Consequences of synaptic plasticity on hippocampal circuit dynamics

中心PI：Malenka，Robert C.主要研究者（项目4）：Deisseroth，Karl/Malenka，Robert C. 项目摘要 学习和记忆必须涉及神经回路动力学的变化，但这种机制 发生的变化在很大程度上仍然未知。该项目将使用一种新型体内成像方式，称为光纤 光度测量，这使得可以收集来自遗传靶向细胞的活动模式，并在深 自由移动动物的大脑结构。应用纤维光度法，实时检测CA 3锥体细胞轴突的活性 投射和CA 1锥体细胞体将在自由行为期间和动物经历 校园依赖性学习和记忆任务。遗传编码钙指标（GECIs）， 不同的荧光特性将在CA 3和CA 1锥体细胞中表达， 轴突投射中的突触前活动与其靶点中的突触后活动之间的关系可以被监测 同时，从而允许在突触前和突触后活动之间的关系的定量， 突触连接的定义集。在麻醉动物中验证这种新方法后， 应用于成熟的依赖于记忆的任务，包括背景恐惧条件反射， 一次尝试回避学习，目的是在清醒的行为动物中可视化CA 3到CA 1的回路 动态随着学习的发生而改变。在最后一系列实验中，将完全基于 结果从其他三个项目在康特中心，分子干预旨在调节LTP或 将进行CA 3-CA 1突触处的稳态突触可塑性以确定它们对 学习和记忆过程中的海马回路动力学。因此，该项目有可能提供长期- 寻求深入了解神经回路的变化，学习和记忆的基础，以及阐明的作用， 突触可塑性的突出形式在这些电路适应。 相关性 学习和记忆是由于大脑中特定回路的长期变化， 可以观察到这些变化的发生。使用一种新的复杂的方法， 在行为主体的电路动力学，这个项目将定义如何在学习过程中特定的电路变化。 收集的信息将提供重要的洞察力，了解大脑如何编码记忆， 在包括精神疾病在内的大脑疾病中，这一过程可能会发生故障。

Center PI: Malenka, Robert C. Principal Investigator (Project 4): Deisseroth, Karl/Malenka, Robert C. Project Summary Learning and memory must involve changes in neural circuit dynamics yet the mechanisms by which such changes occur remain largely unknown. This project will use a novel in vivo imaging modality, termed fiber photometry, which allows collection of activity patterns from genetically-targeted cells and processes in deep brain structures in freely-moving animals. Using fiber photometry, real-time activity in CA3 pyramidal cell axon projections and CA1 pyramidal cell bodies will be monitored during free behavior and while animals undergo hippocampus-dependent learning and memory tasks. Genetically encoded calcium indicators (GECIs) with different fluorescent properties will be expressed in CA3 and CA1 pyramidal cells so that the relationship between presynaptic activity in axonal projections and postsynaptic activity in their targets can be monitored simultaneously, thus allowing quantification of the relationship between pre- and postsynaptic activity at a defined set of synaptic connections. After validation of this novel method in anesthetized animals, it will be applied to well-established hippocampal-dependent memory tasks including contextual fear conditioning and one-trial avoidance learning with the goal of visualizing in awake behaving animals how CA3 to CA1 circuit dynamics change as learning occurs. In a final series of experiments, which will be entirely based on the results from the other three projects in the Conte Center, molecular interventions designed to modulate LTP or homeostatic synaptic plasticity at CA3-CA1 synapses will be performed to determine their effects on hippocampal circuit dynamics during learning and memory. Thus, this project has the potential to provide long- sought insight into the neural circuit changes that underlie learning and memory as well as elucidate the role of prominent forms of synaptic plasticity in these circuit adaptations. Relevance Learning and memory are due to long-lasting changes in specific circuits in the brain but it has not been possible to observe these changes occur. Using a new sophisticated method that allows visualization of neural circuit dynamics in behaving subjects, this project will define how a specific circuit changes during learning. The information collected will provide important insight into how the brain encodes memory and how this process can malfunction during brain disorders including mental illness.