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An entorhinal-visual cortical circuit regulates depression-like behaviors

A Correction to this article was published on 26 April 2022

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Abstract

Major depressive disorder is viewed as a ‘circuitopathy’. The hippocampal-entorhinal network plays a pivotal role in regulation of depression, and its main sensory output, the visual cortex, is a promising target for stimulation therapy of depression. However, whether the entorhinal-visual cortical pathway mediates depression and the potential mechanism remains unknown. Here we report a cortical circuit linking entorhinal cortex layer Va neurons to the medial portion of secondary visual cortex (Ent→V2M) that bidirectionally regulates depression-like behaviors in mice. Analyses of brain-wide projections of Ent Va neurons and two-color retrograde tracing indicated that Ent Va→V2M projection neurons represented a unique population of neurons in Ent Va. Immunostaining of c-Fos revealed that activity in Ent Va neurons was decreased in mice under chronic social defeat stress (CSDS). Both chemogenetic inactivation of Ent→V2M projection neurons and optogenetic inactivation of the projection terminals induced social deficiency, anxiety- and despair-related behaviors in healthy mice. Chemogenetic inactivation of Ent→V2M projection neurons also aggravated these depression-like behaviors in CSDS-resilient mice. Optogenetic activation of Ent→V2M projection terminals rapidly ameliorated depression-like phenotypes. Optical recording using fiber photometry indicated that elevated neural activity in Ent→V2M projection terminals promoted antidepressant-like behaviors. Thus, the Ent→V2M circuit plays a crucial role in regulation of depression-like behaviors, and can function as a potential target for treating major depressive disorder.

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Fig. 1: Brain-wide mapping of Ent Va axonal projections.
Fig. 2: The entorhinal-visual cortical projections.
Fig. 3: CSDS decreases the number of c-Fos positive neurons in Ent Va.
Fig. 4: Inactivation of Ent→V2M projection neurons induces depression-like behaviors.
Fig. 5: Inactivation of Ent→V2M projection neurons promotes depression-like behaviors in resilient mice.
Fig. 6: Activation of Ent→V2M projection terminals is antidepressant.
Fig. 7: Elevated neural activity of the Ent→V2M projection terminals promotes antidepression.

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References

  1. James SL, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and Injuries for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–858.

    Article  Google Scholar 

  2. O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: A multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208–16.

    PubMed  Article  Google Scholar 

  3. Downar J, Daskalakis ZJ. New targets for rTMS in depression: A review of convergent evidence. Brain Stimulation. 2013;6:231–40.

    PubMed  Article  Google Scholar 

  4. Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): A randomised non-inferiority trial. Lancet. 2018;391:1683–92.

    PubMed  Article  Google Scholar 

  5. Chase HW, Boudewyn MA, Carter CS, Phillips ML. Transcranial direct current stimulation: A roadmap for research, from mechanism of action to clinical implementation. Mol Psychiatry. 2020;25:397–407.

    PubMed  Article  Google Scholar 

  6. Stubbeman WF, Zarrabi B, Bastea S, Ragland V, Khairkhah R. Bilateral neuronavigated 20Hz theta burst TMS for treatment refractory depression: An open label study. Brain Stimulation. 2018;11:953–5.

    PubMed  Article  Google Scholar 

  7. Brunoni AR, Moffa AH, Sampaio-Junior B, Borrione L, Moreno ML, Fernandes RA, et al. Trial of electrical direct-current therapy versus escitalopram for depression. N. Engl J Med. 2017;376:2523–33.

    CAS  PubMed  Article  Google Scholar 

  8. Bakker N, Shahab S, Giacobbe P, Blumberger DM, Daskalakis ZJ, Kennedy SH, et al. RTMS of the dorsomedial prefrontal cortex for major depression: Safety, tolerability, effectiveness, and outcome predictors for 10 Hz versus intermittent theta-burst stimulation. Brain Stimulation. 2015;8:208–15.

    PubMed  Article  Google Scholar 

  9. Razza LB, Palumbo P, Moffa AH, Carvalho AF, Solmi M, Loo CK, et al. A systematic review and meta-analysis on the effects of transcranial direct current stimulation in depressive episodes. Depression anxiety. 2020;37:594–608.

    PubMed  Article  Google Scholar 

  10. Sampaio B, Tortella G, Borrione L, Moffa AH, Machado-Vieira R, Cretaz E, et al. Efficacy and safety of transcranial direct current stimulation as an add-on treatment for bipolar depression: A randomized clinical trial. JAMA Psychiatry. 2018;75:158–66.

    Article  Google Scholar 

  11. Zhang Z, Zhang H, Xie CM, Zhang M, Shi Y, Song R, et al. Task-related functional magnetic resonance imaging-based neuronavigation for the treatment of depression by individualized repetitive transcranial magnetic stimulation of the visual cortex. Sci China Life Sci. 2020. 2020. https://doi.org/10.1007/s11427-020-1730-5.

