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

利用来自外部世界的信息，如视觉地标和当地线索，来定位自己在空间中的位置，并形成记忆，这是一项基本的认知功能。众所周知，这些功能需要内嗅皮层和海马体，但精确的内嗅-海马体回路尚不清楚。该计划将结合对行为小鼠的神经活动的记录和最先进的分子操作来建立神经回路，通过这种神经回路，环境中的外部信息可以进入哺乳动物大脑中位置的主要表征之一——海马体位置细胞。海马体位置细胞的一个基本特性是，它们的放电场的位置与外部线索有关，包括远端视觉标志和局部线索（如环境中的物体）。最近发现，内侧内嗅皮层（MEC）中的许多细胞具有空间放电特性，它们锚定在远端视觉标志上，而外侧内嗅皮层（LEC）中的细胞则倾向于根据局部线索放电（Neunuebel et al, 2013）。由于内嗅皮层向海马体提供主要的皮质输入，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进入海马体的假设。这一点得到了来自inge实验室已发表的行为数据的支持，该数据显示LEC病变破坏了对物体及其位置的联想记忆（Wilson等人，2013年），而来自爱丁堡Wood实验室未发表的新数据显示，MEC神经毒性病变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到海马体的精确输入，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。这将通过使用经过基因工程改造的小鼠系来实现，这些小鼠系在特定的内鼻细胞群中表达cre，并结合靶向注射cre依赖性病毒来表达阻断神经递质释放的破伤风轻链毒素（TeLC）或光激活通道（DREADDS）。这些技术将使我们能够在长（TeLC）、中（DREADDS）或短（光遗传学）时间框架内阻断MEC或LEC中特定细胞群的输入。宿主实验室的初步实验目前正在使用这种方法灭活MEC （Wood实验室）和LEC（安吉实验室）第2层的星状细胞。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，特别是对远端视觉地标和局部线索的控制，以及b)远端或局部线索必须与强化位置相关的空间记忆任务。

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.