Navigation beyond the hippocampus: Computations supporting egocentric trajectories into an allocentric world. – NaviGPS

Wayfinding is essential to every living creature. Where I am? Where am I going to? How do I get there? Those are questions an individual faces many times a day. Indeed spatial cognition offers a framework that tackles a challenging and exciting problem: how does the brain process multimodal input to generate a representation of the world that maps external stimuli relative to each other and relative to the self? Four decades of research have extensively focused on the role of the hippocampus. However, it is clear that the hippocampus place code results from the integration of multiple parallel processes taking place in regions other than the hippocampus and occurring in interaction with the hippocampus. Here, in the aim to address how one tracks or generates self-displacement in the world to reach a goal, we will shift the center of gravity of the neural network underpinning navigation from the hippocampus to the retrosplenial cortex. Indeed this cortical area possesses anatomical connections with regions such as the parietal cortex and the hippocampus enabling it to act as an interface between self-based and world-based reference frames. We will characterize neural activity in the retrosplenial cortex via tasks that a) probe its role in fostering a flexible use of self-based or world based navigation strategies b) test the integration of vision and self-motion in self position update. To clarify the computations taking place in this network, we will extend our analysis to the posterior cingulate cortex and the cerebellum which are closely connected to the retrosplenial cortex. In addition, we will conduct simultaneous recordings in the hippocampus to compare the nature of the signals across regions. Advancing research on the retrosplenial cortex is particularly relevant and timely because of the growing number of studies that posit this area as a key element of memory impairments in Alzheimer disease and mild cognitive impairments. Thus, the ultimate goal of our project is to significantly enhance the basic understanding of navigation and identify treatment prospects in the many neurological and psychiatric diseases in which disorientation is a component. To reach this goal, we will rely on a translational cross-species approach that will permit access to information at multiple and complementary levels via experiments conducted in mice, monkeys, and humans. We carefully developed experimental paradigms that allow targeting common processes in the three species and facilitate finding functional equivalence, in light of species specific information processing. We will use experimental procedures as similar as possible across species (including human) to study common mechanisms. Relevant to this goal, several recent studies showed that virtual reality environment tools allow precisely targeting of visual information processing. Thus, for a cross-species translational objective, the use of virtual reality appears the natural choice as it permits experimental control and manipulation of the sensory visual input and can be used in rodents, monkeys and humans. We will record the neural activity (single neurons and local field potential) in the rodent and the macaque monkey as they perform identical tasks in virtual reality. In addition, we employ optogenetics to examine the causal effects of an inactivation of one element of the network on the behavior and neural activity observed in other regions. These experiments will be complemented by magneto-encephalography (MEG) recordings in the human in identical testing conditions to mice and monkeys. This innovative cross-species approach and targeting of brain areas outside the hippocampus will likely generate a rich set of data that will yield knowledge on the genesis of the spatial code and the computation of self-based movements directed towards an allocentric goal.