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

情景记忆是一种基本的认知过程。我们的情节记忆包括特定物体或人的细节、空间位置和背景细节，这些细节使我们能够区分一个事件和另一个事件。情节记忆的一个关键特征是，它整合了事件的特征，以帮助指导未来的行为。例如，对我们今天早上把车停在哪里的情景记忆可以让我们在需要回家的时候准确地定位车的位置。大脑中一个叫做海马体的区域受到损伤，会导致无法形成新的情节记忆。我们最近的工作表明，外侧内嗅皮层(LEC)到海马区的主要输入之一也是整合事件特征所必需的，该事件指向这个LEC-海马区网络在情景记忆中的关键作用。然而，这个网络中整合这些信息的电路机制是未知的。LEC传入海马区的主要靶点之一是齿状回(DG)亚区。DG是大脑中每天都会产生新生神经元的少数几个区域之一，这个过程称为神经发生。这些新生的神经元已经被证明对简单形式的记忆非常重要，比如恐惧条件反射，特别是对于一种名为模式分离的过程，它允许我们区分相似的刺激。然而，这些新生神经元和模式分离在区分非常相似事件的不同情节记忆方面的作用尚不清楚。作为关键的下一步，我们将测试这一假设，即在LEC的输入支持下，神经发生介导了海马区类似情节记忆的模式分离。我们将通过三个具体的目标来检验这一假说的预测：目标1：确定在需要整合情景记忆特征的测试中，新生神经元是否有助于模式分离。目标2：确定LEC输入到DG是否中介了新生神经元的数量，以及在需要整合EM特征的测试中的模式分离。目的：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区细胞的模式分离。我们预期这项研究将产生广泛的影响。情景记忆受到饮食、锻炼和认知刺激等生活方式因素的影响，情景记忆下降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有兴趣在一生中保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目标。我们还预计在减少记忆研究所需的实验室动物数量方面会产生影响。在过去的5年里，估计有43000只动物被用于物体识别的研究，这是目前应用中所有行为任务的基础。这项拟议的研究将研究丰富的环境如何改善这些动物的记忆性能。改进的性能将增加统计能力，并意味着研究这些类型的记忆将需要更少的动物。考虑到涉及的动物数量，只有5%的研究界采用了这一方法，这意味着用于研究的动物可能会减少数千只。

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.