Stimulation of entorhinal cortex–dentate gyrus circuitry is antidepressive

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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Fig. 1: CSDS increases levels of TRIP8b isoform IsoA4 in the DG.
Fig. 2: Ent-specific TRIP8b knockdown increases intrinsic excitability of Ent stellate cells and enhances DG neurogenesis.
Fig. 3: TRIP8b knockdown in the Ent induces antidepressive-like behavior that is neurogenesis–dependent.
Fig. 4: Ent-specific TRIP8b knockdown promotes antidepressive-like behaviors under conditions that mimic chronic stress.
Fig. 5: Chemogenetic stimulation of the Ent–DG circuit drives activity-dependent processes in the DG and antidepressive-like behavior.

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  • 22 June 2018

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References

  1. 1.

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

    Article  Google Scholar 

  2. 2.

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

    Article  Google Scholar 

  3. 3.

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

    CAS  Article  Google Scholar 

  4. 4.

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

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  8. 8.

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

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  16. 16.

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

    CAS  Article  Google Scholar 

  17. 17.

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

    CAS  Article  Google Scholar 

  18. 18.

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

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  21. 21.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  27. 27.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  31. 31.

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

    CAS  Article  Google Scholar 

  32. 32.

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

    CAS  Article  Google Scholar 

  33. 33.

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

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  35. 35.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  38. 38.

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

    CAS  Article  Google Scholar 

  39. 39.

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

    Article  Google Scholar 

  40. 40.

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

    CAS  Article  Google Scholar 

  41. 41.

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

    CAS  Article  Google Scholar 

  42. 42.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  45. 45.

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

    Article  Google Scholar 

  46. 46.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  48. 48.

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

    CAS  Article  Google Scholar 

  49. 49.

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

    CAS  Article  Google Scholar 

  50. 50.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  58. 58.

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

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  64. 64.

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

    CAS  Article  Google Scholar 

  65. 65.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  67. 67.

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  69. 69.

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

    CAS  Article  Google Scholar 

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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).

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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.

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Correspondence to Amelia J. Eisch.

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Yun, S., Reynolds, R.P., Petrof, I. et al. Stimulation of entorhinal cortex–dentate gyrus circuitry is antidepressive. Nat Med 24, 658–666 (2018). https://doi.org/10.1038/s41591-018-0002-1

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