Inhibition of Hippocampal Activity in a Complex Rapid-Learning Spatial Memory Paradigm

Abstract

The hippocampus is classically implicated in allocentric spatial memory, but its contribution to complex navigation in a distal cue-lacking environment, particularly under single-session learning conditions, remains poorly characterized. Here, we investigated the effects of optogenetic inhibition of hippocampal region CA1 on navigational behavior in a novel, high-complexity maze paradigm lacking external distal cues. Water-deprived mice were allowed to freely enter and exit our maze task over the course of a single learning session, where a water reward port was located multiple nodes away from the home cage. The route to obtain the reward was densely populated with sequential decision points, and the nature of the task emphasized the proximal orientation of self in space, rather than orientation via external landmarks. When mice entered into the maze, CA1 was perturbed optogenetically through the expression of Channelrhodopsin-2 (ChR2) in GABAergic hippocampal neurons. We assessed cumulative reward-zone entries, reward visit rate, route directness, route duration, average speed, and spatial node occupancy in order to determine whether hippocampal perturbation altered reward retrieval, route efficiency, or the broader organization of navigation. Across conditions, cumulative reward-zone entries increased over time, suggesting that mice were able to learn the maze within a single session. Optogenetic inhibition did not produce a gross reduction in total reward retrieval. However, the temporal pattern of reward-zone entry differed significantly across conditions, suggesting that perturbation altered how reward-seeking behavior evolved over the course of learning rather than simply increasing or decreasing performance overall. Additional analyses of route directness, direction-specific trajectories, and occupancy patterns further suggested that hippocampal inhibition influenced the structure of navigation more than endpoint reward acquisition itself. These findings are preliminary, but we hope they provide insights on how regional inhibition may alter the dynamics of navigation, rather than task success alone.