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位置中识别不同的物体。因此，我们很快就意识到客厅里的家具已经重新布置，或者当我们在陌生的地方看到某人时，我们实际上可能无法认出他们。这种类型的记忆的形成涉及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。虽然我们可以快速且轻松地形成这些记忆，但失去这种能力，无论是在健康衰老过程中还是在痴呆症中（更严重的是），都可能是毁灭性的。 由于所涉及过程的复杂性，理解记忆的形成和检索是神经科学的一个重大挑战。研究表明，记忆的形成伴随着分布式细胞群内神经元活动的增加，从而产生了被称为“印迹”的记忆物理痕迹。这些印迹存在于相连的大脑区域内，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内嗅皮层是重要的节点。在本研究计划中，我们将分析编码和检索联想识别记忆信息的回路和细胞机制，重点关注外侧内嗅皮层的作用及其与海马体和内侧前额叶皮层的互连性。我们的实验将通过研究印迹细胞的特定输入和输出路径来研究LEC印迹（记忆痕迹）在学习过程中是如何建立的。我们将检查如果我们在定义的记忆回路中阻断这些印迹细胞的功能，我们是否会破坏记忆处理，第三，研究确定特定细胞是否被纳入记忆印迹回路的特定细胞过程，即单个神经元如何使其编码特定类型的信息、存储该信息并在需要时能够检索该信息。使用小鼠，我们将识别 LEC 中在记忆编码和检索过程中分别被激活和重新激活的细胞，即印迹细胞，并确定这些细胞在记忆中的参与是否是由来自海马体和内侧前额叶皮层的传入信息决定的，还是通过将传出信息发送回这些区域来确定的。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行为动物的输入和输出通路，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。这种技术的组合可以在突触细胞和电路层面进行分析，使我们能够理解记忆处理的复杂性。此类研究至关重要，因为记忆障碍的治疗在很大程度上尚未得到满足。因此，我们需要了解记忆形成和检索的细胞机制，但认知障碍的药物治疗缺乏神经解剖学选择性。深部脑刺激（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大脑范围内运作，有针对性的 DBS 可能会提供另一种改善记忆障碍的方法