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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  • 22 June 2018

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  1. 1.

    Kupfer, D. J., Frank, E. & Phillips, M. L. Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet 379, 1045–1055 (2012).

  2. 2.

    Trivedi, M. H. Modeling predictors, moderators and mediators of treatment outcome and resistance in depression. Biol. Psychiatry 74, 2–4 (2013).

  3. 3.

    Rosa, M. A. & Lisanby, S. H. Somatic treatments for mood disorders. Neuropsychopharmacology 37, 102–116 (2012).

  4. 4.

    Kronmüller, K.-T. et al. Hippocampal volume and 2-year outcome in depression. Br. J. Psychiatry 192, 472–473 (2008).

  5. 5.

    Yun, S., Reynolds, R. P., Masiulis, I. & Eisch, A. J. Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis. Nat. Med. 22, 1239–1247 (2016).

  6. 6.

    Miller, B. R. & Hen, R. The current state of the neurogenic theory of depression and anxiety. Curr. Opin. Neurobiol. 30, 51–58 (2015).

  7. 7.

    Stone, S. S. D. et al. Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory. J. Neurosci. 31, 13469–13484 (2011).

  8. 8.

    Suthana, N. et al. Memory enhancement and deep-brain stimulation of the entorhinal area. N. Engl. J. Med. 366, 502–510 (2012).

  9. 9.

    Gerritsen, L. et al. Depression, hypothalamic pituitary adrenal axis, and hippocampal and entorhinal cortex volumes—the SMART Medea study. Biol. Psychiatry 70, 373–380 (2011).

  10. 10.

    Biel, M., Wahl-Schott, C., Michalakis, S. & Zong, X. Hyperpolarization-activated cation channels: from genes to function. Physiol. Rev. 89, 847–885 (2009).

  11. 11.

    Lewis, A. S. et al. Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. J. Neurosci. 31, 7424–7440 (2011).

  12. 12.

    Santoro, B. et al. TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron 62, 802–813 (2009).

  13. 13.

    Lewis, A. S. et al. Alternatively spliced isoforms of TRIP8b differentially control h channel trafficking and function. J. Neurosci. 29, 6250–6265 (2009).

  14. 14.

    Kim, C. S., Chang, P. Y. & Johnston, D. Enhancement of dorsal hippocampal activity by knockdown of HCN1 channels leads to anxiolytic- and antidepressant-like behaviors. Neuron 75, 503–516 (2012).

  15. 15.

    Urban, D. J. & Roth, B. L. DREADDs (designer receptors exclusively activated by designer drugs): chemogenetic tools with therapeutic utility. Annu. Rev. Pharmacol. Toxicol. 55, 399–417 (2015).

  16. 16.

    Fanselow, M. S. & Dong, H.-W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7–19 (2010).

  17. 17.

    Sahay, A. & Hen, R. Adult hippocampal neurogenesis in depression. Nat. Neurosci. 10, 1110–1115 (2007).

  18. 18.

    Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).

  19. 19.

    Kourrich, S., Glasgow, S. D., Caruana, D. A. & Chapman, C. A. Postsynaptic signals mediating induction of long-term synaptic depression in the entorhinal cortex. Neural Plast. 2008, 840374 (2008).

  20. 20.

    Latchney, S. E., Jiang, Y., Petrik, D. P., Eisch, A. J. & Hsieh, J. Inducible knockout of Mef2a, -c, and -d from nestin-expressing stem/progenitor cells and their progeny unexpectedly uncouples neurogenesis and dendritogenesis in vivo. FASEB J. 29, 5059–5071 (2015).

  21. 21.

    Guo, W. et al. Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning. Nat. Med. 17, 559–565 (2011).

  22. 22.

    Petrik, D., Lagace, D. C. & Eisch, A. J. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology 62, 21–34 (2012).

  23. 23.

    Hill, A. S., Sahay, A. & Hen, R. Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology 40, 2368–2378 (2015).

  24. 24.

    Snyder, J. S., Soumier, A., Brewer, M., Pickel, J. & Cameron, H. A. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476, 458–461 (2011).

  25. 25.

    Walker, A. K. et al. The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis. Mol. Psychiatry 20, 500–508 (2015).

  26. 26.

    David, D. J. et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62, 479–493 (2009).

  27. 27.

    Stone, E. A. & Lin, Y. An anti-immobility effect of exogenous corticosterone in mice. Eur. J. Pharmacol. 580, 135–142 (2008).

  28. 28.

    Gourley, S. L. et al. Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression. Biol. Psychiatry 63, 353–359 (2008).

  29. 29.

    Murray, F., Smith, D. W. & Hutson, P. H. Chronic low dose corticosterone exposure decreased hippocampal cell proliferation, volume and induced anxiety and depression like behaviours in mice. Eur. J. Pharmacol. 583, 115–127 (2008).

  30. 30.

    White, W. F., Nadler, J. V., Hamberger, A., Cotman, C. W. & Cummins, J. T. Glutamate as transmitter of hippocampal perforant path. Nature 270, 356–357 (1977).

  31. 31.

    Melzer, S. et al. Long-range-projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex. Science 335, 1506–1510 (2012).

  32. 32.

    Casanova, E. et al. A CamKIIα iCre BAC allows brain-specific gene inactivation. Genesis 31, 37–42 (2001).

  33. 33.

    Krashes, M. J. et al. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507, 238–242 (2014).

  34. 34.

    Vismer, M. S., Forcelli, P. A., Skopin, M. D., Gale, K. & Koubeissi, M. Z. The piriform, perirhinal, and entorhinal cortex in seizure generation. Front. Neural Circuits 9, 27 (2015).