  12. Furtado CP, Maller JJ, Fitzgerald PB. A magnetic resonance imaging study of the entorhinal cortex in treatment-resistant depression. Psychiatry Res - Neuroimaging. 2008;163:133–42.

    Article  Google Scholar 

  13. Kim Y, Perova Z, Mirrione MM, Pradhan K, Henn FA, Shea S, et al. Whole-brain mapping of neuronal activity in the learned helplessness model of depression. Front Neural Circuits. 2016;10:1–11.

    Article  CAS  Google Scholar 

  14. Cheng W, Rolls ET, Qiu J, Liu W, Tang Y, Huang CC, et al. Medial reward and lateral non-reward orbitofrontal cortex circuits change in opposite directions in depression. Brain 2016;139:3296–309.

    PubMed  Article  Google Scholar 

  15. Gos T, Günther K, Bielau H, Dobrowolny H, Mawrin C, Trübner K, et al. Suicide and depression in the quantitative analysis of glutamic acid decarboxylase-Immunoreactive neuropil. J Affect Disord. 2009;113:45–55.

    CAS  PubMed  Article  Google Scholar 

  16. Uezato A, Meador-Woodruff JH, McCullumsmith RE. Vesicular glutamate transporter mRNA expression in the medial temporal lobe in major depressive disorder, bipolar disorder, and schizophrenia. Bipolar Disord. 2009;11:711–25.

    CAS  PubMed  Article  Google Scholar 

  17. Michel TM, Frangou S, Camara S, Thiemeyer D, Jecel J, Tatschner T, et al. Altered glial cell line-derived neurotrophic factor (GDNF) concentrations in the brain of patients with depressive disorder: A comparative post-mortem study. Eur Psychiatry. 2008;23:413–20.

    PubMed  Article  Google Scholar 

  18. Zhang C, Lueptow LM, Zhang HT, O’Donnell JM, Xu Y. The role of phosphodiesterase-2 in psychiatric and neurodegenerative disorders. Adv Neurobiol. 2017;17:307–347.

    PubMed  Article  Google Scholar 

  19. Chen X, Lan T, Wang Y, He Y, Wu Z, Tian Y, et al. Entorhinal cortex-based metabolic profiling of chronic restraint stress mice model of depression. Aging 2020;12:3042–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Yun S, Reynolds RP, Petrof I, White A, Rivera PD, Segev A, et al. Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive. Nat Med. 2018;24:658–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Kobayashi K, Yoshinaga H, Ohtsuka Y. Memory enhancement and deep-brain stimulation of the entorhinal area. N Engl J Med. 2012;366:1945.

    PubMed  Article  Google Scholar 

  22. Stone SSD, Teixeira CM, de Vito LM, Zaslavsky K, Josselyn SA, Lozano AM, et al. Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory. J Neurosci. 2011;31:13469–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Kim CS, Chang PY, Johnston D. Enhancement of dorsal hippocampal activity by knockdown of hcn1 channels leads to anxiolytic- and antidepressant-like behaviors. Neuron 2012;75:503–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Tunc-Ozcan E, Peng CY, Zhu Y, Dunlop SR, Contractor A, Kessler JA. Activating newborn neurons suppresses depression and anxiety-like behaviors. Nat Commun. 2019;10:1–9.

    CAS  Article  Google Scholar 

  25. Sürmeli G, Marcu DC, McClure C, Garden DLF, Pastoll H, Nolan MF. Molecularly defined circuitry reveals input-output segregation in deep layers of the medial entorhinal cortex. Neuron 2015;88:1040–53.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. Kitamura T, Ogawa SK, Roy DS, Okuyama T, Morrissey MD, Smith LM, et al. Engrams and circuits crucial for systems consolidation of a memory. Science 2017;356:73–78.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Ohara S, Onodera M, Simonsen ØW, Yoshino R, Hioki H, Iijima T, et al. Intrinsic Projections of Layer Vb Neurons to Layers Va, III, and II in the Lateral and Medial Entorhinal Cortex of the Rat. Cell Rep. 2018;24:107–16.

    CAS  PubMed  Article  Google Scholar 

  28. Yue Y, Zong W, Li X, Li J, Zhang Y, Wu R, et al. Long-term, in toto live imaging of cardiomyocyte behaviour during mouse ventricle chamber formation at single-cell resolution. Nat Cell Biol. 2020;22:332–40.

    CAS  PubMed  Article  Google Scholar 

  29. Golden SA, Covington HE, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Lu J, Gong X, Yao X, Guang Y, Yang H, Ji R, et al. Prolonged chronic social defeat stress promotes less resilience and higher uniformity in depression-like behaviors in adult male mice. Biochemical Biophysical Res Commun. 2021;553:107–13.

