Development of brain-scale neural circuits underlying vertebrate visuomotor transformations

脊椎动物视觉运动转化的大脑规模神经回路的发展

• 批准号: 10421132
• 负责人: Eva Aimable Naumann
• 金额: $ 34.22万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10421132
• 关键词: Affect; Algorithms; Area; Behavior; Behavioral; Biological Models; Blindness; Brain; Calcium; Cells; Collaborations; Congenital Disorders; Data; Development; Disease; Equilibrium; Eye; Fertilization; Genes; Goals; Health; Image; Individual; Injury; Knowledge; Life; Link; Maintenance; Mammals; Measures; Modeling; Motion; Motor output; Natural regeneration; Nature; Neurons; Newborn Infant; Optics; Pathologic Nystagmus; Phase; Population Dynamics; Process; Recurrence; Research Design; Resolution; Retina; Retinal Degeneration; Retinal Ganglion Cells; Role; Shapes; Signal Transduction; Stimulus; Study models; Swimming; Target Populations; Testing; Time; Training; Vision; Visual; Visual Motion; Visual system structure; Zebrafish; base; behavior test; behavioral response; critical developmental period; design; developmental disease; experimental study; high dimensionality; infancy; insight; loss of function; monocular; mutant; network models; neural circuit; neural correlate; neurodevelopment; neurogenesis; novel; optogenetics; predicting response; predictive modeling; preference; recurrent neural network; regenerative treatment; relating to nervous system; response; sensory input; sight restoration; stem; treatment strategy; two photon microscopy; vision development; visual motor; visual processing

ABSTRACT It remains considerably challenging to restore vision after developmental disturbances, such as congenital infantile nystagmus, and after injury or retinal degeneration. This is because the mechanisms establishing functional connectivity between retinal ganglion cells and their downstream targets in the brain remain poorly understood. This knowledge gap is partly because observing the functional emergence, stabilization, and maintenance of entire visual neural circuits is impossible in mammals. This project will leverage the strategic experimental advantages of the larval zebrafish, a vertebrate model system, to investigate the functional maturation of a conserved neural circuit underlying a visual orienting behavior, the optomotor response (OMR). This will form the basis for understanding how congenital disorders exert their effects and how new neurons added after initial circuit development can support healthy visual processing. Recently, we described the transformation of retinal visual motion signals into motor output and showed that it required many different types of neurons distributed across the brain. These neurons can be classified based on their diverse eye- and direction-specific response profiles, and they collaborate to compute how exactly visual scenes are moving. Fascinatingly, this collaboration supports stable behavior 5 days after fertilization, even though new neurons are added to the circuit throughout life. We will test the central hypothesis that after initial formation, the OMR circuit expands by adding new neurons in balanced response classes, permitting the continued execution of motion- guided behaviors. In Aim 1, we will test how the development of the behavioral repertoire and associated neural circuitry is affected by specific disruption of direction-selective retinal input. By training recurrent neural networks, we will generate predictive models of connectivity between direction-selective retinal ganglion cells and downstream targets. In Aim 2, we will investigate how the functional neural representations mature, and we will quantify the stability of individual neuronal responses over time. By computationally tracking all neurons, we will directly investigate the trajectory of new neuron functional integration into existing circuitry and determine how the balance of functional profiles varies over time and covaries with behavior. In Aim 3, will use holographic photostimulation to examine the role of activity in shaping ultimate circuit role for individual neurons. Together, these experiments will reveal how an entire motion-sensitive vertebrate circuit is functionally assembled, providing insight about the functional connectivity between retinal ganglion cells and their downstream partners and about the nature and utility of neurogenesis. These results will inform regenerative treatment strategies for developmental disorders or injuries to central visual processing areas.

摘要 在发育障碍（如先天性视网膜病变）后恢复视力仍然具有相当大的挑战性。 婴儿期眼球震颤，以及受伤或视网膜变性后。这是因为建立机制 视网膜神经节细胞和它们在大脑中的下游目标之间的功能连接仍然很差 明白这种知识差距部分是因为观察功能的出现，稳定， 哺乳动物不可能维持整个视觉神经回路。该项目将利用战略 实验优势的幼体斑马鱼，脊椎动物模型系统，调查功能 成熟的保守的神经回路潜在的视觉定向行为，视动反应（OMR）。 这将为理解先天性疾病如何发挥作用以及新的神经元如何发挥作用奠定基础。 在最初的电路开发后添加的功能可以支持健康的视觉处理。最近，我们描述了 将视网膜视觉运动信号转换为运动输出，并表明它需要许多不同的类型 分布在大脑中的神经元。这些神经元可以根据它们不同的眼睛进行分类， 方向特定的响应曲线，他们合作计算视觉场景是如何移动的。 有趣的是，这种合作支持受精后5天的稳定行为，即使新的神经元是 添加到整个生命周期的电路。我们将检验中心假设，即在初始形成后，OMR电路 通过在平衡反应类中添加新的神经元来扩展，允许继续执行运动- 引导行为。在目标1中，我们将测试行为库和相关神经系统的发展如何影响神经系统的发育。 回路受到方向选择性视网膜输入的特定破坏的影响。通过训练递归神经网络， 我们将生成方向选择性视网膜神经节细胞之间连接的预测模型， 下游目标在目标2中，我们将研究功能性神经表征是如何成熟的，我们将 量化个体神经元反应随时间的稳定性。通过计算跟踪所有神经元，我们将 直接研究新神经元功能整合到现有电路中的轨迹，并确定如何 功能分布的平衡随时间变化，并与行为相关。在Aim 3中，将使用全息 光刺激，以检查活动在形成单个神经元的最终回路作用中的作用。我们一起努力， 这些实验将揭示整个运动敏感的脊椎动物电路是如何在功能上组装的， 提供有关视网膜神经节细胞及其下游伙伴之间的功能连接的见解 以及神经发生的本质和效用。这些结果将为再生治疗策略提供信息， 发育障碍或中央视觉处理区损伤。