Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive

Sanghee Yun, Ryan P. Reynolds, Iraklis Petrof, Alicia White, Phillip D. Rivera, Amir Segev, Adam D. Gibson, Maiko Suarez, Matthew J. Desalle, Naoki Ito, Shibani Mukherjee, Devon R. Richardson, Catherine E. Kang, Rebecca C. Ahrens-Nicklas, Ivan Soler, Dane M. Chetkovich, Saïd Kourrich, Douglas A. Coulter, Amelia J. Eisch

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


Major depressive disorder (MDD) is considered a 'circuitopathy', and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation - previously well-known for its ability to influence learning and memory - for MDD treatment.

Original languageEnglish
Pages (from-to)658-666
Number of pages9
JournalNature Medicine
Issue number5
StatePublished - 1 May 2018
Externally publishedYes


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