Neural Mechanism for Successful Memory Access in the Cortico-Hippocampal Networks

项目总结 成功的记忆提取是我们大脑中最重要的功能之一。大量研究表明， 海马-内嗅觉(HPC-EC)回路在特定事件的编码和提取中起关键作用 回忆。许多人类患者患有阿尔茨海默病、痴呆症和广谱的 精神病，包括精神分裂症，表现出不同程度的记忆缺陷以及HPC-EC损伤。 然而，人们对特定记忆是如何被访问并形成有意义的记忆的知之甚少 完成指定的任务，特别是在系统级别。本提案关注的是神经动力学 在情景工作记忆任务中成功地访问和提取记忆以阐明神经回路 海马-皮质(HPC-CTX)网络的机制。我的长期目标是阐明神经动力学 并在人类患者中建立新的早期诊断测量/分析 这是由动物模型的活体记录所暗示的。我之前已经演示了两种形式的记忆 在情节记忆任务中至关重要的HPC-EC电路的访问。第一种形式被称为‘伽马 在空间工作记忆任务的运行期间观察到的相位同步 一只动物正准备在T型迷宫的交界处转弯。第二种形式称为‘扩展的 区域间涟漪猝发，由HPC内交替的猝发活动链组成的记忆重放事件- EC网络在安静唤醒或停顿期间在一个大的迷宫上运行。这两种形式的存储器访问 事实证明，这对随后的空间工作记忆行为至关重要。然而，电路机制或 这些神经活动在不同行为状态下的记忆内容尚不清楚。启示性 在存储器访问期间的这种存储器内容对于理解我们的 内存系统工作正常。我们假设(I)HPC和EC指数之间的突发活动的内容 在脱机状态期间检索更长的剧集作为区域间通信，然后(Ii) 先前增强或激活的一组神经元在伽玛相同步期间被短暂激活 激活状态以成功执行内存进程。我们将通过以下方式测试该提案中的三个假设 结合转基因小鼠技术、电路特异性光遗传学、大规模体内电生理学，以及 小鼠的空间工作记忆任务。前两个具体目标将集中在神经内容解码 两种形式的内存访问和第三个特定目标将调查这两种不同形式的内存 进程对HPC-EC网络中内存的成功访问有因果关系。

PROJECT SUMMARY Successful memory retrieval is one of the most important functions in our brain. Numerous studies have shown that hippocampal-entorhinal (HPC-EC) circuits play crucial roles in encoding and retrieval of specific episodic memories. Many human patients who suffer from Alzheimer's disease, dementia and the broad spectrum of psychosis, including schizophrenia, show various ranges of memory deficits along with the HPC-EC damage. However, little is known about how specific memories are accessed and formed into meaningful memories to accomplish given tasks, especially at the systems level. This proposal focuses on the neural dynamics for successful memory access and retrieval during episodic working memory tasks to elucidate the neural circuit mechanism in the hippocampal-cortical (HPC-CTX) network. My long-term goal is to elucidate neural dynamics during psychotic states and to establish novel early-stage diagnostic measurements / analyses in human patients that are hinted at by in vivo recordings in animal models. I have previously demonstrated two forms of memory access in the HPC-EC circuits that are crucial during episodic memory tasks. The first form is called `gamma phase synchrony', which was observed during the running period of a spatial working memory task when the animal was about to make turns at the junction point of a T-maze. The second form is called an `extended interregional ripple burst', a memory replay event that is made of alternating chains of burst activities within HPC- EC network during quiet awake or stopping periods on a large running maze. These two forms of memory access turned out to be crucial for subsequent spatial working memory behavior. However, the circuit mechanism or memory contents during these neural activities under different behavioral states are still unknown. Revealing such memory contents during the memory access period will be crucial to understanding of how exactly our memory system works. We hypothesize that (i) the content of burst activities between HPC and EC index each other to retrieve longer episodes as an inter-regional communication during the off-line state and then (ii) the previously potentiated or activated group of neurons gets briefly activated in gamma phase synchrony during the active state to successfully execute the memory process. We will test three hypotheses in this proposal by combining transgenic mouse technology, circuit specific optogenetics, large-scale in vivo electrophysiology, and a spatial working memory task in mice. The first two specific aims will focus on neural content decoding during two forms of memory access and the third specific aim will investigate whether the two distinct forms of memory process have a causal relationship on the successful accession of memory in the HPC-EC network.