Advertisement

The Netrin-1/DCC Guidance Cue Pathway as a Molecular Target in Depression: Translational Evidence

      Abstract

      The Netrin-1/DCC guidance cue pathway plays a critical role in guiding growing axons toward the prefrontal cortex during adolescence and in the maturational organization and adult plasticity of prefrontal cortex connectivity. In this review, we put forward the idea that alterations in prefrontal cortex architecture and function, which are intrinsically linked to the development of major depressive disorder, originate in part from the dysregulation of the Netrin-1/DCC pathway by a mechanism that involves microRNA-218. We discuss evidence derived from mouse models of stress and from human postmortem brain and genome-wide association studies indicating an association between the Netrin-1/DCC pathway and major depressive disorder. We propose a potential role of circulating microRNA-218 as a biomarker of stress vulnerability and major depressive disorder.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Malhi G.S.
        • Mann J.J.
        Depression.
        Lancet. 2018; 392: 2299-2312
        • Akil H.
        • Gordon J.
        • Hen R.
        • Javitch J.
        • Mayberg H.
        • McEwen B.
        • et al.
        Treatment resistant depression: A multi-scale, systems biology approach.
        Neurosci Biobehav Rev. 2018; 84: 272-288
        • Kessler R.C.
        • Berglund P.
        • Demler O.
        • Jin R.
        • Merikangas K.R.
        • Walters E.E.
        Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 593-602
        • Rice F.
        • Riglin L.
        • Thapar A.K.
        • Heron J.
        • Anney R.
        • O’Donovan M.C.
        • Thapar A.
        Characterizing developmental trajectories and the role of neuropsychiatric genetic risk variants in early-onset depression.
        JAMA Psychiatry. 2019; 76: 306-313
        • Paus T.
        • Keshavan M.
        • Giedd J.N.
        Why do many psychiatric disorders emerge during adolescence?.
        Nat Rev Neurosci. 2008; 9: 947-957
        • Kessler R.C.
        • Amminger G.P.
        • Aguilar-Gaxiola S.
        • Alonso J.
        • Lee S.
        • Ustün T.B.
        Age of onset of mental disorders: A review of recent literature.
        Curr Opin Psychiatry. 2007; 20: 359-364
        • Lee F.S.
        • Heimer H.
        • Giedd J.N.
        • Lein E.S.
        • Šestan N.
        • Weinberger D.R.
        • Casey B.J.
        Adolescent mental health—Opportunity and obligation.
        Science. 2014; 346: 547-549
        • Tottenham N.
        • Galván A.
        Stress and the adolescent brain: Amygdala-prefrontal cortex circuitry and ventral striatum as developmental targets.
        Neurosci Biobehav Rev. 2016; 70: 217-227
        • Liu W.
        • Ge T.
        • Leng Y.
        • Pan Z.
        • Fan J.
        • Yang W.
        • Cui R.
        The role of neural plasticity in depression: From hippocampus to prefrontal cortex.
        Neural Plast. 2017; 2017: 6871089
        • Li Q.
        • Zhao Y.
        • Chen Z.
        • Long J.
        • Dai J.
        • Huang X.
        • et al.
        Meta-analysis of cortical thickness abnormalities in medication-free patients with major depressive disorder.
        Neuropsychopharmacology. 2020; 45: 703-712
        • Botteron K.N.
        • Raichle M.E.
        • Drevets W.C.
        • Heath A.C.
        • Todd R.D.
        Volumetric reduction in left subgenual prefrontal cortex in early onset depression.
        Biol Psychiatry. 2002; 51: 342-344
        • McEwen B.S.
        • Morrison J.H.
        The brain on stress: Vulnerability and plasticity of the prefrontal cortex over the life course.
        Neuron. 2013; 79: 16-29
        • Duman R.S.
        • Aghajanian G.K.
        • Sanacora G.
        • Krystal J.H.
        Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants.
        Nat Med. 2016; 22: 238-249
        • Kang H.J.
        • Voleti B.
        • Hajszan T.
        • Rajkowska G.
        • Stockmeier C.A.
        • Licznerski P.
        • et al.
        Decreased expression of synapse-related genes and loss of synapses in major depressive disorder.
        Nat Med. 2012; 18: 1413-1417
        • Duman R.S.
        • Aghajanian G.K.
        Synaptic dysfunction in depression: Potential therapeutic targets.
        Science. 2012; 338: 68-72
        • Stoeckli E.T.
        Understanding axon guidance: Are we nearly there yet?.
        Development. 2018; 145: dev151415
        • Beamish I.V.
        • Hinck L.
        • Kennedy T.E.
        Making connections: Guidance cues and receptors at nonneural cell-cell junctions.
        Cold Spring Harb Perspect Biol. 2018; 10: a029165
        • Lanoue V.
