, Volume 14, Issue 3, pp 677–686 | Cite as

Neural Substrates of Depression and Resilience



There is an urgent need for more effective medications to treat major depressive disorder, as fewer than half of depressed patients achieve full remission and many are not responsive with currently available antidepressant medications or psychotherapy. It is known that prolonged stressful events are an important risk factor for major depressive disorder. However, there are prominent individual variations in response to stress: a relatively small proportion of people (10–20%) experiencing prolonged stress develop stress-related psychiatric disorders, including depression (susceptibility to stress), whereas most stress-exposed individuals maintain normal psychological functioning (resilience to stress). There have been growing efforts to investigate the neural basis of susceptibility versus resilience to depression. An accumulating body of evidence is revealing the genetic, epigenetic, and neurophysiological mechanisms that underlie stress susceptibility, as well as the active mechanisms that underlie the resilience phenotype. In this review, we discuss, mainly based on our own work, key pathological mechanisms of susceptibility that are identified as potential therapeutic targets for depression treatment. We also review novel mechanisms that promote natural resilience as an alternative strategy to achieve treatment efficacy. These studies are opening new avenues to develop conceptually novel therapeutic strategies for depression treatment.


Major depressive disorder Depression susceptibility Resilience Prefrontal cortex Nucleus accumbens Ventral tegmental area 



This work was supported by grants from the National Institute of Mental Health (M.H.H., R21MH112081; E.J.N., R01MH051399, P50MH096890), the National Institute of Alcohol Abuse and Alcoholism (M.H.H., R01AA022445), the Brain and Behavior Research Foundation (M.H.H., NARSAD), and the Hope for Depression Research Foundation (E.J.N.).

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  1. 1.
    Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994;51:8-19.CrossRefPubMedGoogle Scholar
  2. 2.
    Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002;34:13-25.CrossRefPubMedGoogle Scholar
  3. 3.
    Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 2006;7:137-151.CrossRefPubMedGoogle Scholar
  4. 4.
    Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008;455:894-902.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ferrari AJ, Charlson FJ, Norman RE, et al. The epidemiological modelling of major depressive disorder: application for the Global Burden of Disease Study 2010. PLOS ONE 2013;8:e69637.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ferrari AJ, Charlson FJ, Norman RE, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLOS Med 2013;10:e1001547.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Nestler EJ, Carlezon WA, Jr. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 2006;59:1151-1159.CrossRefPubMedGoogle Scholar
  8. 8.
    Nestler EJ, Gould E, Manji H. Preclinical models: status of basic research in depression. Biol Psychiatry 2002;52:503-528.CrossRefPubMedGoogle Scholar
  9. 9.
    Toseeb U, Brage S, Corder K, et al. Exercise and depressive symptoms in adolescents: a longitudinal cohort study. JAMA Pediatr 2014;168:1093-1100.CrossRefPubMedGoogle Scholar
  10. 10.
    Southwick SM, Vythilingam M, Charney DS. The psychobiology of depression and resilience to stress: implications for prevention and treatment. Annu Rev Clin Psychol 2005;1:255-291.CrossRefPubMedGoogle Scholar
  11. 11.
    Charney DS, Manji HK. Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci STKE 2004;2004:re5.Google Scholar
  12. 12.
    Yehuda R, Flory JD, Southwick S, Charney DS. Developing an agenda for translational studies of resilience and vulnerability following trauma exposure. Ann N Y Acad Sci 2006;1071:379-396.CrossRefPubMedGoogle Scholar
  13. 13.
    Yehuda R. Risk and resilience in posttraumatic stress disorder. J Clin Psychiatry 2004;65:29-36.PubMedGoogle Scholar
  14. 14.
    Krishnan V, Han MH, Graham DL, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 2007;131:391-404.CrossRefPubMedGoogle Scholar
  15. 15.
    Atkinson PA, Martin CR, Rankin J. Resilience revisited. J Psychiatric Ment Health Nurs 2009;16:137-145.CrossRefGoogle Scholar
  16. 16.
