Network analysis of entorhinal-hippocampal circuits for spatial cognition and memory

空间认知和记忆的内嗅-海马回路网络分析

• 批准号: 1958769
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1958769
• 关键词: Network; analysis; entorhinal; hippocampal; circuits

The ability to use information from the outside world, such as visual landmarks and local cues, to locate ourselves in space and to form memories for what happened where, is a fundamental cognitive function. It is known that the entorhinal cortex and hippocampus are required for these functions, but the precise entorhinal-hippocampal circuitry remains unknown. The proposed project will combine recording of neural activity in behaving mice with state-of-the-art molecular manipulations to establish the neural circuitry by which external information in the environment gains access to one of the primary representations of location in the mammalian brain - the hippocampal place cells.A basic property of hippocampal place cells is that the location of their firing fields is anchored to external cues, including both distal visual landmarks, and local cues (such as objects within the environment). It has recently been found that cells in the medial entorhinal cortex (MEC), many of which have spatial firing properties, are anchored to distal visual landmarks, whereas cells in the lateral entorhinal cortex (LEC) tend to fire in relation to local cues (Neunuebel et al, 2013). As the entorhinal cortex provides the main cortical input to the hippocampus, this leads to the hypothesis that distal visual landmark information and local cue information access the hippocampus from the MEC and LEC respectively. This is supported by published behavioural data from the Ainge lab showing that LEC lesions disrupt associative memory for objects and their locations (Wilson et al, 2013), and new unpublished data from the Wood lab in Edinburgh showing that hippocampal place cells of mice that have had neurotoxic lesions of the MEC do not follow distal cues, but instead are more likely to follow local cues. The aim of the project is to determine the precise inputs from MEC and LEC to the hippocampus by which visual landmarks and local cues influence both place cells and spatial behaviour. This will be achieved by making use of lines of mice that have been genetically engineered to express cre in specific populations of entorhinal cells, combined with targeted injections of cre-dependent viruses to express either Tetanus light chain toxin (TeLC) which blocks neurotransmitter release, or light activated channels, or DREADDS. These techniques will allow us to block the inputs from a specific cell population in MEC or LEC over long (TeLC), medium (DREADDS) or short (optogenetics) time frames. Preliminary experiments in the host labs are currently using this approach to inactivate stellate cells in layer 2 of the MEC (Wood lab) and LEC (Ainge lab). The proposed project will assess the effects of inhibiting these cell populations on a) hippocampal place field activity, and specifically their control by distal visual landmarks and local cues and b) spatial memory tasks in which distal or local cues must be associated with reinforced locations.

使用来自外部世界的信息（如视觉地标和本地线索）来确定自己在空间中的位置并对发生在哪里的事情形成记忆的能力是一种基本的认知功能。已知这些功能需要内嗅皮层和海马，但精确的内嗅-海马回路仍然未知。该项目将联合收割机记录行为小鼠的神经活动与最先进的分子操作相结合，以建立神经回路，通过该神经回路，环境中的外部信息可以访问哺乳动物大脑中位置的主要表征之一-海马位置细胞。海马位置细胞的基本特性是其发射场的位置锚定在外部线索上，包括远端视觉地标和局部线索（例如环境内的物体）。最近发现，内侧内嗅皮层（MEC）中的细胞（其中许多具有空间放电特性）被锚定到远端视觉地标，而外侧内嗅皮层（LEC）中的细胞倾向于与局部线索相关地放电（Neunuebel等人，2013）。由于内嗅皮层向海马提供主要的皮层输入，这导致了远端视觉地标信息和局部线索信息分别从MEC和LEC访问海马的假设。这得到了来自Ainge实验室的已发表行为数据的支持，这些数据显示LEC病变破坏了对物体及其位置的联想记忆（Wilson et al，2013），以及来自爱丁堡Wood实验室的新的未发表数据，这些数据显示具有MEC神经毒性病变的小鼠的海马位置细胞不遵循远端线索，而是更有可能遵循局部线索。该项目的目的是确定从MEC和LEC到海马的精确输入，视觉地标和局部线索通过这些输入影响位置细胞和空间行为。这将通过使用已经基因工程改造以在特定的内嗅细胞群体中表达cre的小鼠品系，结合cre依赖性病毒的靶向注射以表达阻断神经递质释放的破伤风轻链毒素（泰尔克）或光激活通道或DREADDS来实现。这些技术将使我们能够在长（泰尔克），中（DREADDS）或短（光遗传学）时间范围内阻断MEC或LEC中特定细胞群的输入。宿主实验室中的初步实验目前正在使用这种方法来使MEC（Wood实验室）和LEC（Ainge实验室）的第2层中的细胞星形化。拟议的项目将评估抑制这些细胞群对a）海马位置场活动的影响，特别是通过远端视觉地标和局部线索对它们的控制，以及B）空间记忆任务，其中远端或局部线索必须与强化位置相关。