Molecular Neurobiology

, Volume 56, Issue 12, pp 8323–8335 | Cite as

Physical Exercise and Neuroinflammation in Major Depressive Disorder

  • Zuleide M. IgnácioEmail author
  • Renato S. da Silva
  • Marcos E. Plissari
  • João Quevedo
  • Gislaine Z. Réus


Major depressive disorder (MDD) is a prevalent psychiatric disorder associated with varied prognosis, chronic course, and duration of illness with reduced quality of life. One factor that significantly contributes to the relevant disease burden of MDD is the heterogeneous treatment response patients experience with current treatment options. A variety of experimental protocols in humans and animals have highlighted that inflammation and neuroinflammation are relevant biological factors that interact with external stimuli and neurophysiological mechanisms, and can trigger MDD. It is well established that exercise is efficacious in treating mild to moderate depression with response rates comparable to mainstream therapies such as antidepressant medication and cognitive behavioral therapy. Several studies have shown that physical exercise is beneficial for a range of chronic diseases. Indeed, physical exercise can promote molecular changes that swerve a chronic pro-inflammatory state to an anti-inflammatory state in both periphery and central nervous system. The changes caused by physical exercise include an increase in PGC1α gene expression, a transcriptional co-activator involved in reducing the synthesis and releasing of pro-inflammatory cytokines, and an increase in anti-inflammatory cytokines. PGC1α changes the metabolism of kynurenine towards, and, in turn, it reduces glutamatergic neurotoxicity. Moreover, some studies have shown that physical exercise promotes alterations in the circuitry of monoaminergic neurotransmission, at least in some aspects, through the effects on the release of proinflammatory cytokines. This review will highlight the effects of physical exercise as therapy and its relation with the biological mechanisms involved in the pathophysiology of MDD, with particular emphasis in the interactions among physical exercise, hypothalamic-pituitary-adrenal (HPA) axis, neuroinflammation, and with the neurotransmitters underlying the main brain circuits involved in the MDD.


Exercise Neuroinflammation Neuroprotection Major depressive disorder 


Funding Information

The Translational Psychiatry Program (USA) is funded by the Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth). Translational Psychiatry Laboratory (Brazil) is one of the members of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). Its research is supported by grants from CNPq (JQ and GZR), FAPESC (ZMI, JQ, and GZR), Instituto Cérebro e Mente (JQ and GZR), and UNESC (JQ and GZR). JQ is a 1A CNPq Research Fellow.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Daly EJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Gaynes BN, Warden D, Morris DW, Luther JF et al (2010) Health-related quality of life in depression: a STAR*D report. Ann Clin Psychiatry 22(1):43–55PubMedPubMedCentralGoogle Scholar
  2. 2.
    Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, Thase ME, Winokur A et al (2018) Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 75(2):139–148CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    World Health Organization (2017) Depression and other common mental disorders: global health estimates. World Health Organization,
  4. 4.