    Krishnan V, Han MH, Mazei-Robison M, et al. AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli. Biol Psychiatry 2008;64:691-700.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Cao JL, Covington HE, 3rd, Friedman AK, et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J Neurosci 2010;30:16453-16458.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Chaudhury D, Walsh JJ, Friedman AK, et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 2013;493:532-536.CrossRefPubMedGoogle Scholar
  19. 19.
    Walsh JJ, Friedman AK, Sun H, et al. Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nat Neurosci 2014;17:27-29.CrossRefPubMedGoogle Scholar
  20. 20.
    Friedman AK, Walsh JJ, Juarez B, et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science 2014;344:313-319.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Friedman AK, Juarez B, Ku SM, et al. KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun 2016;7:11671.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Dias C, Feng J, Sun H, et al. beta-catenin mediates stress resilience through Dicer1/microRNA regulation. Nature 2014;516:51-55.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Golden SA, Covington HE, 3rd, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc 2011;6:1183-1191.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bagot RC, Cates HM, Purushothaman I, et al. Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility. Neuron 2016;90:969-983.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry 1997;54:597-606.CrossRefPubMedGoogle Scholar
  26. 26.
    Bejjani BP, Damier P, Arnulf I, et al. Transient acute depression induced by high-frequency deep-brain stimulation. N Engl J Med 1999;340:1476-1480.CrossRefPubMedGoogle Scholar
  27. 27.
    Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47:351-354.CrossRefPubMedGoogle Scholar
  28. 28.
    Niciu MJ, Henter ID, Luckenbaugh DA, Zarate CA, Jr., Charney DS. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds. Annu Rev Pharmacol Toxicol 2014;54:119-139.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Covington HE, 3rd, Lobo MK, Maze I, et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci 2010;30:16082-16090.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tye KM, Mirzabekov JJ, Warden MR, et al. Dopamine neurons modulate neural encoding and expression of depressionrelated behaviour. Nature 2013;493:537-541.CrossRefPubMedGoogle Scholar
  31. 31.
    Wook Koo J, Labonte B, Engmann O, et al. Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress-induced depressive behaviors. Biol Psychiatry 2016;80:469-478.CrossRefPubMedGoogle Scholar
  32. 32.
    Bagot RC, Parise EM, Pena CJ, et al. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nat Commun 2015;6:7062.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Willner P. The mesolimbic dopamine system as a target for rapid antidepressant action. Int Clin Psychopharmacol 1997;12(Suppl. 3):S7-S14.CrossRefPubMedGoogle Scholar
  34. 34.
    Zhang H, Chaudhury D, Juarez B, et al. Role of locus coeruleus-ventral tegmental area circuit in mediating the resilience to social stress. Neuropsychopharmacology 2015;2015:S237-S238.Google Scholar
  35. 35.
    Krishnan V, Nestler EJ. Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 2010;167:1305-1320.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Monteggia LM, Barrot M, Powell CM, et al. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci U S A 2004;101:10827-10832.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 2006;9:519-525.CrossRefPubMedGoogle Scholar
  38. 38.
    Monteggia LM, Luikart B, Barrot M, et al. Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol Psychiatry 2007;61:187-197.CrossRefPubMedGoogle Scholar
  39. 39.
    Schmidt HD, Duman RS. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol 2007;18:391-418.CrossRefPubMedGoogle Scholar
  40. 40.
    Eisch AJ, Bolanos CA, de Wit J, et al. Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression. Biol Psychiatry 2003;54:994-1005.CrossRefPubMedGoogle Scholar
  41. 41.
    Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006;59:1116-1127.CrossRefPubMedGoogle Scholar
  42. 42.
    Grace AA, Floresco SB, Goto Y, Lodge DJ. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci 2007;30:220-227.CrossRefPubMedGoogle Scholar
  43. 43.
    Lammel S, Ion DI, Roeper J, Malenka RC. Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron 2011;70:855-862.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Koo JW, Mazei-Robison MS, Chaudhury D, et al. BDNF is a negative modulator of morphine action. Science 2012; 338:124-128.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Wanat MJ, Bonci A, Phillips PE. CRF acts in the midbrain to attenuate accumbens dopamine release to rewards but not their predictors. Nat Neurosci 2013;16:383-385.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Vialou V, Feng J, Robison AJ, Nestler EJ. Epigenetic mechanisms of depression and antidepressant action. Annu Rev Pharmacol Toxicol 2013;53:59-87.CrossRefPubMedGoogle Scholar
  47. 47.
