A septo-entorhinal GABAergic pathway that enables switching between episodic memories

New experiences are integrated with existing knowledge to update memory, which is essential for survival in a dynamic environment. Despite this updating, the brain can still access previous memories to guide appropriate behavior. How the brain organizes the retrieval of old and new memories remains unknown. Here we demonstrate a flexible memory switching mechanism in male mice, mediated by medial septum (MS) GABAergic neurons projecting to the medial entorhinal cortex (MEC). This neuronal subset was specifically recruited during retrieval after updating, and inactivation of their projections to the MEC reversed the updated behaviors-indicating a behavioral switch to previous memories-and induced a switch in CA1 population activity patterns back to the pre-update pattern. After updating, the duration of the 'online' state correlated with memory performance. Together, these findings reveal a neural switch mechanism mediated by the septo-entorhinal GABAergic pathway that organizes memory retrieval to enable updating.