Behavioral pattern separation: orchestration by lateral entorhinal cortex-hippocampal circuitry

项目总结/摘要 对高度相似事件的区分被称为行为模式分离。这种情景记忆 压力改变了这一过程，并在人类和啮齿动物模型中减少了一系列大脑疾病， 包括创伤后应激障碍行为模式分离也容易受到“负荷”的影响， 更难区分非常相似（高负荷）与不同（低负荷）的情节。定义 存储器阶段和负载敏感性中的底层电路是未来的关键一步， 可以通过基于电路的操作来处理模式分离。 这个应用程序的重点是在行为模式分离的外侧内嗅皮层（LEC）的作用。 LEC的解剖学连接表明它是这个压力敏感过程的中心。LEC是 受多模态、情绪和压力相关的大脑区域支配。LEC支配下游 海马区对行为模式分离至关重要，包括齿状回（DG）。事实上， IIa层星状扇细胞（LECIIa扇细胞）将谷氨酸直接发送到两个关键的DG细胞，DG颗粒细胞和 成人产生的神经元，这两个关键的“高负荷”模式分离，是非常敏感的， 应力出色的人类成像和啮齿动物病变和神经记录研究也表明LEC具有 行为模式分离中的作用。然而，LEC在协调行为模式中的因果作用 分离及其记忆阶段未经测试。缺乏关于LEC作用的数据是惊人的，因为LEC是 易受压力衰老和疾病的影响LEC与年龄和性别中的不良模式分离之间的联系 疾病-包括压力引起的认知障碍，如创伤后应激障碍-仍然是相关的。的直接证据 LEC在行为模式分离中的作用对于清楚地理解皮质-海马 电路及其在非病理和病理状态下的功能。 在这个修改后的R 01应用程序中，我们提出了三个目标，以提供对LECIIa如何 扇细胞参与行为模式分离，在什么记忆阶段和记忆负荷期间， 如何操纵LEC-DG回路活动以克服压力引起的模式中断 分居目标1.测试行为模式分离的编码和巩固是否依赖于 DG中的LECIIa风扇电池终端。目标二。测试行为模式分离性能/检索是否 由LEC风扇单元-DG电路的活动调制。目标3.测试反复的压力是否会破坏行为 模式分离性能/检索的方式，可以逆转的LEC-DG电路刺激。 来自这些目标的数据将填补现有神经电路模型的主要知识空白， 支持行为模式分离。他们将提供必要的行为和机制的见解， 了解不良的模式分离，并为治疗压力引起的认知功能障碍提供燃料。

PROJECT SUMMARY/ABSTRACT The discrimination of highly similar episodes is termed behavioral pattern separation. This episodic memory process is altered by stress and decreased in humans with and rodent models for a range of brain disorders, including post-traumatic stress disorder (PTSD). Behavioral pattern separation is also susceptible to “load”; it is harder to discriminate episodes that are very similar (high load) vs. different (low load). Defining the underlying circuitry in memory stages and load-sensitivity is a key step to a future where poor behavioral pattern separation might be treated via circuit-based manipulations. The focus of this application is the role of the lateral entorhinal cortex (LEC) in behavioral pattern separation. The anatomical connections of the LEC suggest it is central to this stress-sensitive process. The LEC is innervated by polymodal-, emotion, and stress-linked brain regions. The LEC innervates downstream hippocampal regions critical for behavioral pattern separation, including the dentate gyrus (DG). In fact LEC layer IIa stellate fan cells (LECIIa fan cells) send glutamate directly to two key DG cells, DG granule cells and adult-generated neurons, which are both critical for “high load” pattern separation and are very sensitive to stress. Excellent human imaging and rodent lesion and neural recording studies also suggest the LEC has a role in behavioral pattern separation. However, the LEC’s causal role in orchestrating behavioral pattern separation and its memory stages is untested. The lack of data on LEC’s role is striking given that the LEC is vulnerable to stress, aging, and disease. A link between LEC and the poor pattern separation seen in age and disease — including in stress-induced cognitive disorders like PTSD — remains correlative. Direct evidence of the LEC’s role in behavioral pattern separation is paramount to clear understanding of cortical-hippocampal circuitry and its function in nonpathological and pathological states. In this revised R01 application, we propose three aims to provide fundamental understanding of how LECIIa fan cells are involved in behavioral pattern separation, during what memory stage and which memory load, and how the LEC-DG circuit activity could be manipulated to overcome stress-induced disruption of pattern separation. Aim 1. Test if the encoding and consolidation of behavioral pattern separation rely on the activity of LECIIa fan cell terminals in the DG. Aim 2. Test if behavioral pattern separation performance/retrieval is modulated by the activity of the LEC fan cell-DG circuit. Aim 3. Test if repeated stress disrupts behavioral pattern separation performance/retrieval in a way that can be reversed by LEC-DG circuit stimulation. The data from these Aims will fill major knowledge gaps in the existing models of the neural circuitry that supports behavioral pattern separation. They will provide essential behavioral and mechanistic insight to understand poor pattern separation and to fuel therapeutics to combat stress-induced cognitive dysfunction.