    Covington HE, 3rd, Maze I, LaPlant QC, et al. Antidepressant actions of histone deacetylase inhibitors. J Neurosci 2009;29:11451-11460.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Covington HE, 3rd, Vialou VF, LaPlant Q, Ohnishi YN, Nestler EJ. Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition. Neurosci Lett 2011;493:122-126.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Covington HE, 3rd, Maze I, Vialou V, Nestler EJ. Antidepressant action of HDAC inhibition in the prefrontal cortex. Neuroscience 2015;298:329-335.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Schroeder FA, Lin CL, Crusio WE, Akbarian S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol Psychiatry 2007;62:55-64.CrossRefPubMedGoogle Scholar
  51. 51.
    Sun H, Damez-Werno DM, Scobie KN, et al. ACF chromatin-remodeling complex mediates stress-induced depressive-like behavior. Nat Med 2015;21:1146-1153.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Covington HE, 3rd, Maze I, Sun H, et al. A role for repressive histone methylation in cocaine-induced vulnerability to stress. Neuron 2011;71:656-670.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Southwick SM, Charney DS. Resilience: The Science of Mastering Life's Greatest Challenges: Cambridge University Press. 2012.Google Scholar
  54. 54.
    Feder A, Nestler EJ, Charney DS. Psychobiology and molecular genetics of resilience. Nat Rev Neurosci 2009;10:446-457.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Russo SJ, Murrough JW, Han MH, Charney DS, Nestler EJ. Neurobiology of resilience. Nat Neurosci 2012;15:1475-1484.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Korte SM, Koolhaas JM, Wingfield JC, McEwen BS. The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease. Neurosci Biobehav Rev 2005;29:3-38.CrossRefPubMedGoogle Scholar
  57. 57.
    Lu A, Steiner MA, Whittle N, et al. Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior. Mol Psychiatry 2008;13:1028-1042.CrossRefPubMedGoogle Scholar
  58. 58.
    Vythilingam M, Nelson EE, Scaramozza M, et al. Reward circuitry in resilience to severe trauma: an fMRI investigation of resilient special forces soldiers. Psychiatry Res 2009;172:75-77.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Moore H, Rose HJ, Grace AA. Chronic cold stress reduces the spontaneous activity of ventral tegmental dopamine neurons. Neuropsychopharmacology 2001;24:410-419.CrossRefPubMedGoogle Scholar
  60. 60.
    Anstrom KK, Miczek KA, Budygin EA. Increased phasic dopamine signaling in the mesolimbic pathway during social defeat in rats. Neuroscience 2009;161:3-12.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Razzoli M, Andreoli M, Michielin F, Quarta D, Sokal DM. Increased phasic activity of VTA dopamine neurons in mice 3 weeks after repeated social defeat. Behav Brain Res 2011;218:253-257.CrossRefPubMedGoogle Scholar
  62. 62.
    Valenti O, Gill KM, Grace AA. Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: response alteration by stress preexposure. Eur J Neurosci 2012;35:1312-1321.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Chang CH, Grace AA. Amygdala-ventral pallidum pathway decreases dopamine activity after chronic mild stress in rats. Biol Psychiatry 2014;76:223-230.CrossRefPubMedGoogle Scholar
  64. 64.
    Greenberg GD, Steinman MQ, Doig IE, Hao R, Trainor BC. Effects of social defeat on dopamine neurons in the ventral tegmental area in male and female California mice. Eur J Neurosci 2015;42:3081-3094.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Walsh JJ, Han MH. The heterogeneity of ventral tegmental area neurons: projection functions in a mood-related context. Neuroscience 2014;282C:101-108.CrossRefGoogle Scholar
  66. 66.
    van Dam NT, Kautz M, Friedman AK, et al. Potassium channel modulator ezogabine decreases symptomatology and increases reward response in depression. Annual Meeting of Society of Biological Psychiatry; 2016 SOBP Abstracts In press; Atlanta, Georgia.Google Scholar
  67. 67.
