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

行为模式分离：外侧内嗅皮层-海马回路的编排

基本信息

批准号：
10668849
负责人：
AMELIA J EISCH
金额：
$ 69.49万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668849
关键词：
Adult Age Aging Anatomy Behavioral Behavioral trial Biological Brain Diseases Brain region Cells Chronic Chronic stress Cognition Disorders Data Discrimination Disease Emotions Episodic memory Event Female Fiber Fiber Optics Fright Future Genetic Glutamates Hippocampus Human Impaired cognition Impairment Knowledge Lateral Learning Lesion Link Literature Location Mediating Memory Memory impairment Modeling Mus Neurons Neurosciences Opsin Pathologic Pattern Performance Play Post-Traumatic Stress Disorders Predisposition Process Resolution Retrieval Rodent Rodent Model Role Shapes Stimulus Stress System Testing Therapeutic Uncertainty Viral Virus behavior test brain circuitry clinical practice combat dentate gyrus entorhinal cortex granule cell human imaging improved indexing insight male member memory process neural neural circuit neural model optical fiber receptor sex social defeat stress related disorder touchscreen

项目摘要

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.

项目概要/摘要高度相似的事件的区分被称为行为模式分离。在患有一系列脑部疾病的人类和啮齿动物模型中，这一过程会因压力而改变，并会减少，包括创伤后应激障碍（PTSD），行为模式分离也容易受到“负荷”的影响；很难区分非常相似（高负载）和不同（低负载）的情节。内存阶段和负载敏感度中的底层电路是迈向不良行为的未来的关键一步模式分离可以通过基于电路的操作来处理。该应用的重点是外侧内嗅皮层 (LEC) 在行为模式分离中的作用。 LEC 的解剖连接表明它是这一压力敏感过程的核心。 LEC 受多模式、情绪和压力相关的大脑区域支配。海马区域对于行为模式分离至关重要，实际上包括齿状回（DG）。 IIa 层星状扇细胞（LECIIa 扇细胞）将谷氨酸直接发送至两个关键的 DG 细胞：DG 颗粒细胞和成人生成的神经元，对于“高负载”模式分离至关重要，并且对出色的人类成像和啮齿动物病变以及神经记录研究也表明 LEC 具有压力。然而，LEC 在协调行为模式中的因果作用考虑到 LEC 的分离及其存储阶段尚未经过测试，因此有关 LEC 作用的数据的缺乏是惊人的。容易受到压力、衰老和疾病的影响 LEC 与年龄和年龄方面的不良模式分离之间存在联系。疾病——包括应激诱发的认知障碍，如创伤后应激障碍（PTSD）——仍然是相关的直接证据。 LEC 在行为模式分离中的作用对于清楚地理解皮质-海马至关重要电路及其在非病理和病理状态下的功能。在这个修订后的 R01 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、记忆阶段和记忆负载，以及如何操纵 LEC-DG 电路活动来克服应力引起的模式破坏目标 1. 测试行为模式分离的编码和巩固是否依赖于分离的活动。 DG 中的 LECIIa 风扇单元终端目标 2. 测试行为模式分离性能/检索是否有效。目标 3. 测试重复的压力是否会扰乱行为。模式分离性能/检索的方式可以通过 LEC-DG 电路刺激来逆转。这些目标的数据将填补现有神经回路模型中的主要知识空白支持行为模式分离。它们将为了解不良的模式分离并促进治疗以对抗压力引起的认知功能障碍。