        • Cooper H.M.
        Branching mechanisms shaping dendrite architecture.
        Dev Biol. 2019; 451: 16-24
        • Van Battum E.Y.
        • Brignani S.
        • Pasterkamp R.J.
        Axon guidance proteins in neurological disorders.
        Lancet Neurol. 2015; 14: 532-546
        • Dent E.W.
        • Gupton S.L.
        • Gertler F.B.
        The growth cone cytoskeleton in axon outgrowth and guidance.
        Cold Spring Harb Perspect Biol. 2011; 3a001800
        • Lai Wing Sun K.
        • Correia J.P.
        • Kennedy T.E.
        Netrins: Versatile extracellular cues with diverse functions.
        Development. 2011; 138: 2153-2169
        • Boyer N.P.
        • Gupton S.L.
        Revisiting Netrin-1: One who guides (axons).
        Front Cell Neurosci. 2018; 12: 221
        • Finci L.
        • Zhang Y.
        • Meijers R.
        • Wang J.-H.
        Signaling mechanism of the netrin-1 receptor DCC in axon guidance.
        Prog Biophys Mol Biol. 2015; 118: 153-160
        • Meijers R.
        • Smock R.G.
        • Zhang Y.
        • Wang J.-H.
        Netrin synergizes signaling and adhesion through DCC.
        Trends Biochem Sci. 2020; 45: 6-12
        • Finci L.I.
        • Krüger N.
        • Sun X.
        • Zhang J.
        • Chegkazi M.
        • Wu Y.
        • et al.
        The crystal structure of netrin-1 in complex with DCC reveals the bifunctionality of netrin-1 as a guidance cue.
        Neuron. 2014; 83: 839-849
        • Dominici C.
        • Moreno-Bravo J.A.
        • Puiggros S.R.
        • Rappeneau Q.
        • Rama N.
        • Vieugue P.
        • et al.
        Floor-plate-derived netrin-1 is dispensable for commissural axon guidance.
        Nature. 2017; 545: 350-354
        • Varadarajan S.G.
        • Kong J.H.
        • Phan K.D.
        • Kao T.-J.
        • Panaitof S.C.
        • Cardin J.
        • et al.
        Netrin1 produced by neural progenitors, not floor plate cells, is required for axon guidance in the spinal cord.
        Neuron. 2017; 94: 790-799.e3
        • Moore S.W.
        • Biais N.
        • Sheetz M.P.
        Traction on immobilized netrin-1 is sufficient to reorient axons.
        Science. 2009; 325: 166
        • Shen K.
        • Cowan C.W.
        Guidance molecules in synapse formation and plasticity.
        Cold Spring Harb Perspect Biol. 2010; 2: a001842
        • Manitt C.
        • Nikolakopoulou A.M.
        • Almario D.R.
        • Nguyen S.A.
        • Cohen-Cory S.
        Netrin participates in the development of retinotectal synaptic connectivity by modulating axon arborization and synapse formation in the developing brain.
        J Neurosci. 2009; 29: 11065-11077
        • Horn K.E.
        • Glasgow S.D.
        • Gobert D.
        • Bull S.-J.
        • Luk T.
        • Girgis J.
        • et al.
        DCC expression by neurons regulates synaptic plasticity in the adult brain.
        Cell Rep. 2013; 3: 173-185
        • Goldman J.S.
        • Ashour M.A.
        • Magdesian M.H.
        • Tritsch N.X.
        • Harris S.N.
        • Christofi N.
        • et al.
        Netrin-1 promotes excitatory synaptogenesis between cortical neurons by initiating synapse assembly.
        J Neurosci. 2013; 33: 17278-17289
        • Glasgow S.D.
        • Labrecque S.
        • Beamish I.V.
        • Aufmkolk S.
        • Gibon J.
        • Han D.
        • et al.
        Activity-dependent Netrin-1 secretion drives synaptic insertion of GluA1-containing AMPA receptors in the hippocampus.
        Cell Rep. 2018; 25: 168-182.e6
        • Colón-Ramos D.A.
        • Margeta M.A.
        • Shen K.
        Glia promote local synaptogenesis through UNC-6 (netrin) signaling in C. elegans.
        Science. 2007; 318: 103-106
        • Poon V.Y.
        • Klassen M.P.
        • Shen K.
        UNC-6/netrin and its receptor UNC-5 locally exclude presynaptic components from dendrites.
        Nature. 2008; 455: 669-673
        • Flores C.
        Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system.
        J Psychiatry Neurosci. 2011; 36: 296-310
        • Hoops D.
        • Flores C.
        Making dopamine connections in adolescence.
        Trends Neurosci. 2017; 40: 709-719
        • Manitt C.
        • Eng C.
        • Pokinko M.
        • Ryan R.T.
        • Torres-Berrío A.
        • Lopez J.P.
        • et al.
        dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients.
        Transl Psychiatry. 2013; 3: e338
        • Reynolds L.M.
        • Yetnikoff L.
        • Pokinko M.
        • Wodzinski M.
        • Epelbaum J.G.
        • Lambert L.C.
        • et al.
        Early Adolescence is a Critical Period for the Maturation of Inhibitory Behavior.
        Cereb Cortex. 2019; 29 (3676–2686)
        • Hoops D.
        • Reynolds L.M.
        • Restrepo-Lozano J.-M.
        • Flores C.
        Dopamine development in the mouse orbital prefrontal cortex is protracted and sensitive to amphetamine in adolescence.
        eNeuro. 2018; 5 (ENEURO.0372-17.2017)
        • Cuesta S.
        • Restrepo-Lozano J.M.
        • Silvestrin S.
        • Nouel D.
        • Torres-Berrío A.
        • Reynolds L.M.
        • et al.
        Non-contingent exposure to amphetamine in adolescence recruits miR-218 to regulate Dcc expression in the VTA.
        Neuropsychopharmacology. 2018; 43: 900-911
        • Cuesta S.
        • Restrepo-Lozano J.M.
        • Popescu C.
        • He S.
        • Reynolds L.M.
        • Israel S.
        • et al.
        DCC-related developmental effects of abused- versus therapeutic-like amphetamine doses in adolescence.
        Addict Biol. 2020; 25: e12791
        • Vosberg D.E.
        • Leyton M.
        • Flores C.
        The Netrin-1/DCC guidance system: Dopamine pathway maturation and psychiatric disorders emerging in adolescence.
        Mol Psychiatry. 2020; 25: 297-307
        • Wu Z.
        • Makihara S.
        • Yam P.T.
        • Teo S.
        • Renier N.
        • Balekoglu N.
        • et al.
        Long-range guidance of spinal commissural axons by Netrin1 and sonic hedgehog from midline floor plate cells.
        Neuron. 2019; 101: 635-647.e4
        • Keino-Masu K.
        • Masu M.
        • Hinck L.
        • Leonardo E.D.
        • Chan S.S.
        • Culotti J.G.
        • Tessier-Lavigne M.
        Deleted in colorectal cancer (DCC) encodes a netrin receptor.
        Cell. 1996; 87: 175-185
        • Leonardo E.D.
        • Hinck L.
        • Masu M.
        • Keino-Masu K.
        • Ackerman S.L.
        • Tessier-Lavigne M.
        Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors.
        Nature. 1997; 386: 833-838
        • Manitt C.
        • Kennedy T.E.
        Where the rubber meets the road: Netrin expression and function in developing and adult nervous systems.
        Prog Brain Res. 2002; 137: 425-442
        • Bartoe J.L.
        • McKenna W.L.
        • Quan T.K.
        • Stafford B.K.
        • Moore J.A.
        • Xia J.
        • et al.
        Protein interacting with C-kinase 1/protein kinase Cα-mediated endocytosis converts netrin-1-mediated repulsion to attraction.
        J Neurosci. 2006; 26: 3192-3205
        • Muramatsu R.
        • Nakahara S.
        • Ichikawa J.
        • Watanabe K.
        • Matsuki N.
        • Koyama R.
        The ratio of “deleted in colorectal cancer” to “uncoordinated-5A” netrin-1 receptors on the growth cone regulates mossy fibre directionality.
        Brain. 2010; 133: 60-75
        • Bouchard J.-F.
        • Moore S.W.
        • Tritsch N.X.
        • Roux P.P.
        • Shekarabi M.
        • Barker P.A.
        • Kennedy T.E.
        Protein kinase A activation promotes plasma membrane insertion of DCC from an intracellular pool: A novel mechanism regulating commissural axon extension.
        J Neurosci. 2004; 24: 3040-3050
        • Yetnikoff L.
        • Eng C.
        • Benning S.
        • Flores C.
        Netrin-1 receptor in the ventral tegmental area is required for sensitization to amphetamine.
        Eur J Neurosci. 2010; 31: 1292-1302
        • Osborne P.B.
        • Halliday G.M.
        • Cooper H.M.
        • Keast J.R.
        Localization of immunoreactivity for deleted in colorectal cancer (DCC), the receptor for the guidance factor netrin-1, in ventral tier dopamine projection pathways in adult rodents.
        Neuroscience. 2005; 131: 671-681
        • Manitt C.
        • Labelle-Dumais C.
        • Eng C.
        • Grant A.
        • Mimee A.
        • Stroh T.
        • Flores C.
        Peri-pubertal emergence of UNC-5 homologue expression by dopamine neurons in rodents.
        PLoS One. 2010; 5: e11463
        • Reyes S.
        • Fu Y.
