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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
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.
Downar J, Daskalakis ZJ. New targets for rTMS in depression: A review of convergent evidence. Brain Stimulation. 2013;6:231–40.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Kobayashi K, Yoshinaga H, Ohtsuka Y. Memory enhancement and deep-brain stimulation of the entorhinal area. N Engl J Med. 2012;366:1945.
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.
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.
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.
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.
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.
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.
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.
Golden SA, Covington HE, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91.
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.
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.
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.
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.
Atasoy D, Nicholas Betley J, Su HH, Sternson SM. Deconstruction of a neural circuit for hunger. Nature 2012;488:172–7.
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.
Farrell MS, Roth BL. Pharmacosynthetics: Reimagining the pharmacogenetic approach. Brain Res. 2013;1511:6–20.
Sternson SM, Roth BL. Chemogenetic tools to interrogate brain functions. Annu Rev Neurosci. 2014;37:387–407.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Lozano AM, Lipsman N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 2013;77:406–24.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The original online version of this article was revised: The wrong Supplementary file was originally published with this article; it has now been replaced with the correct file.
About this article
Cite this article
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