Functional Dissection of New Retinal Circuits

 描述(申请人提供)：本方案的目标是解剖和了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能无长突细胞(GAC)回路。拟议的研究是基于我们最近发现的从GAC到特定神经节细胞类型的非传统谷氨酸能突触传递(Lee等人。神经元，2014)。这一发现表明，GAC的神经元回路和视网膜内部视觉计算的新形式令人感兴趣。虽然目前对GAC电路知之甚少，但GAC系统在小鼠视网膜中的几个明显优势为我们提供了一个难得的机会来研究(1)已定义的无长突细胞类型如何与其上游输入神经元建立功能联系，(2)该细胞类型如何对视觉输入做出反应和处理，以及(3)该细胞类型如何与下游目标神经元形成突触电路，并促进视网膜内部的视觉计算。作为一种兴奋性(和潜在的双重兴奋/抑制)无长突细胞类型，Gacs也为我们提供了一个独特的机会来探索新的共同神经传递形式的可能性，并测试视网膜无长突细胞功能的新理论。这项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，在一种强大的全视网膜制备转基因小鼠系中解决上述问题，在该转基因小鼠系中，GAC可以被特异性地识别和基因操纵。将这些先进技术集成到一系列精心设计的实验中，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，这是其他实验方法无法达到的水平。该提案将追求三个具体目标：(1)了解GAC的细胞和树突反应特性；(2)了解GAC输出电路的连通性和功能；(3)了解双极细胞类型对GAC的功能输入。这些研究的结果有望为一种新的视网膜回路的连接体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的线索。

 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.