        • Double K.L.
        • Cottam V.
        • Thompson L.H.
        • Kirik D.
        • et al.
        Trophic factors differentiate dopamine neurons vulnerable to Parkinson’s disease.
        Neurobiol Aging. 2013; 34: 873-886
        • Manitt C.
        • Mimee A.
        • Eng C.
        • Pokinko M.
        • Stroh T.
        • Cooper H.M.
        • et al.
        The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry.
        J Neurosci. 2011; 31: 8381-8394
        • Park H.L.
        • Kim M.S.
        • Yamashita K.
        • Westra W.
        • Carvalho A.L.
        • Lee J.
        • et al.
        DCC promoter hypermethylation in esophageal squamous cell carcinoma.
        Int J Cancer. 2008; 122: 2498-2502
        • Derks S.
        • Bosch L.J.W.
        • Niessen H.E.C.
        • Moerkerk P.T.M.
        • van den Bosch S.M.
        • Carvalho B.
        • et al.
        Promoter CpG island hypermethylation- and H3K9me3 and H3K27me3-mediated epigenetic silencing targets the deleted in colon cancer (DCC) gene in colorectal carcinogenesis without affecting neighboring genes on chromosomal region 18q21.
        Carcinogenesis. 2009; 30: 1041-1048
        • Torres-Berrío A.
        • Lopez J.P.
        • Bagot R.C.
        • Nouel D.
        • Dal Bo G.
        • Cuesta S.
        • et al.
        DCC confers susceptibility to depression-like behaviors in humans and mice and is regulated by miR-218.
        Biol Psychiatry. 2017; 81: 306-315
        • Moore L.D.
        • Le T.
        • Fan G.
        DNA methylation and its basic function.
        Neuropsychopharmacology. 2013; 38: 23-38
        • Wang X.
        • Chen Q.
        • Yi S.
        • Liu Q.
        • Zhang R.
        • Wang P.
        • et al.
        The microRNAs let-7 and miR-9 down-regulate the axon-guidance genes Ntn1 and Dcc during peripheral nerve regeneration.
        J Biol Chem. 2019; 294: 3489-3500
        • Jang H.S.
        • Shin W.J.
        • Lee J.E.
        • Do J.T.
        CpG and Non-CpG Methylation in Epigenetic Gene Regulation and Brain Function.
        Genes (Basel). 2017; 8: 148
        • Zhou C.
        • Ye M.
        • Ni S.
        • Li Q.
        • Ye D.
        • Li J.
        • et al.
        DNA methylation biomarkers for head and neck squamous cell carcinoma.
        Epigenetics. 2018; 13: 398-409
        • Gogtay N.
        • Giedd J.N.
        • Lusk L.
        • Hayashi K.M.
        • Greenstein D.
        • Vaituzis A.C.
        • et al.
        Dynamic mapping of human cortical development during childhood through early adulthood.
        Proc Natl Acad Sci U S A. 2004; 101: 8174-8179
        • Sowell E.R.
        • Peterson B.S.
        • Thompson P.M.
        • Welcome S.E.
        • Henkenius A.L.
        • Toga A.W.
        Mapping cortical change across the human life span.
        Nat Neurosci. 2003; 6: 309-315
        • Petanjek Z.
        • Judaš M.
        • Šimic G.
        • Rasin M.R.
        • Uylings H.B.M.
        • Rakic P.
        • Kostovic I.
        Extraordinary neoteny of synaptic spines in the human prefrontal cortex.
        Proc Natl Acad Sci U S A. 2011; 108: 13281-13286
        • Fung S.J.
        • Webster M.J.
        • Sivagnanasundaram S.
        • Duncan C.
        • Elashoff M.
        • Weickert C.S.
        Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia.
        Am J Psychiatry. 2010; 167: 1479-1488
        • Caballero A.
        • Granberg R.
        • Tseng K.Y.
        Mechanisms contributing to prefrontal cortex maturation during adolescence.
        Neurosci Biobehav Rev. 2016; 70: 4-12
        • Larsen B.
        • Luna B.
        Adolescence as a neurobiological critical period for the development of higher-order cognition.
        Neurosci Biobehav Rev. 2018; 94: 179-195
        • Naneix F.
        • Marchand A.R.
        • Di Scala G.
        • Pape J.-R.
        • Coutureau E.
        Parallel maturation of goal-directed behavior and dopaminergic systems during adolescence.
        J Neurosci. 2012; 32: 16223-16232
        • Tarazi F.I.
        • Baldessarini R.J.
        Comparative postnatal development of dopamine D1, D2 and D4 receptors in rat forebrain.
        Int J Dev Neurosci. 2000; 18: 29-37
        • Reynolds L.M.
        • Pokinko M.
        • Torres-Berrío A.
        • Cuesta S.
        • Lambert L.C.
