The synaptic basis of learning in the auditory system

描述（由申请人提供）：大脑显著的学习能力背后的突触机制仍不清楚。一个新的模型预测，学习技能的获得和储存涉及到经验驱动的共同活动突触聚集到短长度的树突上。这种突触聚集假说的直接证据很少。本研究建议描述了第一次全面测试的模型，提供定量分析的仓鸮听觉定位途径的微观解剖学变化。我们最近发现，猫头鹰的视觉学习涉及选择性调整突触聚集在树突上的空间特异性神经元，位于下丘。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。使用多种范例，我们将检查与正常电路的重新表达和新电路的获取相关的变化。结果将揭示正常、增强和增量训练范式参与突触聚集机制的程度。在第三组实验中，我们将检查模型的单独预测，非共激活突触是否在树突上分离。最后一组实验的目的是提供验证这些结果在“解剖学的基础真相。“具体来说，我们将使用一种新开发的高通量方法进行连续切片透射电子显微镜，以重建正常和学习电路的完整布线图。这些新的连接体将有助于解决假设驱动的目标，这项赠款和发现为基础的方法。总的来说，我们的实验有望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育和可塑性的基础。这些知识对于长期开发旨在纠正学习障碍的疗法应该是非常宝贵的。

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.