    Hasler G, Drevets WC, Manji HK, Charney DS (2004) Discovering endophenotypes for major depression. Neuropsychopharmacology 29(10):1765–1781CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, Sanislow C, Wang P (2010) Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 167(7):748–751CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Friedman ES, Davis LL, Zisook S, Wisniewski SR, Trivedi MH, Fava M, Rush AJ, CO-MED Study Team (2012) Baseline depression severity as a predictor of single and combination antidepressant treatment outcome: results from the CO-MED trial. Eur Neuropsychopharmacol 22(3):183–199CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Rush AJ, Wisniewski SR, Zisook S, Fava M, Sung SC, Haley CL, Chan HN, Gilmer WS et al (2012) Is prior course of illness relevant to acute or longer-term outcomes in depressed out-patients? A STAR*D report. Psychol Med 42(6):1131–1149CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Trivedi MH, Morris DW, Pan JY, Grannemann BD, John Rush A (2005) What moderator characteristics are associated with better prognosis for depression? Neuropsychiatr Dis Treat 1(1):51–57CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Friedman ES, Wisniewski SR, Gilmer W, Nierenberg AA, Rush AJ, Fava M, Zisook S, Balasubramani GK et al (2009) Sociodemographic, clinical, and treatment characteristics associated with worsened depression during treatment with citalopram: results of the NIMH STAR(*)D trial. Depress Anxiety 26(7):612–621CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zhang K, Zhu Y, Zhu Y, Wu S, Liu H, Zhang W, Xu C, Zhang H et al (2016) Molecular, functional, and structural imaging of major depressive disorder. Neurosci Bull 32(3):273–285CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Clark M, Di Benedetti D, Perez V (2016) Cognitive dysfunction and work productivity in major depressive disorder. Expert Rev Pharmacoecon Outcomes Res 16(4):455–463CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hammar A, Sørensen L, Ardal G, Oedegaard KJ, Kroken R, Roness A, Lund A (2010) Enduring cognitive dysfunction in unipolar major depression: a test-retest study using the Stroop paradigm. Scand J Psychol 51(4):304–308PubMedPubMedCentralGoogle Scholar
  13. 13.
    Rethorst CD, South CC, Rush AJ, Greer TL, Trivedi MH (2017) Prediction of treatment outcomes to exercise in patients with nonremitted major depressive disorder. Depress Anxiety 34(12):1116–1122CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Thase ME, Haight BR, Richard N, Rockett CB, Mitton M, Modell JG, VanMeter S, Harriett AE et al (2005) Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. J Clin Psychiatry 66:974–981CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hasselbalch BJ, Knorr U, Kessing LV (2011) Cognitive impairment in the remitted state of unipolar depressive disorder: a systematic review. J Affect Disord 134(1–3):20–31CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Al-Sukhni M, Maruschak NA, McIntyre RS (2015) Vortioxetine: a review of efficacy, safety and tolerability with a focus on cognitive symptoms in major depressive disorder. Expert Opin Drug Saf 14(8):1291–1304CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Sun L, Sun Q, Qi J (2017) Adult hippocampal neurogenesis: an important target associated with antidepressant effects of exercise. Rev Neurosci 28(7):693–703CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gourgouvelis J, Yielder P, Murphy B (2017) Exercise promotes neuroplasticity in both healthy and depressed brains: an fMRI pilot study. Neural Plast 2017:8305287CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Babyak M, Blumenthal JA, Herman S, Khatri P, Doraiswamy M, Moore K, Craighead WE, Baldewicz TT et al (2000) Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 62(5):633–638CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Stathopoulou G, Powers MB, Berry AC, Smits JAJ, Otto MW (2006) Exercise interventions for mental health: a quantitative and qualitative review. Clin Psychol Sci Pract 13(2):179–193CrossRefGoogle Scholar
  21. 21.
    Blumenthal JA, Babyak MA, Doraiswamy PM, Watkins L, Hoffman BM, Barbour KA, Herman S, Craighead WE et al (2007) Exercise and pharmacotherapy in the treatment of major depressive disorder. Psychosom Med 69(7):587–596CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Schuch FB, Vancampfort D, Rosenbaum S, Richards J, Ward PB, Veronese N, Solmi M, Cadore EL et al (2016) Exercise for depression in older adults: a meta-analysis of randomized controlled trials adjusting for publication bias. Braz J Psychiatry 38(3):247–254CrossRefGoogle Scholar
  23. 23.
    Phillips C, Fahimi A (2018) Immune and neuroprotective effects of physical activity on the brain in depression. Front Neurosci 12:498CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Barha CK, Galea LA, Nagamatsu LS, Erickson KI, Liu-Ambrose T (2017) Personalising exercise recommendations for brain health: considerations and future directions. Br J Sports Med 51(8):636–639CrossRefGoogle Scholar
  25. 25.
    Dinan TG (2009) Inflammatory markers in depression. Curr Opin Psychiatry 22(1):32–36CrossRefGoogle Scholar
  26. 26.
    Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67(5):446–457CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gómez-Lázaro E, Arregi A, Beitia G, Vegas O, Azpiroz A, G armendia L (2011) Individual differences in chronically defeated male mice: behavioral, endocrine, immune, and neurotrophic changes as markers of vulnerability to the effects of stress. Stress 14(5):537–548CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lu Y, Ho CS, Liu X, Chua AN, Wang W, McIntyre RS, Ho RC (2017) Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression. PLoS One 12(10):e0186700CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, Rebusi N, Heshmati M et al (2014) Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci U S A 111(45):16136–16141CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Slavich GM, Irwin MR (2014) From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull 140(3):774–815CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Frank MG, Weber MD, Watkins LR, Maier SF (2015) Stress sounds the alarmin: the role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming. Brain Behav Immun 48:1–7CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Joshi PC, Benerjee S (2018) Effects of glucocorticoids in depression: role of astrocytes. AIMS Neuroscience 5(3):200–210CrossRefGoogle Scholar
  34. 34.
    Gądek-Michalska A, Tadeusz J, Rachwalska P, Bugajski J (2013) Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems. Pharmacol Rep 65(6):1655–1662CrossRefGoogle Scholar
  35. 35.
    Tsigos C, Chrousos GP (1994) Physiology of the hypothalamic-pituitary-adrenal axis in health and dysregulation in psychiatric and autoimmune disorders. Endocrinol Metab Clin N Am 23:451–466CrossRefGoogle Scholar
  36. 36.
    Chrousos GP (2009) Stress and disorders of the stress system. Nat Rev Endocrinol 5(7):374–381CrossRefGoogle Scholar
  37. 37.
    Sapolsky RM, Romero LM, Munck AU (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21(1):55–89PubMedPubMedCentralGoogle Scholar
  38. 38.
    Silverman MN, Deuster PA (2014) Biological mechanisms underlying the role of physical fitness in health and resilience. Interface Focus 4(5):20140040CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Dhabhar FS (2009) Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation 16(5):300–317CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Rohleder N (2012) Acute and chronic stress induced changes in sensitivity of peripheral inflammatory pathways to the signals of multiple stress systems --2011 Curt Richter award winner. Psychoneuroendocrinology 37(3):307–316CrossRefGoogle Scholar
  41. 41.
    Liang S, Wu X, Hu X, Wang T, Jin F (2018) Recognizing depression from the microbiota-gut-brain axis. Int J Mol Sci 19(6):E1592CrossRefGoogle Scholar
  42. 42.
    Liu CH, Zhang GZ, Li B, Li M, Woelfer M, Walter M, Wang L (2019) Role of inflammation in depression relapse. J Neuroinflammation 16(1):90CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15(3 Pt 1):1768–1777CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Besedovsky HO, del Rey A (1992) Immune-neuroendocrine circuits: integrative role of cytokines. Front Neuroendocrinol 13:61–94PubMedGoogle Scholar
  45. 45.
    Girotti M, Donegan JJ, Morilak DA (2013) Influence of hypothalamic IL-6/gp130 receptor signaling on the HPA axis response to chronic stress. Psychoneuroendocrinology 38(7):1158–1169CrossRefGoogle Scholar
  46. 46.
    Lamers F, Vogelzangs N, Merikangas KR, de Jonge P, Beekman AT, Penninx BW (2013) Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry 18(6):692–699CrossRefGoogle Scholar
  47. 47.
    Carvalho LA, Juruena MF, Papadopoulos AS, Poon L, Kerwin R, Cleare AJ, Pariante CM (2008) Clomipramine in vitro reduces glucocorticoid receptor function in healthy subjects but not in patients with major depression. Neuropsychopharmacology 33(13):3182–3189CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Pariante CM (2017) Why are depressed patients inflamed? A reflection on 20 years of research on depression, glucocorticoid resistance and inflammation. Eur Neuropsychopharmacol 27(6):554–559CrossRefGoogle Scholar
  49. 49.
