Reversible inhibition of medial septum interneurons abolishes initial acquisition of new place-reward associations and reveals a progressive reduction in dependence on medial septal function

Medial septum (MS) interneurons, crucial for spatial learning, can be temporarily inhibited using DREADD-based reversible techniques. This disruption impairs the initial acquisition of new place-reward associations in rodents navigating an 8-arm maze. When the correct goal arm fluctuated daily, MS inhibition caused a significant decline in learning.

However, after the goal arm remained constant across days, performance initially suffered but eventually became resilient to MS inhibition. Once the mice achieved an asymptote in performance, reintroducing a new random goal arm no longer hindered learning. This finding suggests that consistent training within the same environment induces a broader reorganization of neural systems supporting spatial behavior.

Eventually, mice develop a septum-independent task-solving strategy that enables both retrieval of established goal locations and acquisition of new ones in a stable setting. This transition might involve the adoption of non-spatial strategies, such as visual pattern recognition or the utilization of directional cues. Introducing a salient change in the visual environment, like a single room light, significantly altered the visual configurations from the arm entry points but did not cause a consistent directional shift relative to the cue.

This indicates that the light contributed to an integrated visuo-spatial representation rather than functioning as the reference frame origin. The mice ultimately transitioned from a hippocampus/MS-dependent spatial strategy to a non-hippocampus-dependent visual pattern matching solution.