The synaptic basis of learning in the auditory system

描述(由申请者提供)：大脑非凡的学习能力背后的突触机制仍然不清楚。一个新的模型预测，学习技能的获得和存储涉及到经验驱动的共同活跃的突触聚集到较短的树突上。这种突触聚集假说的直接证据很少。这项研究计划描述了对该模型的第一次全面测试，该测试将通过对谷仓猫头鹰听觉定位路径的微观解剖变化的定量分析来提供。我们最近发现，幼年猫头鹰的听觉-视觉学习包括选择性地调整位于下丘内的空间特定神经元树突上的突触聚集。在前两组实验中，我们将确定类似的变化是否发生在成年人身上。使用多种范式，我们将研究与正常电路的重新表达和新电路的获得有关的变化。结果将揭示正常、增强和递增训练范例在多大程度上参与突触聚集机制。在第三组实验中，我们将检验该模型的一个单独预测，即非共同活跃的突触是否分离在树突上。最后一组实验的目的是在“解剖学基础真相”上验证这些结果。具体地说，我们将使用一种新开发的高通量串联切片透射电子显微镜方法来重建正常电路和学习电路的完整接线图。这些新颖的连接对于解决这笔赠款的假设驱动的目标和基于发现的方法都是有用的。总而言之，我们的实验承诺揭示突触重组的基本原则，这些原则是青少年和成年人大脑中感觉回路正常发展和可塑性的基础。事实证明，这些知识对于旨在治疗学习障碍的疗法的长期发展是无价的。 与公共健康相关：大脑具有非凡的学习能力，但我们对潜在的生物学机制的理解仍然很原始。这项提议旨在测试一种新的理论，即突触--神经细胞之间的功能性连接--如何在个人学习新技能并在以后的生活中回忆起它们时进行重组。这些机制的知识对于最终制定治疗广泛学习障碍的策略应该是非常有价值的。

DESCRIPTION (provided by applicant): The synaptic mechanisms that underlie the brain's remarkable capacity for learning remain unclear. One new model predicts that the acquisition and storage of learned skills involves the experience-driven clustering of co-active synapses onto short lengths of dendrite. Direct evidence for this synaptic clustering hypothesis is scant. This research proposal describes the first comprehensive tests of the model, to be provided by quantitative analysis of microanatomical changes in the barn owl auditory localization pathway. We recently showed that auditory-visual learning in juvenile owls involves selective adjustments in synaptic clustering on the dendrites of space-specific neurons, located within the inferior colliculus. In the first two sets of experiments we will determine whether similar changes occur in adults. Using multiple paradigms we will examine changes related both to the re-expression of normal circuitry and the acquisition of novel circuitry. The results will reveal the extent to which normal, enhanced and incremental training paradigms engage the synaptic clustering mechanism. In the third set of experiments we will examine a separate prediction of the model, whether non co-active synapses segregate on dendrites. The final set of experiments is designed to provide validation of these results at 'anatomical ground truth.' Specifically, we will use a newly developed high throughput method for serial section transmission electron microscopy to reconstruct the complete wiring diagram of the normal and learned circuits. These novel connectomes will be useful both for addressing the hypothesis-driven aims of this grant and for discovery-based approaches. Collectively, our experiments promise to reveal basic principles of synaptic reorganization that underlie the normal development and plasticity of sensory circuits, in both juvenile and adult brains. Such knowledge should prove invaluable for the long-term development of therapies aimed at the remediation of learning disorders. PUBLIC HEALTH RELEVANCE: The brain possesses a remarkable capacity for learning, yet our understanding of the underlying biological mechanisms remains primitive. This proposal is aimed at testing a new theory for how synapses - the functional connections between nerve cells - reorganize as individuals learn new skills and recall them later in life. Knowledge of these mechanisms should prove invaluable for the eventual development of strategies to treat a wide spectrum of learning disorders.