着重要作用：它必须在广泛的照明条件下提供从视锥光感受器到视网膜二级神经元的可靠，高保真的信号流。在这里，视锥光感受器与水平细胞和双极细胞的树突形成复杂的突触。不同类型的双极细胞将视锥细胞输出传递到具有不同功能特性的信号通路。水平细胞形成单个电耦合的外侧中间神经元网络，并且经由反馈突触调制视锥输出，并且因此根据网络感测到的背景照明来调整视锥输出增益。从水平细胞到视锥细胞的连接已经被深入研究了几十年，但到目前为止，我们仍然缺乏一个全面和连贯的图片的机制调制锥输出的HC及其在视网膜光适应的作用。已经描述了三种不同的突触机制来介导反馈：GABA介导的反馈、半通道介导的突触反馈和质子（pH-）介导的反馈。在一个单一的物种内的多个反馈机制的矛盾的结果可能会导致不同的适应状态和/或不同的实验条件。因此，目前还不清楚不同的反馈机制是否并行运作，或者它们是否是最近研究提出的多方面反馈网络的一部分。此外，尚不清楚这些途径是否/如何在功能上连接。通过结合三种遗传方法-（i）转基因小鼠系，其中视锥细胞选择性地表达遗传编码的钙生物传感器，（ii）用编码钙和氯生物传感器的病毒转染的水平细胞，以及（iii）基因沉默技术敲除水平细胞中的半通道-与双光子钙成像，我们希望解开小鼠外视网膜中光适应的突触机制。特别是，我们的目标是探测HC反馈机制存在于不同的背景光水平，首先直接在锥体轴突终端（作为对锥体输出的影响），然后在HC树突（作为突触前信号，产生反馈）。为了深入了解不同的反馈机制的时空方面，我们将分析如何从光谱上不同的（绿色和蓝色）锥类型的彩色输入集成在HC在解剖和功能水平，然后研究如何将这种输入转化为（本地和/或全球网络）反馈。我们认为，一个全面的视网膜外反馈模型系统可能为研究大脑其他神经元回路中的并行突触机制提供新的动力。