Neural Circuits and Synapses for Early Visual Processing

描述（由申请人提供）：我的长期目标是了解视觉处理在神经回路和突触水平的生物学基础。我正在追求这一目标， 在哺乳动物视网膜中，我们可以有效地研究组织的体外自然功能;在那里，我们对组成电路的细胞类型有基本的了解：3-4个光感受器（视杆细胞和视锥细胞），~50个中间神经元（水平，双极和无长突细胞），和~20个输出神经元（神经节细胞）。了解视网膜回路的一个主要障碍是大约40种无长突细胞中的大多数的未知功能。这些（主要是）抑制性中间神经元在神经节细胞感受野计算中起着重要作用，但我们目前只对四种类型有相当详细的了解，专门用于视杆视觉（AII，A17），方向选择性（星爆）和神经调节（多巴胺能）。其余30多种类型的假设功能包括特征选择性（例如，方向调节）、感受野环绕的产生、ON和OFF通路之间的“交叉”抑制以及ON或OFF通路内的前馈抑制。然而，理解无长突细胞在视网膜回路中的作用存在主要障碍：我们缺乏将特定功能分配给单个无长突细胞类型的能力，并且在大多数情况下，我们不知道特定细胞类型的突触后靶点及其在网络功能中的相关作用。为了推动这一领域的发展，我们建议使用一种综合的、多学科的方法来测试新型无长突细胞电路的替代假设功能。目的1将通过记录树突（神经递质释放的部位）中的钙信号来确定遗传上鉴定的无长突细胞类型的感受野特性。目的二是利用光遗传学技术确定特定无长突细胞类型的突触后神经节细胞靶点。目的3将通过测量无长突细胞的可逆失活如何影响神经节细胞感受野特性来确定无长突细胞类型在回路中的功能作用。这三种方法的结合将提供现有的方法研究无长突细胞的重大进展，并应广泛适用于整个哺乳动物中枢神经系统的神经回路功能的研究。此外，研究无长突细胞的功能及其与其他视网膜神经元的相互连接将有助于开发新的诊断和治疗的长期目标（即，光遗传学、假体）用于眼部疾病。

DESCRIPTION (provided by applicant): My long-term goal is to understand the biological basis of visual processing at the level of neural circuits and synapses. I am pursuing this goal in the mammalian retina, where we can efficiently study the tissue's natural function in vitro; and where we have a basic understanding of the cell types that compose the circuits: 3-4 photoreceptors (rods and cones), ~50 interneurons (horizontal, bipolar and amacrine cells), and ~20 output neurons (ganglion cells). A major obstacle to understanding retinal circuitry is the unknown function of the majority of the ~40 types of amacrine cell. These (primarily) inhibitory interneurons play a major role in ganglion cell receptive field computations, but we presently have a fairly detailed understanding of just four types, specialized for rod vision (AII, A17), direction selectivity (starburst) and neuromodulation (dopaminergic). Hypothesized functions for the remaining 30+ types include feature selectivity (e.g., orientation tuning), generation of receptive field surrounds, 'cross-over' inhibition between the ON and OFF pathways, and feedforward inhibition within either the ON or OFF pathways. However, there are major barriers to understanding the role of amacrine cells in retinal circuitry: we lack the ability to assign specific functions to individual amacrine cell types, and in most cases we do not know a specific cell type's postsynaptic targets and its associated role in network function. To move the field forward, we propose to test between alternative hypothesized functions for novel amacrine cell circuits using an integrated, multidisciplinary approach. Aim 1 will determine receptive field properties of genetically-identified amacrine cell types by recording Ca signals in their dendrites the sites of neurotransmitter release. Aim 2 will determine a specific amacrine cell type's postsynaptic ganglion cell targets using optogenetics. Aim 3 will determine the functional role of an amacrine cell type in the circuit by measuring how its reversible inactivation affects ganglion cell receptive field properties. The combination of these three approaches will provide major advances over existing methods for studying amacrine cells and should be broadly applicable to the study of neural circuit function throughout the mammalian central nervous system. Furthermore, studying the function of amacrine cells and their interconnections with other retinal neurons will contribute to the long-term goal of developing new diagnoses and treatments (i.e., optogenetic, prosthetic) for eye disease.