Integrating and storing visuo-spatial cues in the retrosplenial cortex

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Where and how memory is encoded and stored in the brain is one of the 'holy grails' of neuroscience. Nearly 100 years ago Richard Semon hypothesised that external stimuli produce a "permanent record,... written or engraved on the irritable substance," i.e. the brain, and coined the term 'engram' for this memory trace. But only a handful of studies have so far been able to identify engrams for specific situations, mostly involving fear memory in brain areas such as the hippocampus and amygdala. In our pilot study we were the first to demonstrate that a specific pattern of neuronal activity in an area of the brain known as the retrosplenial cortex (RSC) is directly correlated with the performance of mice in a spatial memory task in a so-called radial arm maze. The RSC has emerged as a key area involved in episodic and topographical memory in humans as well as spatial memory in rodents. The dysgranular portion (Rdg) receives dense inputs from both visual areas and the hippocampal complex (parahippocampal region and subiculum), and it contains spatially-responsive cells, making it a prime candidate for integrating navigational information. Our pilot study did not tell us what those RSC engrams actually represent: they could reflect a representation of the environment, a representation of rewarded, remembered locations in the environment, or a representation of the animal's movement and navigation within the environment. This question is linked to the relative importance of hippocampal vs. visual inputs for RSC engram formation. In order to tackle it we will pharmacologically inactivate either the hippocampus or the visual cortex and carry out a number of manipulations on the maze and the reward the mice receive for remembering the correct locations. We will then compare the performance of the animals with stability of the RSC engrams.The second question we will tackle is whether visual input to the Rdg is necessary for spatial memory and if this role is time-limited such that other inputs, such as tactile or self-motion cues, can substitute for visual input. We will achieve this by either training mice in a normally lit environment and then successively remove visual cues, finally transferring them into a dark room during the memory testing phase, or by training and testing animals in darkness, thereby maximising the potential for cross-modal plasticity, and re-testing them after removal of tactile cues, leaving only self-motion (path integration) cues. The third question concerns how visual and locomotion inputs are integrated in the Rdg. We will again use fluorescent activity indicators to test whether cells activated as constituents of a spatial memory engram (<10% of all Rdg cells) also respond to visual stimuli and/or during locomotion. We will train head-fixed mice on a virtual corridor task on a linear treadmill and analyse the correlation of individual neurons with task performance. By removing visual stimuli or pharmacologically silencing visual inputs to Rdg or by creating a mismatch between visual stimuli and path length, we will establish whether Rdg neurons involved in spatial memory engrams depend primarily on visual input or path integration.Finally, we will investigate how the spatial memory network, involving the hippocampus, retrosplenial cortex and visual cortex, interacts over time, and to what extent engram formation and/or retrieval depends on them. We will pharmacologically inactivate either the hippocampus or the visual cortex and assess the effects on engram formation or expression. In addition, we will record electrical activity in retrosplenial cortex, hippocampus and visual cortex at the same time, and we will analyse the direction of information flow between the three brain areas at different stages of the acquisition and retrieval of spatial memory.