    Wu T, Huang Y, Gong Y, Xu Y, Lu J, Sheng H, Ni X (2019) Treadmill exercise ameliorates depression-like behavior in the rats with prenatal dexamethasone exposure: the role of hippocampal mitochondria. Front Neurosci 13:264CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Ignácio ZM, Réus GZ, Quevedo J, Kalinichev M, Francis D (2017) Maternal deprivation. Reference module in neuroscience and biobehavioral psychology. Elsevier, ISBN 9780128093245Google Scholar
  51. 51.
    Fischer R, Maier O (2015) Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxidative Med Cell Longev 2015:610813CrossRefGoogle Scholar
  52. 52.
    Tugyan K, Uysal N, Ozdemir D, Sonmez U, Pekcetin C, Erbil G, Sonmez A (2006) Protective effect of melatonin against maternal deprivation-induced acute hippocampal damage in infant rats. Neurosci Lett 398(1–2):145–150CrossRefGoogle Scholar
  53. 53.
    Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15:300–312CrossRefGoogle Scholar
  54. 54.
    Yirmiya R, Rimmerman N, Reshef R (2015) Depression as a microglial disease. Trends Neurosci 38(10):637–658CrossRefGoogle Scholar
  55. 55.
    Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91(2):461–553CrossRefGoogle Scholar
  56. 56.
    Bayer TA, Buslei R, Havas L, Falkai P (1999) Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci Lett 271(2):126–128CrossRefGoogle Scholar
  57. 57.
    Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, Suridjan I, Kennedy JL et al (2015) Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry 72(3):268–275CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Réus GZ, Jansen K, Titus S, Carvalho AF, Gabbay V, Quevedo J (2015) Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: evidences from animal and human studies. J Psychiatr Res 68:316–328CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Réus GZ, Silva RH, de Moura AB, Presa JF, Abelaira HM, Abatti M, Vieira A, Pescador B et al (2018) Early maternal deprivation induces microglial activation, alters glial fibrillary acidic protein immunoreactivity and Indoleamine 2,3-dioxygenase during the development of offspring rats. Mol Neurobiol 56:1096–1108. CrossRefPubMedGoogle Scholar
  60. 60.
    Vina J, Sanchis-Gomar F, Martinez-Bello V, Gomez-Cabrera MC (2012) Exercise acts as a drug; the pharmacological benefits of exercise. Br J Pharmacol 167(1):1–12CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Pescatello LS, Riebe D, Arena R (2014) American College of Sports Medicine. ACSM’s Guidelines for Exercise Testing and Prescription, 9th ed. Baltimore (MD): Lippincott Williams & Wilkins.Google Scholar
  62. 62.
    Caldarone E, Severi P, Lombardi M, D'Emidio S, Mazza A, Bendini MG, Leggio M (2017) Hypertensive response to exercise and exercise training in hypertension: odd couple no more. Clin Hypertens 23:11CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    AminiLari Z, Fararouei M, Amanat S, Sinaei E, Dianatinasab S, AminiLari M, Daneshi N, Dianatinasab M (2017) The effect of 12 weeks aerobic, resistance, and combined exercises on Omentin-1 levels and insulin resistance among type 2 diabetic middle-aged women. Diabetes Metab J 41(3):205–212CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Li CL, Chiu YC, Bai YB, Lin JD, Stanaway F, Chang HY (2017) The co-occurrence of depressive symptoms and cognitive impairment and its relationship with self-care behaviors among community dwelling older adults with diabetes. Diabetes Res Clin Pract 129:73–78CrossRefGoogle Scholar
  65. 65.
