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

联想识别记忆，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，我们很快就会意识到，客厅里的家具已经被重新布置了，或者确实，当我们在一个陌生的地方看到某人时，我们可能无法认出他们。这种类型的记忆的形成包括对对象和位置的快速‘一次’编码，并且随后可以在呈现适当的提示时检索记忆关联。当我们快速而轻松地形成这些记忆时，失去这种能力，无论是在健康老化期间，还是在痴呆症中更戏剧性地丧失，都可能是毁灭性的。由于涉及的过程的复杂性，理解记忆的形成和提取是神经科学中的一大挑战。已有研究表明，记忆的形成伴随着分布的细胞群内神经元活动的增加，这产生了一种被称为“印记”的记忆的物理痕迹。这些印记存在于相互连接的大脑区域中，形成记忆回路，我们已经确定了一个记忆回路，其中海马体、内侧前额叶皮质和外侧内嗅皮层是重要的节点。在这项研究中，我们将分析联想识别记忆信息的编码和提取的电路和细胞机制，重点是外侧内嗅觉皮质的作用，以及它与海马体和内侧前额叶皮质的相互联系。我们的实验将通过研究印记细胞的特定输入和输出路径，来研究学习过程中LEC印记(记忆痕迹)是如何建立的。我们将检查如果我们阻止这些印记单元在定义的存储电路内的功能是否会扰乱记忆处理，第三，调查确定特定细胞是否被并入记忆印记电路的特定细胞过程，即，是关于单个神经元的什么使其编码特定类型的信息，存储该信息，并使该信息能够在需要时被检索。利用小鼠，我们将识别LEC中在记忆编码和提取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由来自海马体和内侧前额叶皮质的传入信息决定的，还是通过将传出信息发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动物的输入和输出路径，使用成像和显微镜来描绘神经网络的精确结构，并再次调查印记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，从而使我们能够理解记忆处理的复杂性。这样的研究至关重要，因为记忆障碍的治疗在很大程度上是一种未得到满足的临床需求。因此，我们需要了解记忆形成和提取的细胞机制，但认知障碍的药物治疗缺乏神经解剖学上的选择性。像深部脑刺激(DBS)这样的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水平上运行，有针对性的DBS可能提供另一种改善记忆损伤的方法

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