Lateral Entorhinal Cortex (LEC) and episodic memory: examining LEC's impact on pattern separation and neurogenesis

外侧内嗅皮层 (LEC) 和情景记忆：检查 LEC 对模式分离和神经发生的影响

基本信息

批准号：
BB/X007197/1
负责人：
James Ainge
金额：
$ 70.53万
依托单位：
University of St Andrews
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FX007197%2F1
关键词：
Lateral Entorhinal Cortex LEC episodic

项目摘要

Episodic memory is a fundamental cognitive process. Our episodic memories include details of specific objects or people, spatial locations and contextual details that allow us to differentiate between one event and another. A key feature of episodic memory is that it integrates the features of events to help guide future behaviour. For example, an episodic memory of where we parked our car this morning will allow us to accurately locate the car when we need to go home. Damage to an area of the brain called the hippocampus produces an inability to form new episodic memories. Our own recent work has shown that one of the main inputs to the hippocampus from lateral entorhinal cortex (LEC) is also necessary to integrate the features of an event pointing towards a key role for this LEC-hippocampus network in episodic memory. However, the circuit mechanisms within this network that integrate this information are unknown. One of the main targets for LEC input to hippocampus is the dentate gyrus (DG) subfield. DG is one of a small number of regions in the brain where newborn neurons are generated every day in a process called neurogenesis. These newborn neurons have been shown to be important for simple forms of memory such as fear conditioning, specifically for a process called pattern separation which allows us to discriminate between similar stimuli. However, the role of these newborn neurons and pattern separation in distinguishing between different episodic memories for very similar events is unknown. As a critical next step we will test the hypothesis that neurogenesis mediates pattern separation of similar episodic memories in the hippocampus supported by input from LEC. We will test predictions from this hypothesis through 3 specific aims:Aim 1: To determine whether newborn neurons facilitate pattern separation in tests requiring integration of the features of episodic memory.Aim 2: To determine whether LEC inputs to DG mediate the number of newborn neurons and pattern separation in tests requiring integration of EM features. Aim 3: To determine whether neurogenesis affects pattern separation in hippocampal place cells during tests requiring integration of episodic memory features.We anticipate wide reaching impact of this research. Episodic memory is affected by lifestyle factors such as diet, exercise and cognitive stimulation and decline in episodic memory is the first symptom of Alzheimer's disease. Understanding the neural mechanisms that support episodic memory will give specific targets to researchers interested in maintaining healthy cognitive function through the lifespan as well as those attempting to develop therapeutic strategies for disorders of memory. We also anticipate impact in the reduction of the number of laboratory animals needed in memory studies. In the last 5 years an estimated 43000 animals were used in studies of object recognition, the basis of all of the behavioural tasks in the current application. The proposed research will examine how enriched environments could improve memory performance in these animals. Improved performance would increase statistical power and mean that fewer animals would be needed to study these types of memory. Given the number of animals involved uptake by only 5% of the research community could mean thousands fewer animals being used in research.

情景记忆是一个基本的认知过程。我们的情景记忆包括特定物体或人的细节、空间位置和上下文细节，使我们能够区分一个事件和另一个事件。情景记忆的一个关键特征是它整合了事件的特征来帮助指导未来的行为。例如，对今天早上我们把车停在哪里的情景记忆将使我们能够在需要回家时准确地找到汽车的位置。大脑中海马体的损伤导致无法形成新的情景记忆。我们自己最近的工作表明，从外侧内嗅皮层（LEC）到海马体的主要输入之一对于整合事件的特征也是必要的，这些特征指向该 LEC-海马体网络在情景记忆中的关键作用。然而，该网络内整合这些信息的电路机制尚不清楚。 LEC 输入海马体的主要目标之一是齿状回 (DG) 子区。 DG 是大脑中每天在称为神经发生的过程中产生新生神经元的少数区域之一。这些新生神经元已被证明对于简单形式的记忆（例如恐惧调节）非常重要，特别是对于一种称为模式分离的过程非常重要，该过程使我们能够区分相似的刺激。然而，这些新生神经元和模式分离在区分非常相似的事件的不同情景记忆中的作用尚不清楚。作为下一步的关键，我们将测试这样的假设：神经发生介导海马体中相似情景记忆的模式分离，并由 LEC 的输入支持。我们将通过 3 个具体目标来测试这一假设的预测：目标 1：确定新生神经元在需要整合情景记忆特征的测试中是否促进模式分离。目标 2：确定 DG 的 LEC 输入是否介导新生神经元的数量以及需要集成 EM 功能的测试中的模式分离。目标 3：确定在需要整合情景记忆特征的测试中，神经发生是否影响海马位置细胞的模式分离。我们预计这项研究将产生广泛的影响。情景记忆受到饮食、运动和认知刺激等生活方式因素的影响，情景记忆衰退是阿尔茨海默病的首发症状。了解支持情景记忆的神经机制将为那些有兴趣在一生中维持健康认知功能的研究人员以及那些试图开发记忆障碍治疗策略的研究人员提供具体的目标。我们还预计减少记忆研究所需的实验动物数量会产生影响。在过去 5 年中，估计有 43000 只动物被用于物体识别研究，这是当前应用中所有行为任务的基础。拟议的研究将研究丰富的环境如何提高这些动物的记忆能力。性能的提高将提高统计能力，意味着研究这些类型的记忆需要更少的动物。鉴于研究界仅 5% 的动物数量可能意味着用于研究的动物数量将减少数千只。