    Morris JK, Vidoni ED, Johnson DK, Van Sciver A, Mahnken JD, Honea RA, Wilkins HM, Brooks WM et al (2017) Aerobic exercise for Alzheimer's disease: a randomized controlled pilot trial. PLoS One 12(2):e0170547CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Mandsager K, Harb S, Cremer P, Phelan D, Nissen SE, Jaber W (2018) Association of cardiorespiratory fitness with long-term mortality among adults undergoing exercise treadmill testing. JAMA Netw Open 1(6):e183605CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Willis BL, Leonard D, Barlow CE, Martin SB, DeFina LF, Trivedi MH (2018) Association of midlife cardiorespiratory fitness with incident depression and cardiovascular death after depression in later life. JAMA Psychiatry 75(9):911–917CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Deslandes A, Moraes H, Ferreira C, Veiga H, Silveira H, Mouta R, Pompeu FA, Coutinho ES et al (2009) Exercise and mental health: many reasons to move. Neuropsychobiology 59(4):191–198CrossRefGoogle Scholar
  69. 69.
    Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE (2013) Exercise for depression. Cochrane Database Syst Rev 9:CD004366Google Scholar
  70. 70.
    Carneiro LS, Fonseca AM, Vieira-Coelho MA, Mota MP, Vasconcelos-Raposo J (2015) Effects of structured exercise and pharmacotherapy vs. pharmacotherapy for adults with depressive symptoms: a randomized clinical trial. J Psychiatr Res 71:48–55CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Kerling A, Kück M, Tegtbur U, Grams L, Weber-Spickschen S, Hanke A, Stubbs B, Kahl KG (2017) Exercise increases serum brain-derived neurotrophic factor in patients with major depressive disorder. J Affect Disord 215:152–155CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Choi KW, Chen CY, Stein MB, Klimentidis YC, Wang MJ, Koenen KC, Smoller JW (2019) Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Assessment of bidirectional relationships between physical activity and depression among adults: a 2-sample Mendelian randomization study. JAMA Psychiatry 76:399. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Alkadhi KA (2018) Exercise as a positive modulator of brain function. Mol Neurobiol 55(4):3112–3130CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Olson RL, Brush CJ, Ehmann PJ, Alderman BL (2017) A randomized trial of aerobic exercise on cognitive control in major depression. Clin Neurophysiol 128(6):903–913CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Andrade A, Steffens RAK, Vilarino GT, Sieczkowska SM, Coimbra DR (2017) Does volume of physical exercise have an effect on depression in patients with fibromyalgia? J Affect Disord 208:214–217CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Vancampfort D, Rosenbaum S, Schuch F, Ward PB, Richards J, Mugisha J, Probst M, Stubbs B (2017) Cardiorespiratory fitness in severe mental illness: a systematic review and meta-analysis. Sports Med 47(2):343–352CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Walker ER, McGee RE, Druss BG (2015) Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis. JAMA Psychiatry 72(4):334–341CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Gordon BR, McDowell CP, Hallgren M, Meyer JD, Lyons M, Herring MP (2018) Association of Efficacy of resistance exercise training with depressive symptoms: meta-analysis and meta-regression analysis of randomized clinical trials. JAMA Psychiatry 75(6):566–576CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Deuster PA, Chrousos GP, Luger A, DeBolt JE, Bernier LL, Trostmann UH, Kyle SB, Montgomery LC et al (1989) Hormonal and metabolic responses of untrained, moderately trained, and highly trained men to three exercise intensities. Metabolism 38:141–148CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Singh A, Petrides JS, Gold PW, Chrousos GP, Deuster PA (1999) Differential hypothalamic–pituitary– adrenal axis reactivity to psychological and physical stress. J Clin Endocrinol Metab 84:1944–1948PubMedPubMedCentralGoogle Scholar
  81. 81.
