MEDIAN RAPHE PROJECTION INTO THE DORSAL DENTATE GYRUS MODULATES ANXIETY BEHAVIOR AND COPING WITH LEARNING UNDER STRESS

The Median Raphe (MR) provides a major, mainly serotonergic, input to the hippocampus, particularly influencing the dentate gyrus (DG), but its specific role remains unclear. Here, focusing on the dorsal DG, we investigated its contribution to anxiety-like behavior and learning under stress, using a pathway-specific chemogenetic approach in male Sprague-Dawley rats. Retrograde Cre-expressing AAV was injected into the dorsal DG, and Cre-dependent excitatory (hM3Dq) or inhibitory (hM4Di) DREADDs were expressed in MR neurons. Behavioral assessments included the Open Field (OF), Elevated Plus Maze (EPM), and an extended Two-Way Shuttle Avoidance task (eTWSA).
MR-dorsal DG pathway activation had no significant impact, but its inhibition decreased anxiety-like behavior in the EPM and improved eTWSA performance, particularly in behaviorally "diverged" animals. Knocked down in the dorsal DG EphA7, a molecule involved in basket cell synapse stabilization on DG granule cells, prevented the anxiolytic effects and behavioral divergence induced by MR–dorsal DG inhibition, but did not prevent improved eTWSA performance.
These findings suggest a dissociation between mechanisms of emotional regulation and stress-related learning mechanisms within the dorsal DG, with the MR input to DG basket interneurons modulating anxiety but not learning flexibility. The results highlight a subregion- and pathway-specific role of the MR-hippocampal input in modulating behavior.