Article

Stimulation of entorhinal cortex–dentate gyrus circuitry is antidepressive

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Abstract

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.

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Acknowledgements

We thank S. G. Birnbaum, I. M. Bowen, L. Peca, S. Stojadinovic, and Z. Zhang for assistance in experimental techniques. We thank E. D. Marsh and A. J. McCoy for guidance on use of computer code. We thank C. A. Tamminga and J. M. Zigman for sharing animals and tissues that were useful for pilot experiments. We thank G. A. Barr, I. M. Bowen, and S. E. Latchney for helpful discussions and feedback. This work was supported by grants from the National Institutes of Health to A.J.E. (DA023701, DA023555, MH107945) and D.M.C. (NS059934, MH104471), the National Aeronautics and Space Administration to A.J.E. (NNX07AP84G, NNX12AB55G, NNX15AE09G) and an Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression/Brain and Behavior Foundation to A.J.E. S.Y. was funded by a National Institute of Mental Health Basic Science Institutional NRSA Training Grant (Training Program in the Neurobiology of Mental Illness,T32-MH076690, principal investigator: C. A. Tamminga). P.D.R. was funded by National Institute on Drug Abuse NRSA Institutional Training Grant (Basic Science Training Program in the Drug Abuse Research, T32-DA007290, principal investigator: A. J. Eisch).

Author information

Author notes

    • Phillip D. Rivera

    Present address: Department of Pediatrics, Massachusetts General Hospital for Children, Charlestown, MA, USA

    • Naoki Ito

    Present address: Oriental Medicine Research Center, Kitasato University, Tokyo, Japan

    • Dane M. Chetkovich

    Present address: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA

Affiliations

  1. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Sanghee Yun
    • , Ivan Soler
    • , Douglas A. Coulter
    •  & Amelia J. Eisch
  2. Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA, USA

    • Sanghee Yun
    • , Ryan P. Reynolds
    • , Iraklis Petrof
    • , Alicia White
    • , Adam D. Gibson
    • , Maiko Suarez
    • , Matthew J. DeSalle
    • , Rebecca C. Ahrens-Nicklas
    • , Ivan Soler
    • , Douglas A. Coulter
    •  & Amelia J. Eisch
  3. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Phillip D. Rivera
    • , Amir Segev
    • , Naoki Ito
    • , Shibani Mukherjee
    • , Devon R. Richardson
    • , Saïd Kourrich
    •  & Amelia J. Eisch
  4. Department of Neurology and Clinical Neurological Sciences, Northwestern University, Chicago, IL, USA

    • Catherine E. Kang
    •  & Dane M. Chetkovich

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Contributions

S.Y. conceived the study, performed most experiments, generated the figures, and wrote the manuscript. R.P.R. assisted with experiments and generated figure schematics. I.P. and A.W. performed EEG experiments. A.S. and S.K. performed the electrophysiology experiments. P.D.R., A.D.G., M.S., M.J.D., N.I., S.M., D.R.R., and I.S. assisted with experiments. C.E.K. and D.M.C. provided Trip8b knockout mouse brains and TRIP8b-specific and TRIP8b-isoform-specific antibodies (Northwestern University). R.C.A.-N. wrote the code for the in vivo EEG experiment analysis (Children’s Hospital of Philadelphia Research Institute). D.A.C. guided the EEG experiments. A.J.E. conceived the study, assisted with experiments, guided figure preparation, and wrote the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Amelia J. Eisch.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–11 and Supplementary Table 1

  2. Reporting Summary