    Singh A, Zelazowska EB, Petrides JS, Raybourne RB, Sternberg EM, Gold PW, Deuster PA (1996) Lymphocyte subset responses to exercise and glucocorticoid suppression in healthy men. Med Sci Sports Exerc 28:822–828CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Aguiar AS Jr, Araújo AL, da-Cunha TR, Speck AE, Ignácio ZM, De-Mello N, Prediger RD (2009) Physical exercise improves motor and short-term social memory deficits in reserpinized rats. Brain Res Bull 79(6):452–457CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Rethorst CD, Greer TL, Toups MS, Bernstein I, Carmody TJ, Trivedi MH (2015) IL-1β and BDNF are associated with improvement in hypersomnia but not insomnia following exercise in major depressive disorder. Transl Psychiatry 5:e611CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Meyer JD, Koltyn KF, Stegner AJ, Kim JS, Cook DB (2016) Relationships between serum BDNF and the antidepressant effect of acute exercise in depressed women. Psychoneuroendocrinology 74:286–294CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Gómez-Galán M, Femenía T, Åberg E, Graae L, Van Eeckhaut A, Smolders I, Brené S, Lindskog M (2016) Running opposes the effects of social isolation on synaptic plasticity and transmission in a rat model of depression. PLoS One 11(10):e0165071CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Lin TW, Kuo YM (2013) Exercise benefits brain function: the monoamine connection. Brain Sci 3(1):39–53CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Klempin F, Beis D, Mosienko V, Kempermann G, Bader M, Alenina N (2013) Serotonin is required for exercise-induced adult hippocampal neurogenesis. J Neurosci 33(19):8270–8275CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Cunha MP, Oliveira Á, Pazini FL, Machado DG, Bettio LE, Budni J, Aguiar AS Jr, Martins DF et al (2013) The antidepressant-like effect of physical activity on a voluntary running wheel. Med Sci Sports Exerc 45(5):851–859CrossRefGoogle Scholar
  89. 89.
    Nicastro TM, Greenwood BN (2016) Central monoaminergic systems are a site of convergence of signals conveying the experience of exercise to brain circuits involved in cognition and emotional behavior. Curr Zool 62(3):293–306CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Greenwood BN, Fleshner M (2008) Exercise, learned helplessness, and the stress-resistant brain. NeuroMolecular Med 10(2):81–98CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Sciolino NR, Holmes PV (2012) Exercise offers anxiolytic potential: a role for stress and brain noradrenergic-galaninergic mechanisms. Neurosci Biobehav Rev 36(9):1965–1984CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Sarbadhikari SN, Saha AK (2006) Moderate exercise and chronic stress produce counteractive effects on different areas of the brain by acting through various neurotransmitter receptor subtypes: a hypothesis. Theor Biol Med Model 3:33CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Greenwood BN (2018) The role of dopamine in overcoming aversion with exercise. Brain Res 1713:102–108. CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Cassilhas RC, Lee KS, Fernandes J, Oliveira MG, Tufik S, Meeusen R, de Mello MT (2012) Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms. Neuroscience 202:309–317CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Fernandes J, Arida RM (2016) Does resistance exercise exert a role in hippocampal neurogenesis? J Physiol 594(22):6799CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Nokia MS, Lensu S, Ahtiainen JP, Johansson PP, Koch LG, Britton SL, Kainulainen H (2016) Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained. J Physiol 594(7):1855–1873CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Novaes Gomes FG, Fernandes J, Vannucci Campos D, Cassilhas RC, Viana GM, D'Almeida V, de Moraes Rêgo MK, Buainain PI et al (2014) The beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling is impaired by anabolic androgenic steroids. Psychoneuroendocrinology. 50:106–117CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Handschin C, Spiegelman BM (2008) The role of exercise and PGC1alpha in inflammation and chronic disease. Nature 454(7203):463–469CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Bremmer MA, Beekman ATF, Deeg DJH, Penninx BWJH, Dik MG, Hack CE, Hoogendijk WJG (2008) Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord 106(3):249–255CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Réus GZ, Fries GR, Stertz L, Badawy M, Passos IC, Barichello T, Kapczinski F, Quevedo J (2015) The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience 300:141–154CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Paolucci EM, Loukov D, Bowdish DME, Heisz JJ (2018) Exercise reduces depression and inflammation but intensity matters. Biol Psychol 133:79–84CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Korsager LM, Matchkov VV (2016) Hypertension and physical exercise: the role of oxidative stress. Medicina (Kaunas) 52(1):19–27CrossRefGoogle Scholar
  104. 104.