        • Del Cid Pellitero E.
        • et al.
        DCC receptors drive prefrontal cortex maturation by determining dopamine axon targeting in adolescence.
        Biol Psychiatry. 2018; 83: 181-192
        • Shaw G.A.
        • Dupree J.L.
        • Neigh G.N.
        Adolescent maturation of the prefrontal cortex: Role of stress and sex in shaping adult risk for compromise.
        Genes Brain Behav. 2020; 19e12626
        • Delevich K.
        • Okada N.J.
        • Rahane A.
        • Zhang Z.
        • Hall C.D.
        • Wilbrecht L.
        Sex and pubertal status influence dendritic spine density on frontal corticostriatal projection neurons in mice.
        Cereb Cortex. 2020; 30: 3543-3557
        • Reynolds L.M.
        • Makowski C.S.
        • Yogendran S.V.
        • Kiessling S.
        • Cermakian N.
        • Flores C.
        Amphetamine in adolescence disrupts the development of medial prefrontal cortex dopamine connectivity in a DCC-dependent manner.
        Neuropsychopharmacology. 2015; 40: 1101-1112
        • Torres-Berrío A.
        • Nouel D.
        • Cuesta S.
        • Parise E.M.
        • Restrepo-Lozano J.M.
        • Larochelle P.
        • et al.
        miR-218: A molecular switch and potential biomarker of susceptibility to stress.
        Mol Psychiatry. 2020; 25: 951-964
        • Reynolds L.M.
        • Flores C.
        Guidance cues: Linking drug use in adolescence with psychiatric disorders.
        Neuropsychopharmacology. 2019; 44: 225-226
        • Levinson D.F.
        The genetics of depression: A review.
        Biol Psychiatry. 2006; 60: 84-92
        • Ripke S.
        • Wray N.R.
        • Lewis C.M.
        • Hamilton S.P.
        • Weissman M.M.
        • et al.
        • Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium
        A mega-analysis of genome-wide association studies for major depressive disorder.
        Mol Psychiatry. 2013; 18: 497-511
        • Kendler K.S.
        • Karkowski L.M.
        • Prescott C.A.
        Causal relationship between stressful life events and the onset of major depression.
        Am J Psychiatry. 1999; 156: 837-841
        • Liu R.T.
        • Alloy L.B.
        Stress generation in depression: A systematic review of the empirical literature and recommendations for future study.
        Clin Psychol Rev. 2010; 30: 582-593
        • Nestler E.J.
        • Hyman S.E.
        Animal models of neuropsychiatric disorders.
        Nat Neurosci. 2010; 13: 1161-1169
        • Czéh B.
        • Fuchs E.
        • Wiborg O.
        • Simon M.
        Animal models of major depression and their clinical implications.
        Prog Neuropsychopharmacol Biol Psychiatry. 2016; 64: 293-310
        • Bale T.L.
        • Abel T.
        • Akil H.
        • Carlezon W.A.
        • Moghaddam B.
        • Nestler E.J.
        • et al.
        The critical importance of basic animal research for neuropsychiatric disorders.
        Neuropsychopharmacology. 2019; 44: 1349-1353
        • Labonté B.
        • Engmann O.
        • Purushothaman I.
        • Menard C.
        • Wang J.
        • Tan C.
        • et al.
        Sex-specific transcriptional signatures in human depression.
        Nat Med. 2017; 23: 1102-1111
        • Willner P.
        The chronic mild stress (CMS) model of depression: History, evaluation and usage.
        Neurobiol Stress. 2017; 6: 78-93
        • Berton O.
        • McClung C.A.
        • Dileone R.J.
        • Krishnan V.
        • Renthal W.
        • Russo S.J.
        • et al.
        Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.
        Science. 2006; 311: 864-868
        • Golden S.A.
        • Covington H.E.
        • Berton O.
        • Russo S.J.
        A standardized protocol for repeated social defeat stress in mice.
        Nat Protoc. 2011; 6: 1183-1191
        • Krishnan V.
        • Han M.-H.
        • Graham D.L.
        • Berton O.
        • Renthal W.
        • Russo S.J.
        • et al.
        Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.
        Cell. 2007; 131: 391-404
        • Harris A.Z.
        • Atsak P.
        • Bretton Z.H.
        • Holt E.S.
        • Alam R.
        • Morton M.P.
        • et al.
        A novel method for chronic social defeat stress in female mice.
        Neuropsychopharmacology. 2018; 43: 1276-1283
        • Newman E.L.
        • Covington H.E.
        • Suh J.
        • Bicakci M.B.
        • Ressler K.J.
        • DeBold J.F.
        • Miczek K.A.
        Fighting females: Neural and behavioral consequences of social defeat stress in female mice.
        Biol Psychiatry. 2019; 86: 657-668
        • Takahashi A.
