Circuit and cellular analysis of the lateral entorhinal cortex in associative recognition memory

联想识别记忆中外侧内嗅皮层的电路和细胞分析

• 批准号: BB/Y006402/1
• 负责人: Clea Warburton
• 金额: $ 93.25万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY006402%2F1
• 关键词: Circuit; cellular; analysis; lateral; entorhinal

Associative recognition memory, enables us to recognise distinct objects in the context of the environment or location in which the stimulus was encountered. Thus we quickly recognise that the furniture in our living room has been rearranged, or indeed we can fail to recognise someone when we see them in an unfamiliar location. The formation this type of memory involves rapid 'one-shot' encoding of both the object and location, and the memory association can then be subsequent retrieved, on presentation of a suitable cue. While we form these memories rapidly and with apparent ease, to lose this ability, either during health aging or more dramatically in dementia can be devastating. Due to the complexity of the processes involved, understanding memory formation and retrieval is a major challenge in neuroscience. It has been shown that memory formation is accompanied by increased neuronal activity within distributed cell populations, which create a physical trace of the memory termed an 'engram'. These engrams exist within connected brain regions, forming memory circuits, and we have identified a memory circuit in which the hippocampus, medial prefrontal cortex and lateral entorhinal cortex are important nodes. In this research proposal we will analyse the circuit and cellular mechanisms by which associative recognition memory information is encoded and retrieved, with a focus on the role of the lateral entorhinal cortex, and its interconnectivity with the hippocampus and medial prefrontal cortex.Our experiments will examine how LEC engram (memory trace) is set up during learning, by investigating the specific input and output pathways of the engram cells. We will examine whether if we block the function of these engram cells within the defined memory circuit we will disrupt memory processing, and thirdly to investigate the specific cellular processes that determine whether a specific cells becomes incorporated into the memory engram circuit, i.e. what is it about an individual neuron that makes it code a particular type of information, store that information, and enable the information to be retrieved when it is required. Using mice we will identify the cells in LEC that are activated and reactivated during memory encoding and retrieval respectively, i.e. the engram cells and establish whether the involvement of these cells in memory is determined by incoming information from the hippocampus, and medial prefrontal cortex, or by sending outgoing information back to these regions regions. To answer our research questions we will use newly developed techniques to selectively silence input and output pathways, in behaving animals, use imaging and microscopy to delineate the precise architecture of the neural networks and thirdly investigate whether the engram cells have a unique physiological profile. This combination of techniques, which enables analysis at a synaptic cellular and circuit level enable us to understand the complexity of memory processing. Such research is vital as treatments for memory disorders are a largely unmet clinical need. We therefore need understand the cellular mechanisms with enable memories to be formed and retrieved, however drug treatments for cognitive impairments lack neuroanatomical selectivity. Interventions such as deep brain stimulation (DBS) target distinct neural networks, and thus by understanding how memory network operate on a brain wide level, targeted DBS, may offer an alternative way to ameliorate memory impairments

联想识别记忆，使我们能够在遇到刺激的环境或地点的背景下识别不同的物体。因此，我们很快就能认出客厅里的家具被重新摆放过，或者当我们在不熟悉的地方看到某人时，我们可能认不出他来。这种类型的记忆的形成包括对物体和位置的快速“一次性”编码，然后在出现合适的提示时，可以随后检索记忆关联。虽然我们形成这些记忆的速度很快，而且看起来很容易，但失去这种能力，无论是在健康老化期间，还是在更严重的痴呆症中，都可能是毁灭性的。由于所涉及的过程的复杂性，理解记忆的形成和检索是神经科学的一个主要挑战。研究表明，记忆的形成伴随着分布式细胞群中神经元活动的增加，这就产生了记忆的物理痕迹，称为“印痕”。这些印记存在于相连的大脑区域中，形成记忆回路，我们已经确定了一个记忆回路，其中海马体、内侧前额叶皮层和外侧鼻内皮层是重要的节点。在本研究计划中，我们将分析联想识别记忆信息编码和检索的电路和细胞机制，重点关注外侧内嗅皮层的作用，以及它与海马和内侧前额叶皮层的相互联系。我们的实验将通过研究印迹细胞的特定输入和输出途径来研究学习过程中LEC印迹（记忆痕迹）是如何建立的。我们将研究如果我们阻断这些记忆印迹细胞在定义的记忆回路中的功能，我们是否会破坏记忆处理，第三，研究特定的细胞过程，决定特定细胞是否被纳入记忆印迹回路，即，是什么让单个神经元编码特定类型的信息，存储该信息，并使信息能够在需要时被检索。在小鼠实验中，我们将识别LEC中分别在记忆编码和检索过程中被激活和再激活的细胞，即印迹细胞，并确定这些细胞参与记忆是由海马和内侧前额叶皮层的输入信息决定的，还是由向这些区域发送输出信息决定的。为了回答我们的研究问题，我们将使用新开发的技术来选择性地沉默输入和输出通路，在行为动物中，使用成像和显微镜来描绘神经网络的精确结构，第三，研究印迹细胞是否具有独特的生理特征。这种技术的结合，使我们能够在突触细胞和电路水平上进行分析，使我们能够理解记忆处理的复杂性。这样的研究是至关重要的，因为治疗记忆障碍在很大程度上是一个未满足的临床需求。因此，我们需要了解记忆形成和恢复的细胞机制，然而，认知障碍的药物治疗缺乏神经解剖学上的选择性。脑深部电刺激（DBS）等干预措施针对不同的神经网络，因此，通过了解记忆网络如何在全脑范围内运作，靶向DBS可能为改善记忆障碍提供另一种方法