    CAS  Article  Google Scholar 

  31. Guo H, Huang ZL, Wang W, Zhang SX, Li J, Cheng K, et al. iTRAQ-based proteomics suggests Ephb6 as a potential regulator of the ERK pathway in the prefrontal cortex of chronic social defeat stress model mice. Proteom - Clin Appl. 2017;11:1–12.

    CAS  Google Scholar 

  32. He Y, Li W, Tian Y, Chen X, Cheng K, Xu K, et al. iTRAQ-based proteomics suggests LRP6, NPY and NPY2R perturbation in the hippocampus involved in CSDS may induce resilience and susceptibility. Life Sci. 2018;211:102–17.

    CAS  PubMed  Article  Google Scholar 

  33. Guo B, Chen J, Chen Q, Ren K, Feng D, Mao H, et al. Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice. Nat Neurosci. 2019;22:1223–34.

    CAS  PubMed  Article  Google Scholar 

  34. Atasoy D, Nicholas Betley J, Su HH, Sternson SM. Deconstruction of a neural circuit for hunger. Nature 2012;488:172–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Shen CJ, Zheng D, Li KX, Yang JM, Pan HQ, Yu XD, et al. Cannabinoid CB1 receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior. Nat Med. 2019;25:337–49.

    CAS  PubMed  Article  Google Scholar 

  36. Farrell MS, Roth BL. Pharmacosynthetics: Reimagining the pharmacogenetic approach. Brain Res. 2013;1511:6–20.

    CAS  PubMed  Article  Google Scholar 

  37. Sternson SM, Roth BL. Chemogenetic tools to interrogate brain functions. Annu Rev Neurosci. 2014;37:387–407.

    CAS  PubMed  Article  Google Scholar 

  38. Gunaydin LA, Grosenick L, Finkelstein JC, Kauvar IV, Fenno LE, Adhikari A, et al. Natural neural projection dynamics underlying social behavior. Cell 2014;157:1535–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Cui G, Jun SB, Jin X, Luo G, Pham MD, Lovinger DM, et al. Deep brain optical measurements of cell type-specific neural activity in behaving mice. Nat Protoc. 2014;9:1213–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Zhong W, Li Y, Feng Q, Luo M. Learning and stress shape the reward response patterns of serotonin neurons. J Neurosci. 2017;37:8863–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Renier N, Adams EL, Kirst C, Wu Z, Azevedo R, Kohl J, et al. Mapping of brain activity by automated volume analysis of immediate early genes. Cell 2016;165:1789–802.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Zhang Z, Yao X, Yin X, Ding Z, Huang T, Huo Y, et al. Multi-Scale Light-Sheet Fluorescence Microsc Fast Whole Brain Imaging. Front Neuroanat. 2021;15:732464.

    PubMed  PubMed Central  Article  Google Scholar 

  43. Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci USA. 2007;104:5163–8.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. Dana H, Sun Y, Mohar B, Hulse BK, Kerlin AM, Hasseman JP, et al. High-performance calcium sensors for imaging activity in neuronal populations and microcompartments. Nat Methods. 2019;16:649–57.

    CAS  PubMed  Article  Google Scholar 

  45. Huang L, Xi Y, Peng Y, Yang Y, Huang X, Fu Y, et al. A visual circuit related to habenula underlies the antidepressive effects of light therapy. Neuron 2019;102:128–42.e8.

    CAS  PubMed  Article  Google Scholar 

  46. An K, Zhao H, Miao Y, Xu Q, Li Y, Ma Y, et al. A circadian rhythm-gated subcortical pathway for nighttime-light-induced depressive-like behaviors in mice. Nat Neurosci. 2020. June 1, 2020. https://doi.org/10.1038/s41593-020-0640-8.

  47. Zhou Z, Liu X, Chen S, Zhang Z, Liu Y, Montardy Q, et al. A VTA GABAergic neural circuit mediates visually evoked innate defensive responses. Neuron 2019;103:473–88.e6.

    CAS  PubMed  Article  Google Scholar 

  48. Lozano AM, Lipsman N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 2013;77:406–24.

    CAS  PubMed  Article  Google Scholar 

  49. Guo ZV, Inagaki HK, Daie K, Druckmann S, Gerfen CR, Svoboda K. Maintenance of persistent activity in a frontal thalamocortical loop. Nature 2017;545:181–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Carreno FR, Donegan JJ, Boley AM, Shah A, DeGuzman M, Frazer A, et al. Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine. Mol Psychiatry. 2016;21:1298–308.