        • Chung J.-R.
        • Zhang S.
        • Zhang H.
        • Grossman Y.
        • Aleyasin H.
        • et al.
        Establishment of a repeated social defeat stress model in female mice.
        Sci Rep. 2017; 7: 12838
        • Yohn C.N.
        • Ashamalla S.A.
        • Bokka L.
        • Gergues M.M.
        • Garino A.
        • Samuels B.A.
        Social instability is an effective chronic stress paradigm for both male and female mice.
        Neuropharmacology. 2019; 160: 107780
        • Iñiguez S.D.
        • Flores-Ramirez F.J.
        • Riggs L.M.
        • Alipio J.B.
        • Garcia-Carachure I.
        • Hernandez M.A.
        • et al.
        Vicarious social defeat stress induces depression-related outcomes in female mice.
        Biol Psychiatry. 2018; 83: 9-17
        • Koo J.W.
        • Chaudhury D.
        • Han M.-H.
        • Nestler E.J.
        Role of mesolimbic brain-derived neurotrophic factor in depression.
        Biol Psychiatry. 2019; 86: 738-748
        • Chaudhury D.
        • Walsh J.J.
        • Friedman A.K.
        • Juarez B.
        • Ku S.M.
        • Koo J.W.
        • et al.
        Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons.
        Nature. 2013; 493: 532-536
        • O’Toole N.
        • Zhang T.-Y.
        • Wen X.
        • Diorio J.
        • Silveira P.P.
        • Labonté B.
        • et al.
        Epigenetic signatures of chronic social stress in stress-susceptible animals.
        bioRxiv. 2019; https://doi.org/10.1101/690826
        • Small E.M.
        • Sutherland L.B.
        • Rajagopalan K.N.
        • Wang S.
        • Olson E.N.
        microRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.
        Circ Res. 2010; 107: 1336-1344
        • Wray N.R.
        • Pergadia M.L.
        • Blackwood D.H.R.
        • Penninx B.W.J.H.
        • Gordon S.D.
        • Nyholt D.R.
        • et al.
        Genome-wide association study of major depressive disorder: New results, meta-analysis, and lessons learned.
        Mol Psychiatry. 2012; 17: 36-48
        • Dunn E.C.
        • Wiste A.
        • Radmanesh F.
        • Almli L.M.
        • Gogarten S.M.
        • Sofer T.
        • et al.
        Genome-wide association study (GWAS) and genome-wide by environment interaction study (GWEIS) of depressive symptoms in African American and Hispanic/Latina women.
        Depress Anxiety. 2016; 33: 265-280
        • Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium
        Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways.
        Nat Neurosci. 2015; 18: 199-209
        • Smith B.H.
        • Campbell H.
        • Blackwood D.
        • Connell J.
        • Connor M.
        • Deary I.J.
        • et al.
        Generation Scotland: The Scottish Family Health Study—A new resource for researching genes and heritability.
        BMC Med Genet. 2006; 7: 74
        • Zeng Y.
        • Navarro P.
        • Fernandez-Pujals A.M.
        • Hall L.S.
        • Clarke T.K.
        • Thomson P.A.
        • et al.
        A combined pathway and regional heritability analysis indicates NETRIN1 pathway is associated with major depressive disorder.
        Biol Psychiatry. 2017; 81: 336-346
        • Barbu M.C.
        • Zeng Y.
        • Shen X.
        • Cox S.R.
        • Clarke T.-K.
        • Gibson J.
        • et al.
        Association of whole-genome and NETRIN1 signaling pathway-derived polygenic risk scores for major depressive disorder and white matter microstructure in the UK Biobank.
        Biol Psychiatry Cogn Neurosci Neuroimaging. 2019; 4: 91-100
        • Ward J.
        • Lyall L.M.
        • Bethlehem R.A.I.
        • Ferguson A.
        • Strawbridge R.J.
        • Lyall D.M.
        • et al.
        Novel genome-wide associations for anhedonia, genetic correlation with psychiatric disorders, and polygenic association with brain structure.
        Transl Psychiatry. 2019; 9: 327
        • Vosberg D.E.
        • Zhang Y.
        • Menegaux A.
        • Chalupa A.
        • Manitt C.
        • Zehntner S.
        • et al.
        Mesocorticolimbic connectivity and volumetric alterations in DCC mutation carriers.
        J Neurosci. 2018; 38: 4655-4665
        • Okbay A.
        • Baselmans B.M.L.
        • De Neve J.-E.
        • Turley P.
        • Nivard M.G.
        • Fontana M.A.
        • et al.
        Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.
        Nat Genet. 2016; 48: 624-633
        • Wray N.R.
        • Ripke S.
        • Mattheisen M.
        • Trzaskowski M.
        • Byrne E.M.
