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<p>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.</p>

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Median Raphe projection into the dorsal dentate gyrus modulates anxiety behavior and coping with learning under stress

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月2日

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  • J. Quan,
  • M. Kriebel,
  • R. Anunu,
  • M. Snippe-Strauss,
  • H Volkmer,
  • Gal Richter-Levin

摘要

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.