Connecting Synaptic Plasticity, Neural Circuits, and Behavior

描述（由申请人提供）：行为的经验依赖性变化依赖于通过突触可塑性重塑神经网络。由于这个原因，突触可塑性在进化上是保守的，并有助于几乎所有的非本能行为模式。尽管突触可塑性很重要且研究也很深入，但我们对突触可塑性如何重塑神经活动模式以实现行为改变的了解仍然存在很大差距。例如，转录因子CREB有助于可塑性，这是啮齿动物、果蝇、海蛞蝓和蠕虫记忆形成的基础，但将CREB连接到突触的具体机制尚不清楚。这一差距仍然存在，因为它还没有可能检查单细胞分辨率的突触的细胞生物学，并同时将这些细胞生物学特性与行为联系起来。在这个建议中，我将使用线虫C. elegans是一种模式生物，特别适合于桥接分子遗传学、突触生理学和神经回路功能。我已经开发了一些工具，使我能够在体内无缝地分析基因突变对单个神经元中单个突触蛋白的影响，测量对神经传递的影响，并确定经验依赖行为的后果。我将使用这些工具来定义CREB如何调节突触前功能和神经回路逻辑的条件下，导致经验依赖的变化，温度相关的迁移行为。这些研究将开始缩小行为可塑性和神经回路功能之间的差距。支持可塑性的途径和基因在生物体中是保守的，对从精神分裂症到药物滥用等疾病都很重要。由于这些原因，这项工作将为许多不同领域的研究提供信息，并有可能确定治疗干预的新靶点。

DESCRIPTION (provided by applicant): Experience-dependent changes in behavior rely upon the reshaping of neural networks through synaptic plasticity. For this reason, synaptic plasticity is evolutionarily conserved and contributes to virtually all non- instinctive behavioral patterns. Despite its importance and intense study, a substantial gap remains in our knowledge of how synaptic plasticity reshapes patterns of neural activity to achieve behavioral changes. For instance, the transcription factor CREB contributes to plasticity that underlies memory formation in rodents, fruit flies, sea slugs, and worms, but the specific mechanisms that connect CREB to the synapse are unclear. This gap remains because it has not been possible to examine the cell biology of the synapse with single-cell resolution and simultaneously link these cell biological properties to behavior. In this proposal, I will address this gap in knowledge using the nematode C. elegans, a model organism uniquely suited to bridging molecular genetics, synaptic physiology, and neural circuit function. I have developed tools that allow me to move seamlessly in vivo between analyzing the consequences of genetic mutations on individual synaptic proteins in single neurons, measuring the impact on neurotransmission, and determining the consequences for experience-dependent behavior. I will use these tools to define how CREB modulates presynaptic function and neural circuit logic under conditions that lead to experience-dependent changes in temperature-associated migration behavior. The proposed studies will begin to close the gap between plasticity and neural circuit function in behavior. The pathways and genes that support plasticity are conserved across organisms and are important for diseases ranging from schizophrenia to substance abuse. For these reasons, this work will inform research in many different fields and holds the potential to identify novel targets for therapeutic interventions.