        • Abdellaoui A.
        • et al.
        Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.
        Nat Genet. 2018; 50: 668-681
        • Ward J.
        • Strawbridge R.J.
        • Bailey M.E.S.
        • Graham N.
        • Ferguson A.
        • Lyall D.M.
        • et al.
        Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia.
        Transl Psychiatry. 2017; 7: 1264
        • Strawbridge R.J.
        • Ward J.
        • Ferguson A.
        • Graham N.
        • Shaw R.J.
        • Cullen B.
        • et al.
        Identification of novel genome-wide associations for suicidality in UK Biobank, genetic correlation with psychiatric disorders and polygenic association with completed suicide.
        EBioMedicine. 2019; 41: 517-525
        • Smith D.J.
        • Escott-Price V.
        • Davies G.
        • Bailey M.E.S.
        • Colodro-Conde L.
        • Ward J.
        • et al.
        Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.
        Mol Psychiatry. 2016; 21: 749-757
        • Arnau-Soler A.
        • Macdonald-Dunlop E.
        • Adams M.J.
        • Clarke T.-K.
        • MacIntyre D.J.
        • Milburn K.
        • et al.
        Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland.
        Transl Psychiatry. 2019; 9: 14
        • Leday G.G.R.
        • Vértes P.E.
        • Richardson S.
        • Greene J.R.
        • Regan T.
        • Khan S.
        • et al.
        Replicable and coupled changes in innate and adaptive immune gene expression in two case-control studies of blood microarrays in major depressive disorder.
        Biol Psychiatry. 2018; 83: 70-80
        • Aberg K.A.
        • Shabalin A.A.
        • Chan R.F.
        • Zhao M.
        • Kumar G.
        • van Grootheest G.
        • et al.
        Convergence of evidence from a methylome-wide CpG-SNP association study and GWAS of major depressive disorder.
        Transl Psychiatry. 2018; 8: 162
        • Roberson-Nay R.
        • Wolen A.R.
        • Lapato D.M.
        • Lancaster E.E.
        • Webb B.T.
        • Verhulst B.
        • et al.
        Twin study of aarly-onset major depression finds DNA methylation enrichment for neurodevelopmental genes.
        bioRxiv. 2018; https://doi.org/10.1101/422345
        • Lee P.H.
        • Anttila V.
        • Won H.
        • Feng Y.-C.A.
        • Rosenthal J.
        • Zhu Z.
        • et al.
        Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders.
        Cell. 2019; 179: 1469-1482.e11
        • Yuan H.
        • Mischoulon D.
        • Fava M.
        • Otto M.W.
        Circulating microRNAs as biomarkers for depression: Many candidates, few finalists.
        J Affect Disord. 2018; 233: 68-78
        • Gururajan A.
        • Clarke G.
        • Dinan T.G.
        • Cryan J.F.
        Molecular biomarkers of depression.
        Neurosci Biobehav Rev. 2016; 64: 101-133
        • Drysdale A.T.
        • Grosenick L.
        • Downar J.
        • Dunlop K.
        • Mansouri F.
        • Meng Y.
        • et al.
        Erratum: Resting-state connectivity biomarkers define neurophysiological subtypes of depression.
        Nat Med. 2017; 23: 264
        • Ruan Q.
        • D’Onofrio G.
        • Sancarlo D.
        • Bao Z.
        • Greco A.
        • Yu Z.
        Potential neuroimaging biomarkers of pathologic brain changes in mild cognitive impairment and Alzheimer’s disease: A systematic review.
        BMC Geriatr. 2016; 16: 104
        • Strawbridge R.
        • Young A.H.
        • Cleare A.J.
        Biomarkers for depression: Recent insights, current challenges and future prospects.
        Neuropsychiatr Dis Treat. 2017; 13: 1245-1262
        • Issler O.
        • Chen A.
        Determining the role of microRNAs in psychiatric disorders.
        Nat Rev Neurosci. 2015; 16: 201-212
        • Tavakolizadeh J.
        • Roshanaei K.
        • Salmaninejad A.
        • Yari R.
        • Nahand J.S.
        • Sarkarizi H.K.
        • et al.
        microRNAs and exosomes in depression: Potential diagnostic biomarkers.
        J Cell Biochem. 2018; 119: 3783-3797
        • Chen X.
        • Ba Y.
        • Ma L.
        • Cai X.
        • Yin Y.
        • Wang K.
        • et al.
        Characterization of microRNAs in serum: A novel class of biomarkers for diagnosis of cancer and other diseases.
        Cell Res. 2008; 18: 997-1006
        • Gheysarzadeh A.
        • Sadeghifard N.
        • Afraidooni L.
        • Pooyan F.
        • Mofid M.R.
        • Valadbeigi H.
        • et al.
        Serum-based microRNA biomarkers for major depression: miR-16, miR-135a, and miR-1202.
