Experience-dependent Modulation of Synaptic Circuits in the Hippocampus

 描述(由申请人提供)：了解大脑如何随着经验变化是神经科学中的一个基本问题。记忆系统由多个电路支持，这些电路连接包含来自特定学习经验的信息的神经元集合。我们建议研究空间记忆的持久存储是如何改变海马体回路中的突触的。我们的目标是在突触回路水平上定义记忆痕迹的组织，作为全面研究计划的一部分，以了解认知的过程和机制，其功能障碍可能导致认知障碍。我们研究了学习主动位置回避任务的小鼠海马(CA3)和内嗅皮质(EC Layer III)突触输入到CA1神经元的功能变化。主动位置回避任务是一种空间学习任务，依赖于突触的可塑性及其在背侧海马区的持久性。重要的是，海马区突触功能的变化在训练后至少持续了一个月，并且只有在位置回避记忆也持续存在的动物中才能观察到。在暴露于行为领域(未经训练的对照)或接受不可避免的电击(带轭的对照)的动物中，突触功能没有发生变化。因此，突触功能的变化是学习经验的结果，并与空间记忆本身有关。有趣的是，我们的观察表明，这些变化相当大，可能反映了学习经历对突触电路的影响，而不仅仅是几个被推断为存储明确信息的特定比特的突触。这是一个新的观点；似乎在神经回路中存储记忆涉及突触回路功能的广泛变化，这可能作为表达外在信息的支持框架。我们建议使用这一稳健的实验范式来进一步研究记忆的存储如何改变海马电路中的突触功能。我们试图确定持续性突触变化是否局限于在学习过程中活跃的神经元子集(特定目标1)，并确定这些变化是否平行于已知突触可塑性产物的mRNAs和蛋白质表达的变化(特定目标2)。使用这种方法，我们将努力分析特定的学习经历如何在CA3-CA1和EC-CA1突触输入的水平上持久地改变CA1神经元，以洞察海马区突触回路中记忆痕迹的识别和组织。我们希望通过研究学习信息如何调制构成神经集合活动的突触电路，来扩大我们对神经集合如何在系统水平上支持记忆的理解。因此，这项科学努力有望在“突触体”和“连接体”之间架起一座桥梁。

 DESCRIPTION (provided by applicant): Understanding how the brain changes with experience is a fundamental question in neuroscience. Memory systems are supported by multiple circuits that connect the neuronal ensembles that contain bits of information from particular learned experiences. We propose to investigate how synapses within the hippocampus circuit are changed by the persistent storage of a spatial memory. Our goal is to define the organization of memory traces at the level of synaptic circuits as part of a comprehensive research program to understand the processes and mechanisms of cognition, the malfunction of which may underlie cognitive disorders. We characterized the functional changes of hippocampal (CA3) and entorhinal cortical (EC layer III) synaptic inputs to CA1 neurons in mice that learned an active place avoidance task, a spatial learning task that depends on synaptic plasticity and its persistence in the dorsal hippocampus. Importantly, changes in hippocampal synaptic function persisted for at least 1 month after training and were observed only in animals in which the place avoidance memory also persisted. Changes in synaptic function did not occur in animals that were exposed to the behavioral arena (untrained control) or received delivery of unavoidable shocks (yoked control). Thus the changes in synaptic function were a consequence of the learning experience and were associated with the spatial memory itself. Interestingly, our observations indicated that these changes are rather large, probably reflecting an impact of learning experience on synaptic circuits beyond the few synapses that are inferred to store the specific bits of explicit information. This is a novel perspective; it seems that storing memory in a neural circuit involves broad changes in synaptic circuit function that may act as a supporting framework for the expression of the explicit information. We propose to use this robust experimental paradigm to further study how the storing of memories changes synaptic function within the hippocampal circuit. We seek to determine whether the persistent synaptic changes are localized to the subset of neurons that were active during the learning experience (Specific Aim 1) and to determine whether these changes parallel changes in the expression of mRNAs and proteins of known synaptic plasticity products (Specific Aim 2). Using this approach, we will direct our efforts to provide an analysis of how particular learned experiences persistently modify CA1 neurons at the level of CA3- CA1 and EC-CA1 synaptic inputs to gain insight toward the identification and organization of memory traces within synaptic circuits of the hippocampus. We hope to expand our understanding of how neural ensembles support memory at the systems level by investigating how learned information modulates the synaptic circuits that underlie the ensemble activity. As such, this scientific effort is expected to bridge the scales of the "synaptome" and the "connectome."