The synaptic basis of learning in the auditory system

描述（由申请人提供）：大脑卓越的学习能力背后的突触机制尚不清楚。一个新的模型预测，学习技能的获取和存储涉及到经验驱动的共同活动突触聚集在短长度的树突上。这种突触聚类假说的直接证据很少。本研究计划描述了该模型的第一次综合测试，将通过定量分析仓鸮听觉定位通路的微观解剖变化来提供。我们最近发现，幼年猫头鹰的视听学习涉及到位于下丘的特定空间神经元树突上的突触聚类的选择性调整。在前两组实验中，我们将确定成年人是否也会发生类似的变化。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相关的变化。结果将揭示正常、增强和增量训练范式在多大程度上参与突触聚类机制。在第三组实验中，我们将检验该模型的一个单独预测，即非共同活动的突触是否在树突上分离。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。具体来说，我们将使用一种新开发的高通量方法，用于串行切片透射电子显微镜来重建正常和学习电路的完整接线图。这些新的连接体将有助于解决该资助的假设驱动目标和基于发现的方法。总的来说，我们的实验有望揭示突触重组的基本原理，这些原理是青少年和成人大脑中感觉回路正常发育和可塑性的基础。这些知识对于旨在纠正学习障碍的治疗方法的长期发展应该证明是无价的。

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.