Metabolic Brain Disease

, Volume 24, Issue 4, pp 587–597 | Cite as

Exercise increases BDNF levels in the striatum and decreases depressive-like behavior in chronically stressed rats

  • Lelanie Marais
  • Dan J. Stein
  • Willie M. U. Daniels
Original Paper Original Article


Early life stress in humans can affect the development of neurons and neurotransmitter systems and predispose an individual to the subsequent development of depression. Similarly, in rats, maternal separation causes anxiety and depressive-like behavior and decreased corticosterone levels. Patients receiving pharmacological treatment for depression often experience negative side-effects or do not respond optimally and therefore the use of exercise as alternative antidepressant treatment is investigated. The aim of the study was to see whether rats subjected to both early life stress and chronic stress later in life show differences in depressive-like behavior, neurotrophin levels, stress hormone levels and antioxidant capacity of serum after chronic voluntary exercise as treatment. Rat pups were maternally separated and one group were allowed access to running wheels for 6 weeks while control rats were also handled and put in cages without running wheels. All rats were subjected to chronic restraint stress during adulthood. A forced swim test was done to test for depressive-like behavior. Neurotrophins were measured in the ventral hippocampus and striatum; baseline stress hormones were measured in blood plasma as well as the anti-oxidative potential of serum. Compared to controls, rats that exercised had no difference in baseline stress hormones, but had decreased immobility times in the forced swim test, increased brain derived neurotrophic factor (BDNF) levels in the striatum and decreased anti-oxidative potential of their serum. The mechanism by which depressive-like behavior was improved may have been mediated through increased striatal BDNF levels, resulting in increased neuroplasticity and the prevention of neuronal death.


Maternal separation Animal models of depression Brain derived neurotrophic factor Exercise 


  1. Blier P, De Montigny C, Chaput Y (1987) Modifications of the serotonin system by antidepressant treatments: implications for the therapeutic response in major depression. J. Clin. