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

关联识别记忆使我们能够在遇到刺激的环境或位置的上下文中识别不同的对象。因此，我们很快认识到客厅里的家具已经重新排列，或者确实我们在不熟悉的位置看到某人时无法识别它们。形成这种类型的内存涉及对象和位置的快速“一击”编码，然后可以在呈现合适的提示后检索内存关联。尽管我们迅速且明显地形成这些记忆，但要失去这种能力，无论是在健康衰老期间还是在痴呆症中更明显的情况可能是毁灭性的。 由于所涉及的过程的复杂性，了解记忆形成和检索是神经科学的主要挑战。已经表明，记忆形成伴随着分布式细胞群体内的神经元活动的增加，这会产生称为“ engram”的内存的物理轨迹。这些Engram存在于连接的大脑区域内，形成记忆电路，我们已经确定了一个记忆电路，其中海马，内侧前额叶皮层和侧面内嗅皮层是重要的节点。在这项研究建议中，我们将分析与侧内肾上腺皮质的作用进行编码和检索的电路和细胞机制，并侧重于外侧内肾上腺皮质的作用及其与海马和内侧前额叶皮层的相互联系。我们将检查是否会在定义的内存电路中阻止这些Engram单元的功能，我们将中断存储器处理，第三，要调查确定特定单元格是否将特定单元纳入存储器Engram电路中的特定细胞过程，即，即使它使其代码的单个神经元对特定类型的信息进行编码，并启用该信息，并启用该信息，以便在需要的情况下检索信息。使用小鼠，我们将分别识别在记忆编码和检索过程中激活和重新激活和重新激活和重新激活的LEC中的细胞，即Engram细胞，并确定这些细胞在记忆中的参与是通过海马中内侧前额叶皮质的输入信息确定的，还是通过向这些地区发送到这些地区。为了回答我们的研究问题，我们将使用新开发的技术选择性地沉默的输入和输出途径，在行为动物中，使用成像和显微镜来描述神经网络的精确体系结构，并第三研究子格细胞是否具有独特的生理概况。这种技术的组合，可以在突触细胞和电路水平上进行分析，从而使我们能够理解内存处理的复杂性。这样的研究至关重要，因为对记忆障碍的治疗是很大程度上未满足的临床需求。因此，我们需要了解具有使记忆形成和检索的细胞机制，但是认知障碍的药物治疗缺乏神经解剖学选择性。诸如深脑刺激（DB）之类的干预措施针对不同的神经网络，因此通过了解内存网络在大脑范围内如何运行，有针对性的DBS可以提供​​一种减轻记忆障碍的替代方法