        J Res Med Sci. 2018; 23: 69
        • Fiori L.M.
        • Lopez J.P.
        • Richard-Devantoy S.
        • Berlim M.
        • Chachamovich E.
        • Jollant F.
        • et al.
        Investigation of miR-1202, miR-135a, and miR-16 in major depressive disorder and antidepressant response.
        Int J Neuropsychopharmacol. 2017; 20: 619-623
        • Lopez J.P.
        • Lim R.
        • Cruceanu C.
        • Crapper L.
        • Fasano C.
        • Labonte B.
        • et al.
        miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment.
        Nat Med. 2014; 20: 764-768
        • Issler O.
        • Haramati S.
        • Paul E.D.
        • Maeno H.
        • Navon I.
        • Zwang R.
        • et al.
        microRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity.
        Neuron. 2014; 83: 344-360
        • Belzeaux R.
        • Bergon A.
        • Jeanjean V.
        • Loriod B.
        • Formisano-Tréziny C.
        • Verrier L.
        • et al.
        Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.
        Transl Psychiatry. 2012; 2: e185
        • Lopez J.P.
        • Fiori L.M.
        • Cruceanu C.
        • Lin R.
        • Labonte B.
        • Cates H.M.
        • et al.
        microRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes.
        Nat Commun. 2017; 8: 15497
        • Mendes-Silva A.P.
        • Diniz B.S.
        • Tolentino Araújo G.T.
        • de Souza Nicolau E.
        • Pereira K.S.
        • Silva Ferreira C.M.
        • Barroso L.S.
        Mirnas and their role in the correlation between major depressive disorder, mild cognitive impairment and Alzheimer’s disease.
        Alzheimer’s Dement. 2017; 13: P1017-P1018
        • Vickers K.C.
        • Palmisano B.T.
        • Shoucri B.M.
        • Shamburek R.D.
        • Remaley A.T.
        microRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins.
        Nat Cell Biol. 2011; 13: 423-433
        • Hu G.
        • Drescher K.M.
        • Chen X.M.
        Exosomal miRNAs: Biological properties and therapeutic potential.
        Front Genet. 2012; 3: 56
        • Hoye M.L.
        • Regan M.R.
        • Jensen L.A.
        • Lake A.M.
        • Reddy L.V.
        • Vidensky S.
        • et al.
        Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis.
        Brain. 2018; 141: 2561-2575
        • Belzeaux R.
        • Lin R.
        • Turecki G.
        Potential use of microRNA for monitoring therapeutic response to antidepressants.
        CNS Drugs. 2017; 31: 253-262
        • Torres-Berrío A.
        • Morgunova A.
        • Flores C.
        Adolescent levels of circulating miR-218 predict susceptibility to chronic social defeat stress in adult mice. Presented at the annual meeting of the Society for Neuroscience, November 3–7, San Diego.
        (Accessed November 7, 2018)
        • Scott K.M.
        • McLaughlin K.A.
        • Smith D.A.R.
        • Ellis P.M.
        Childhood maltreatment and DSM-IV adult mental disorders: Comparison of prospective and retrospective findings.
        Br J Psychiatry. 2012; 200: 469-475
        • Cattaneo A.
        • Cattane N.
        • Malpighi C.
        • Czamara D.
        • Suarez A.
        • Mariani N.
        • et al.
        FoxO1, A2M, and TGF-β1: Three novel genes predicting depression in gene × environment interactions are identified using cross-species and cross-tissues transcriptomic and miRNomic analyses.
        Mol Psychiatry. 2018; 23: 2192-2208
        • Yetnikoff L.
        • Pokinko M.
        • Arvanitogiannis A.
        • Flores C.
        Adolescence: A time of transition for the phenotype of dcc heterozygous mice.
        Psychopharmacology (Berl). 2014; 231: 1705-1714
        • Yetnikoff L.
        • Almey A.
        • Arvanitogiannis A.
        • Flores C.
        Abolition of the behavioral phenotype of adult netrin-1 receptor deficient mice by exposure to amphetamine during the juvenile period.
        Psychopharmacology (Berl). 2011; 217: 505-514
        • Amare A.T.
        • Vaez A.
        • Hsu Y.-H.
        • Direk N.
        • Kamali Z.
        • Howard D.M.
        • et al.
        Bivariate genome–wide association analyses of the broad depression phenotype combined with major depressive disorder, bipolar disorder or schizophrenia reveal eight novel genetic loci for depression.
        Mol Psychiatry. 2020; 25: 1420-1429
        • Howard D.M.
        • Adams M.J.
        • Clarke T.-K.
        • Hafferty J.D.
        • Gibson J.
        • Shirali M.
        • et al.
        Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.
        Nat Neurosci. 2019; 22: 343-352