At the beginning of the project, we focused on several methodological and technological developments that are necessary to achieve the project's aims. We constructed new behavioural mazes, designed our own electrode recording device, and then established a strategy to combine high-density recordings together with optogenetic circuit manipulations from behaving rats. By using these methodologies, we investigated a scientific question proposed in each Work Package, as described in the following:
The primary aim of WP1 is to understand how an animal plans an efficient route to a destination by avoiding obstacles along the journey. For this aim, we have designed a modified version of the goal-directed navigation task in an open-field arena (Pfeiffer and Foster, 2013). The major modifications in our task design can be summarised in the following two points. First, we introduced a wall in the maze, so that the animal is required to find a goal-directed path avoiding the wall. Second, we let the animals perform this task in complete darkness, imposing the animals to rely on a cognitive map, rather than sensory perceptions. We confirmed that rats could successfully learn the position of the wall and take a smooth wall-avoiding path to the destination, supporting that rats use a cognitive map, especially under limited access to sensory signals. As a neural mechanism supporting this ability, we discovered that neurons in the hippocampus exhibit firing before starting the navigation, which corresponds to the animal’s subsequent goal-directed journey. We then asked whether this goal-directed activity in the hippocampus depends on the goal information provided by the prefrontal cortex. We inactivated neurons in the nucleus reuniens - an anatomical hub between the prefrontal cortex and the hippocampus - and found that the animals exhibited a significant impairment in taking an efficient route to the goal. Corresponding to this deficit, we also found that the goal-directed activity in the hippocampus was largely diminished during the silencing of reuniens neurons. Together, the WP1 identified a neural circuit that plays a key role in route planning for navigation.
The main achievement of WP2 is the discovery of a goal map in a subregion of the prefrontal cortex - the orbitofrontal cortex (Basu et al., Nature 2021). This finding inspired further investigation of its circuit mechanisms. For example, we are currently investigating two questions; 1) how this goal information can influence the goal-directed activity in the hippocampus, and 2) whether or not a goal decision in the orbitofrontal cortex is guided by the dopamine-striatum system.
In WP3, we investigated a neural representation of flexible route decisions. For this aim, we designed a new behavioural task in which a rat is forced to take different paths to reach the same goal locations. This task design allowed us to investigate whether the prefrontal cortex forms a goal representation irrespective of route choices, dissociating a representation of goals from that for routes or actions. By using this behavioural task, we confirmed that neurons in the orbitofrontal cortex form a goal representation that is consistent irrespective of route choices, suggesting that the OFC’s goal representation is in a rather abstract fashion.
Finally, in WP4, we had to change our initial plan because, unlike my original hypothesis, we found that the hippocampal CA1 neurons do not strongly project to the retrosplenial cortex (RSC). We thus instead focused on the connections from the medial entorhinal cortex (MEC) to the RSC and discovered that the information about environmental boundaries in the MEC is transferred to the RSC but with a different coordinate system from a world-centred allocentric to self-referenced egocentric coordinate frame (van Wijngaarden et al., eLife 2020).
Altogether, the project successfully identified the wider brain circuits necessary for navigation beyond well-studied hippocampal formation. As spatial navigation requires multistep computations, our results provided a key step toward a holistic understanding of navigation circuits in the brain.