    Rethorst CD, Toups MS, Greer TL, Nakonezny PA, Carmody TJ, Grannemann BD, Huebinger RM, Barber RC et al (2013) Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder. Mol Psychiatry 18(10):1119–1124CrossRefGoogle Scholar
  105. 105.
    Maes M, Kubera M, Obuchowiczwa E, Goehler L, Brzeszcz J (2011) Depression's multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways. Neuro Endocrinol Lett 32(1):7–24PubMedPubMedCentralGoogle Scholar
  106. 106.
    Pedersen BK (2009) The diseasome of physical inactivity--and the role of myokines in muscle--fat cross talk. J Physiol 587(Pt 23):5559–5568CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Pedersen BK, Fischer CP (2007) Beneficial health effects of exercise--the role of IL-6 as a myokine. Trends Pharmacol Sci 28(4):152–156CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Petersen AM, Pedersen BK (2005) The anti-inflammatory effect of exercise. J Appl Physiol (1985) 98(4):1154–1162CrossRefGoogle Scholar
  109. 109.
    Ruas JL, White JP, Rao RR, Kleiner S, Brannan KT, Harrison BC, Greene NP, Wu J et al (2012) A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 151(6):1319–1331CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Villena JA (2015) New insights into PGC-1 coactivators: redefining their role in the regulation of mitochondrial function and beyond. FEBS J 282(4):647–672CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Jodeiri Farshbaf M, Ghaedi K, Megraw TL, Curtiss J, Shirani Faradonbeh M, Vaziri P, Nasr-Esfahani MH (2016) Does PGC1α/FNDC5/BDNF elicit the beneficial effects of exercise on neurodegenerative disorders? NeuroMolecular Med 18(1):1–15CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Handschin C, Choi CS, Chin S, Kim S, Kawamori D, Kurpad AJ, Neubauer N, Hu J et al (2007) Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk. J Clin Invest 117(11):3463–3474CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Valle I, Alvarez-Barrientos A, Arza E, Lamas S, Monsalve M (2005) PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc Res 66(3):562–573CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, Handschin C, Zheng K et al (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127(2):397–408CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Ji LL (2008) Modulation of skeletal muscle antioxidant defense by exercise: role of redox signaling. Free Radic Biol Med 44(2):142–152CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O (2012) Oxidative stress and antioxidant defense. World Allergy Organ J 5(1):9–19CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Agudelo LZ, Femenía T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, Correia JC, Izadi M et al (2014) Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159(1):33–45CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Cervenka I, Agudelo LZ, Ruas JL (2017) Kynurenines: tryptophan’s metabolites in exercise, inflammation, and mental health. Science 357(6349):eaaf9794CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Erhardt S, Olsson SK, Engberg G (2009) Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders. CNS Drugs 23(2):91–101CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Bay-Richter C, Linderholm KR, Lim CK, Samuelsson M, Träskman-Bendz L, Guillemin GJ, Erhardt S, Brundin L (2015) A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. Brain Behav Immun 43:110–117CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Savitz J, Drevets WC, Smith CM, Victor TA, Wurfel BE, Bellgowan PS, Bodurka J, Teague TK et al (2015) Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder. Neuropsychopharmacology 40(2):463–471CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Schlittler M, Goiny M, Agudelo LZ, Venckunas T, Brazaitis M, Skurvydas A, Kamandulis S, Ruas JL et al (2016) Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans. Am J Physiol Cell Physiol 310(10):C836–C840CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Schwieler L, Samuelsson M, Frye MA, Bhat M, Schuppe-Koistinen I, Jungholm O, Johansson AG, Landén M et al (2016) Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients. J Neuroinflammation 13(1):51CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Valente-Silva P, Ruas JL (2017) Tryptophan-kynurenine metabolites in exercise and mental health. In: Spiegelman B (ed) Hormones, metabolism and the benefits of exercise. Research and Perspectives in Endocrine Interactions. Springer, ChamGoogle Scholar
  125. 125.