    Krystal JH, Neumeister A. Noradrenergic and serotonergic mechanisms in the neurobiology of posttraumatic stress disorder and resilience. Brain Res 2009;1293:13-23.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Charney DS. Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry 2004;161:195-216.CrossRefPubMedGoogle Scholar
  69. 69.
    Valentino RJ, Van Bockstaele E. Endogenous opioids: the downside of opposing stress. Neurobiol Stress 2015;1:23-32.CrossRefPubMedGoogle Scholar
  70. 70.
    Valentino RJ, Foote SL, Page ME. The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses. Ann N Y Acad Sci 1993;697:173-188.CrossRefPubMedGoogle Scholar
  71. 71.
    Koob GF. Corticotropin-releasing factor, norepinephrine, and stress. Biol Psychiatry 1999;46:1167-1180.CrossRefPubMedGoogle Scholar
  72. 72.
    Nestler EJ, Alreja M, Aghajanian GK. Molecular control of locus coeruleus neurotransmission. Biol Psychiatry 1999;46:1131-1139.CrossRefPubMedGoogle Scholar
  73. 73.
    Reyes BA, Bangasser DA, Valentino RJ, Van Bockstaele EJ. Using high resolution imaging to determine trafficking of corticotropin-releasing factor receptors in noradrenergic neurons of the rat locus coeruleus. Life Sci 2014;112:2-9.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Bingham B, McFadden K, Zhang X, Bhatnagar S, Beck S, Valentino R. Early adolescence as a critical window during which social stress distinctly alters behavior and brain norepinephrine activity. Neuropsychopharmacology 2011;36:896-909.CrossRefPubMedGoogle Scholar
  75. 75.
    McCall JG, Al-Hasani R, Siuda ER, et al. CRH Engagement of the locus coeruleus noradrenergic system mediates stress induced anxiety. Neuron 2015;87:605-620.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Nestler EJ, Aghajanian GK. Molecular and cellular basis of addiction. Science 1997;278:58-63.CrossRefPubMedGoogle Scholar
  77. 77.
    Hermans EJ, van Marle HJ, Ossewaarde L, et al. Stress-related noradrenergic activity prompts large-scale neural network reconfiguration. Science 2011;334:1151-1153.CrossRefPubMedGoogle Scholar
  78. 78.
    Paladini CA, Williams JT. Noradrenergic inhibition of midbrain dopamine neurons. J Neurosci 2004;24:4568-4575.CrossRefPubMedGoogle Scholar
  79. 79.
    Arencibia-Albite F, Paladini C, Williams JT, Jimenez-Rivera CA. Noradrenergic modulation of the hyperpolarization-activated cation current (Ih) in dopamine neurons of the ventral tegmental area. Neuroscience 2007;149:303-314.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 2009;10:211-223.CrossRefPubMedGoogle Scholar
  81. 81.
    Isingrini E, Perret L, Rainer Q, et al. Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons. Nat Neurosci 2016;19:560-563.CrossRefPubMedGoogle Scholar
  82. 82.
    Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci 2011;12:623-637.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Nestler EJ. FosB: a transcriptional regulator of stress and antidepressant responses. Eur J Pharmacol 2015;753:66-72.CrossRefPubMedGoogle Scholar
  84. 84.
    Vialou V, Robison AJ, Laplant QC, et al. DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat Neurosci 2010;13:745-752.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Lobo MK, Zaman S, Damez-Werno DM, et al. DeltaFosB induction in striatal medium spiny neuron subtypes in response to chronic pharmacological, emotional, and optogenetic stimuli. J Neurosci 2013;33:18381-18395.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Vialou V, Maze I, Renthal W, et al. Serum response factor promotes resilience to chronic social stress through the induction of DeltaFosB. J Neurosci 2010;30:14585-14592.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Wilkinson MB, Dias C, Magida J, et al. A novel role of the WNT-dishevelled-GSK3beta signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. J Neurosci 2011;31:9084-9092.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Vialou V, Bagot RC, Cahill ME, et al. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of DeltaFosB. J Neurosci 2014;34:3878-3887.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  1. 1.Department of Pharmacological Sciences and Institute for Systems BiomedicineIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Fishberg Department of Neuroscience and Friedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkUSA

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