Dynamics and molecular mechanism of synaptic connectivity change during learning

描述（申请人提供）：突触是哺乳动物大脑中信息处理的场所。虽然在学习过程中突触的产生和持久性使它们成为电路修饰和记忆存储的潜在底物，但突触结构变化和突触多样性的分子机制仍有待阐明。树突棘是大脑中大多数兴奋性突触的突触后部位。使用体内双光子成像和回顾性阵列断层扫描的创新组合，该提案的目标是确定学习相关突触的分子组成和局部连接，并揭示学习过程中电路重塑的原理。我们提出三个具体目标。目的1研究兴奋性突触的突触后结构棘在突触发生过程中的蛋白表达。将这些表达模式与先前存在的稳定棘进行比较，以确定在学习过程中形成的新棘的分子特征。目标2确定了与学习相关的新棘的突触前伙伴，并剖析了局部回路在学习过程中如何“重新加权”或“重新布线”。目的3研究不同皮层锥体神经元的棘动力学对运动学习的反应，并确定在学习过程中形成的新棘是否接受独特的突触前输入。这项研究的成功完成不仅将为突触形成和多样性的生物学提供重要的见解，还将为神经科学家提供一个新的工具箱，以突出大脑最近形成的新连接。发现学习过程中突触如何重塑将为未来研究突触结构/功能如何被与学习缺陷相关的病理改变奠定基础。

DESCRIPTION (provided by applicant): Synapses are the sites of information processing in the mammalian brain. While generation and persistence of synapses during learning make them potential substrate for circuit modification and memory storage, the molecular mechanisms underlying synaptic structural changes and synapse diversity remain to be elucidated. Dendritic spines are the postsynaptic sites for the majority of excitatory synapses in the brain. Using an innovative combination of in vivo two-photon imaging and retrospective Array Tomography, the goals of this proposal are to determine the molecular composition and local connectivity of learning-related synapses, and to reveal principles of circuit remodeling during learning. We propose three specific aims. Aim 1 examines the protein expression of individual spines (postsynaptic structures of excitatory synapses) during the process of synaptogenesis. Such expression patterns will be compared with those of preexisting stable spines to determine the molecular signature of new spines formed during learning. Aim 2 identifies the presynaptic partners for learning-associated new spines, and dissects how local circuits "reweigh" or "rewire" during learning. Aim 3 investigates how spine dynamics of pyramidal neurons from different cortical layers respond to motor learning, and determines if new spines formed during learning receive unique presynaptic inputs. Successful completion of the research will not only provide critical insights into the biology of synapse formation and diversity, but also offer neuroscientists a novel tool box to highlight new connections formed in a brain's recent past. Discovering how synapses remodel during learning will build a foundation for future investigation of how synaptic structure/function is altered by pathologies associated with learning defects.