    Hutton CP, Déry N, Rosa E, Lemon JA, Rollo CD, Boreham DR, Fahnestock M, de Catanzaro D et al (2015) Synergistic effects of diet and exercise on hippocampal function in chronically stressed mice. Neuroscience 308:180–193CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Zheng H, Liu Y, Li W, Yang B, Chen D, Wang X, Jiang Z, Wang H et al (2006) Beneficial effects of exercise and its molecular mechanisms on depression in rats. Behav Brain Res 168(1):47–55CrossRefGoogle Scholar
  127. 127.
    Brockett AT, LaMarca EA, Gould E (2015) Physical exercise enhances cognitive flexibility as well as astrocytic and synaptic markers in the medial prefrontal cortex. PLoS One 10(5):e0124859CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Brambilla D, Franciosi S, Opp MR, Imeri L (2007) Interleukin-1 inhibits firing of serotonergic neurons in the dorsal raphe nucleus and enhances GABAergic inhibitory post-synaptic potentials. Eur J Neurosci 26(7):1862–1869CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Haase J, Brown E (2015) Integrating the monoamine, neurotrophin and cytokine hypotheses of depression-a central role for the serotonin transporter? Pharmacol Ther 147:1–11CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Kiank C, Zeden JP, Drude S, Domanska G, Fusch G, Otten W, Schuett C (2010) Psychological stress-induced, IDO1-dependent tryptophan catabolism: implications on immunosuppression in mice and humans. PLoS One 5(7):e11825CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Phillips C (2017) Physical activity modulates common neuroplasticity substrates in major depressive and bipolar disorder. Neural Plast 2017:7014146PubMedPubMedCentralGoogle Scholar
  132. 132.
    Li HB, Huo CJ, Su Q, Li X, Bai J, Zhu GQ, Kang YM (2018) Exercise training attenuates proinflammatory cytokines, oxidative stress and modulates neurotransmitters in the rostral ventrolateral medulla of salt-induced hypertensive rats. Cell Physiol Biochem 48(3):1369–1381CrossRefGoogle Scholar
  133. 133.
    Feinstein DL, Heneka MT, Gavrilyuk V, Dello Russo C, Weinberg G, Galea E (2002) Noradrenergic regulation of inflammatory gene expression in brain. Neurochem Int 41(5):357–365CrossRefGoogle Scholar
  134. 134.
    Mori K, Ozaki E, Zhang B, Yang L, Yokoyama A, Takeda I, Maeda N, Sakanaka M et al (2002) Effects of norepinephrine on rat cultured microglial cells that express alpha1, alpha2, beta1 and beta2 adrenergic receptors. Neuropharmacology 43(6):1026–1034CrossRefGoogle Scholar
  135. 135.
    Wu SY, Wang TF, Yu L, Jen CJ, Chuang JI, Wu FS, Wu CW, Kuo YM (2011) Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway. Brain Behav Immun 25(1):135–146CrossRefGoogle Scholar
  136. 136.
    Nestler EJ, Carlezon WA Jr (2006) The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 59:1151–1159CrossRefGoogle Scholar
  137. 137.
    Rajkowska G, Miguel-Hidalgo JJ (2007) Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 6(3):219–233CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory of Physiology, Pharmacology and PsychopathologyFederal University of Southern FrontierChapecóBrazil
  2. 2.Laboratory of Translational PsychiatryUniversity of Southern Santa CatarinaCriciúmaBrazil
  3. 3.Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical SchoolThe University of Texas Health Science Center at Houston (UTHealth)HoustonUSA
  4. 4.Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical SchoolThe University of Texas Health Science Center at Houston (UTHealth)HoustonUSA
  5. 5.Neuroscience Graduate Program, Graduate School of Biomedical SciencesThe University of Texas Health Science Center at Houston (UTHealth)HoustonUSA

Personalised recommendations