Neuronal plasticity in retinal circuit development and disease

总结 神经元的可塑性在发育过程中很高，在成熟时很低。高可塑性使开发电路， 完善它们的连接并获得特定的功能，而低可塑性限制了成熟回路中的重新布线， 限制了神经变性和损伤的功能恢复。我们的建议集中在三个问题上：（1） 细胞类型特异性可塑性机制如何支持特定回路的发展？(2)什么控制 从高可塑性到低可塑性的成熟转变(3)我们如何增强成熟神经元的可塑性， 促进神经退化和损伤的功能恢复？我们将在视网膜中解决这些问题 双极细胞双极细胞是视觉系统的二级神经元，并从视觉系统传递光感受器信号。 从外层视网膜到内层视网膜的无长突细胞和神经节细胞。双极细胞失去输入时， 死于视网膜变性，这是视力损害的最常见的遗传原因（即，> 1：2000人 全球）。视网膜变性是一组异质性疾病，通常进展缓慢， 在这个实验中，用剩余的光感受器重新连接双极细胞可以挽救视力。目标1， 我们的建议，我们将描述三种双极细胞类型的发育可塑性，它们参与两个 支持特定视觉引导行为的视网膜回路。因此，我们将细胞类型特异性可塑性 特定回路的发展及其支持的行为的机制。在目标2中，我们将描述 分子和机制，有助于成熟开关从高到低可塑性，在相同的 双极细胞我们将把对这些分子和机制的见解转化为病毒工具， 发育可塑性到成熟神经元。在目标3中，我们将测试这些工具拯救连接的能力 在两种视网膜变性小鼠模型中的作用。在整个提案中，我们将使用腺- 相关病毒来操纵可塑性。我们将通过共聚焦显微镜分析双极细胞的形态和连通性， 和超分辨率成像。我们将通过双光子Ca 2+成像和膜片钳来监测回路功能 电生理学，我们将测试视动反应和感知对比敏感度，以评估视觉 老鼠的功能总之，这些研究将提供对表达和控制机制的见解， 可塑性，并将这些见解转化为增强成熟双极细胞可塑性以挽救视力的策略 在视网膜退化过程中。

SUMMARY Neuronal plasticity is high during development and low at maturity. High plasticity enables developing circuits to refine their connections and attain specific functions, whereas low plasticity restricts rewiring in mature circuits, limiting functional recovery from neurodegeneration and injury. Our proposal focuses on three questions: (1) How do cell-type-specific plasticity mechanisms support the development of specific circuits? (2) What controls the maturational switch from high to low plasticity? (3) How can we enhance plasticity of mature neurons to promote functional recovery from neurodegeneration and injury? We will address these questions in retinal bipolar cells. Bipolar cells are second-order neurons of the visual system and relay photoreceptor signals from the outer retina to amacrine and ganglion cells in the inner retina. Bipolar cells lose input when photoreceptors die in retinal degeneration, the most common heritable cause of visual impairment (i.e., > 1:2000 people worldwide). Retinal degeneration, a heterogeneous group of diseases, often progresses slowly, leaving a window of opportunity, in which rewiring of bipolar cells with remaining photoreceptors could rescue vision. In Aim 1 of our proposal, we will characterize the developmental plasticity of three bipolar cell types, which participate in two retinal circuits that support specific visually guided behaviors. Thus, we will link cell-type-specific plasticity mechanisms to the development of specific circuits and the behaviors they support. In Aim 2, we will characterize molecules and mechanisms that contribute to the maturational switch from high to low plasticity in the same bipolar cells. We will translate insights into these molecules and mechanisms into viral tools to restore developmental plasticity to mature neurons. In Aim 3, we will test the ability of these tools to rescue connectivity and function in two mouse models of retinal degeneration. Throughout this proposal, we will use adeno- associated viruses to manipulate plasticity. We will analyze bipolar cell morphology and connectivity by confocal and superresolution imaging. We will monitor circuit function by two-photon Ca2+ imaging and patch clamp electrophysiology, and we will test optokinetic responses and perceptual contrast sensitivity to assess visual function of mice. Together, these studies will provide insights into the expression and control mechanisms of plasticity and translate these insights into strategies to enhance plasticity of mature bipolar cells to rescue vision during retinal degeneration.