    CAS  PubMed  Article  Google Scholar 

  51. Padilla-Coreano N, Bolkan SS, Pierce GM, Blackman DR, Hardin WD, Garcia-Garcia AL, et al. Direct ventral hippocampal-prefrontal input is required for anxiety-related neural activity and behavior. Neuron 2016;89:857–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Warden MR, Selimbeyoglu A, Mirzabekov JJ, Lo M, Thompson KR, Kim SY, et al. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 2012;492:428–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Pi G, Gao D, Wu D, Wang Y, Lei H, Zeng W, et al. Posterior basolateral amygdala to ventral hippocampal CA1 drives approach behaviour to exert an anxiolytic effect. Nat Commun. 2020;11:1–15.

    Article  CAS  Google Scholar 

  54. Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 2018;554:317–22.

    CAS  PubMed  Article  Google Scholar 

  55. Cui Y, Yang Y, Ni Z, Dong Y, Cai G, Foncelle A, et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature 2018;554:323–7.

    CAS  PubMed  Article  Google Scholar 

  56. Proulx CD, Aronson S, Milivojevic D, Molina C, Loi A, Monk B, et al. A neural pathway controlling motivation to exert effort. Proc Natl Acad Sci USA. 2018;115:5792–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Gehrlach DA, Dolensek N, Klein AS, Roy Chowdhury R, Matthys A, Junghänel M, et al. Aversive state processing in the posterior insular cortex. Nat Neurosci. 2019;22:1424–37.

    CAS  PubMed  Article  Google Scholar 

  58. Bagot RC, Parise EM, Peña CJ, Zhang HX, Maze I, Chaudhury D, et al. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nat Commun. 2015;6:7062.

    CAS  PubMed  Article  Google Scholar 

  59. Salminen-Vaparanta N, Vanni S, Noreika V, Valiulis V, Móró L, Revonsuo A. Subjective characteristics of TMS-induced phosphenes originating in human V1 and V2. Cereb Cortex. 2014;24:2751–60.

    PubMed  Article  Google Scholar 

  60. Schmaal L, Hibar DP, Sämann PG, Hall GB, Baune BT, Jahanshad N, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA major depressive disorder working group. Mol Psychiatry. 2017;22:900–9.

    CAS  PubMed  Article  Google Scholar 

  61. Maciag D, Hughes J, O’Dwyer G, Pride Y, Stockmeier CA, Sanacora G, et al. Reduced density of Calbindin Immunoreactive GABAergic neurons in the occipital cortex in major depression: Relevance to neuroimaging studies. Biol Psychiatry. 2010;67:465–70.

    CAS  PubMed  Article  Google Scholar 

  62. Desseilles M, Balteau E, Sterpenich V, Thien TDV, Darsaud A, Vandewalle G, et al. Abnormal neural filtering of irrelevant visual information in depression. J Neurosci. 2009;29:1395–403.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Furey ML, Drevets WC, Hoffman EM, Frankel E, Speer AM, Zarate CA. Potential of pretreatment neural activity in the visual cortex during emotional processing to predict treatment response to scopolamine in major depressive disorder. JAMA Psychiatry. 2013;70:280–90.

    PubMed  PubMed Central  Article  Google Scholar 

  64. Castrén E, Rantamäki T. The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Developmental Neurobiol. 2010;70:289–97.

    Article  CAS  Google Scholar 

  65. Han Y, Kebschull JM, Campbell RAA, Cowan D, Imhof F, Zador AM, et al. The logic of single-cell projections from visual cortex. Nature 2018;556:51–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

We thank Hailan Hu, Cheng Zhan and Ji Hu for comments on the manuscript. We also thank Pengfei Wei, Yu Wang, Yan Huo, Tianyi Huang, Fan Di, Hongjiang Yang, Yuexin Yang and Xiao Yao for generous assistance in the experiments of animal breeding, electrophysiological recording and morphology; the Cell Biology Facility, Center of Biomedical Analysis at Tsinghua University for imaging of brain sections; the Animal Core Facility at Tsinghua University for maintaining the mouse lines. This work was supported by the National Natural Science Foundation of China (32021002) to ZVG and the National Key R&D Program of China (2017YFA0505700) to PX.

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JL, ZVG, and PX conceived the project. JL performed the experiments with inputs from ZZZ (Light-sheet fluorescence imaging), XXY (Reward licking setup and code programing), YJT (Fiber photometry), YG, XG, YH, WZ, HYW, KC, YW (CSDS modeling and behavior tests) and XWC (Ent→Visual cortical projection tracing). JL analyzed the data with inputs from RNJ and HC (code programing). JL and ZVG wrote the manuscript with comments from other authors.

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Correspondence to Peng Xie or Zengcai V. Guo.

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Lu, J., Zhang, Z., Yin, X. et al. An entorhinal-visual cortical circuit regulates depression-like behaviors. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01540-8

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