  35. 35.

    Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

  36. 36.

    Lagace, D. C. et al. Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance. Proc. Natl. Acad. Sci. USA 107, 4436–4441 (2010).

  37. 37.

    Russo, S. J., Murrough, J. W., Han, M.-H., Charney, D. S. & Nestler, E. J. Neurobiology of resilience. Nat. Neurosci. 15, 1475–1484 (2012).

  38. 38.

    Eichenbaum, H. A cortical–hippocampal system for declarative memory. Nat. Rev. Neurosci. 1, 41–50 (2000).

  39. 39.

    Tulving, E. Episodic memory: from mind to brain. Annu. Rev. Psychol. 53, 1–25 (2002).

  40. 40.

    Jacobs, J. et al. Direct electrical stimulation of the human entorhinal region and hippocampus impairs memory. Neuron 92, 983–990 (2016).

  41. 41.

    Surget, A. et al. Antidepressants recruit new neurons to improve stress response regulation. Mol. Psychiatry 16, 1177–1188 (2011).

  42. 42.

    Ma, D. K. et al. Neuronal activity–induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323, 1074–1077 (2009).

  43. 43.

    Boldrini, M. et al. Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biol. Psychiatry 72, 562–571 (2012).

  44. 44.

    Kheirbek, M. A. et al. Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron 77, 955–968 (2013).

  45. 45.

    Vivar, C. et al. Monosynaptic inputs to new neurons in the dentate gyrus. Nat. Commun. 3, 1107 (2012).

  46. 46.

    Sahay, A. et. al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466–470 (2011).

  47. 47.

    Airan, R. D. et al. High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317, 819–823 (2007).

  48. 48.

    Crupi, R., Marino, A. & Cuzzocrea, S. New therapeutic strategy for mood disorders. Curr. Med. Chem. 18, 4284–4298 (2011).

  49. 49.

    Malberg, J. E. & Schechter, L. E. Increasing hippocampal neurogenesis: a novel mechanism for antidepressant drugs. Curr. Pharm. Des. 11, 145–155 (2005).

  50. 50.

    Lozano, A. M. & Lipsman, N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 77, 406–424 (2013).

  51. 51.

    Yamaguchi, M., Saito, H., Suzuki, M. & Mori, K. Visualization of neurogenesis in the central nervous system using nestin promoter-GFP transgenic mice. Neuroreport 11, 1991–1996 (2000).

  52. 52.

    Hommel, J. D., Sears, R. M., Georgescu, D., Simmons, D. L. & DiLeone, R. J. Local gene knockdown in the brain using viral-mediated RNA interference. Nat. Med. 9, 1539–1544 (2003).

  53. 53.

    Zolotukhin, S. et al. Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Ther. 6, 973–985 (1999).

  54. 54.

    Mandyam, C. D., Harburg, G. C. & Eisch, A. J. Determination of key aspects of precursor cell proliferation, cell cycle length and kinetics in the adult mouse subgranular zone. Neuroscience 146, 108–122 (2007).

  55. 55.

    Alonso, A. & Klink, R. Differential electroresponsiveness of stellate and pyramidal-like cells of medial entorhinal cortex layer II. J. Neurophysiol. 70, 128–143 (1993).

  56. 56.

    Corbett, B. F. et al. Sodium channel cleavage is associated with aberrant neuronal activity and cognitive deficits in a mouse model of Alzheimer’s disease. J. Neurosci. 33, 7020–7026 (2013).

  57. 57.

    Dengler, C. G., Yue, C., Takano, H. & Coulter, D. A. Massively augmented hippocampal dentate granule cell activation accompanies epilepsy development. Sci. Rep. 7, 42090 (2017).

  58. 58.

    Clarkson, R. et al. Characterization of image quality and image-guidance performance of a preclinical microirradiator. Med. Phys. 38, 845–856 (2011).

  59. 59.

    Spencer, S. et al. Circadian genes Period 1 and Period 2 in the nucleus accumbens regulate anxiety-related behavior. Eur. J. Neurosci. 37, 242–250 (2013).

  60. 60.

    Eaton, S. L. et al. Total protein analysis as a reliable loading control for quantitative fluorescent Western blotting. PLoS One 8, e72457 (2013).

  61. 61.

    Ables, J. L. et al. Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells. J. Neurosci. 30, 10484–10492 (2010).

  62. 62.

    DeCarolis, N. A. et al. In vivo contribution of nestin- and GLAST-lineage cells to adult hippocampal neurogenesis. Hippocampus 23, 708–719 (2013).

  63. 63.

    Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671–675 (2012).

  64. 64.

    Petrik, D. et al. Functional and mechanistic exploration of an adult neurogenesis-promoting small molecule. FASEB J. 26, 3148–3162 (2012).

  65. 65.

    Krishnan, V. & Nestler, E. J. The molecular neurobiology of depression. Nature 455, 894–902 (2008).

  66. 66.

    Nakasato, A. et al. Swim stress exaggerates the hyperactive mesocortical dopamine system in a rodent model of autism. Brain Res. 1193, 128–135 (2008).

  67. 67.

    Mulder, G. B. & Pritchett, K. The elevated plus-maze. Contemp. Top. Lab. Anim. Sci. 43, 39–40 (2004).

  68. 68.

    Surget, A. et al. Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol. Psychiatry 64, 293–301 (2008).

  69. 69.

    Johnson, J. Not seeing is not believing: improving the visibility of your fluorescence images. Mol. Biol. Cell 23, 754–757 (2012).

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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


  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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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.

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