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

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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lab showing that LEC lesions disrupt associative memory for objects and their locations (Wilson et al, 2013), and new unpublished data from the Wood lab in Edinburgh showing that hippocampal place cells of mice that have had neurotoxic lesions of the MEC do not follow distal cues, but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.