Functional Dissection of New Retinal Circuits

 描述（由申请人提供）：该提案的目标是剖析和理解哺乳动物视网膜中的功能神经回路，重点是新发现的谷氨酸无长突细胞（GAC）回路。拟议的研究基于我们最近发现的从 GAC 到特定神经节细胞类型的非常规谷氨酸突触传递（Lee 等人，Neuron，2014）。这一发现表明 GAC 的神经元回路和视网膜内层视觉计算的新形式令人感兴趣。尽管目前对 GAC 电路知之甚少，但小鼠视网膜中 GAC 系统的几个独特优势为我们提供了一个难得的机会来研究（1）特定的无长突细胞类型如何与其上游输入神经元建立功能连接，（2）该细胞类型如何响应和处理视觉输入，以及（3）该细胞类型如何与下游目标神经元形成突触电路并有助于视网膜内的视觉计算。作为一种兴奋性（以及潜在的双重兴奋性/抑制性）无长突细胞类型，GAC 还为我们提供了一个独特的机会来研究新形式的共同神经传递的可能性并测试视网膜无长突细胞功能的新理论。拟议的研究将结合电生理学、双光子成像、光遗传学和化学遗传学，在转基因小鼠品系的强大整体视网膜制备中解决上述问题，其中 GAC 可以被特异性识别和基因操作。将这些先进技术整合到一组精心设计的实验中的能力将使我们能够获得有关 GAC 网络的详细生理、神经化学和电路信息，其水平是其他实验方法无法达到的。该提案将追求三个具体目标：（1）了解 GAC 的细胞和树突响应特性，（2）了解 GAC 输出电路的连接性和功能，以及（3）了解从双极细胞类型到 GAC 的功能输入。这些研究的结果预计将为新型视网膜回路的连接组和生理学提供新的见解，并为健康和疾病中的视网膜回路和视网膜功能提供重要线索。

 DESCRIPTION (provided by applicant): The goal of this proposal is to dissect and understand functional neural circuits in the mammalian retina, with a focus on the newly identified glutamatergic amacrine cell (GAC) circuit. The proposed studies are based on our recent finding of unconventional glutamatergic synaptic transmission from GACs to specific ganglion cell types (Lee et al. Neuron, 2014). This finding suggests intriguing neuronal circuits of GACs and new forms of visual computation in the inner retina. Although little is currently known about the GAC circuitry, several distinct advantages of the GAC system in the mouse retina present a rare opportunity for us to investigate (1) how a defined amacrine cell type makes functional connections with its upstream input neurons, (2) how this cell type responds to and processes visual inputs, and (3) how this cell type forms synaptic circuits with downstream target neurons and contributes to visual computation in the inner retina. Being an excitatory (and potentially dual excitatory/inhibitory) amacrine cell type, GACs also provide a unique opportunity for us to investigate the possibility of new forms of co-neurotransmission and test new theories of amacrine cell function in the retina. The proposed studies will address the above questions using a combination of electrophysiology, two-photon imaging, optogenetics, and chemogenetics in a powerful wholemount retinal preparation of a transgenic mouse line in which GACs can be specifically identified and genetically manipulated. The ability to integrate these advanced techniques in a set of carefully designed experiments will allow us to obtain detailed physiological, neurochemical, and circuit information about the GAC network at a level unattainable by other experimental approaches. The proposal will pursue three specific aims: (1) understand the cellular and dendritic response properties of GACs, (2) understand the connectivity and the function of the GAC output circuit, and (3) understand the functional inputs from bipolar cell types to GACs. Results from these studies are expected to provide novel insights into both the connectome and the physiology of a novel retinal circuit and shed important light on retinal circuitry and retinal function in health and disease.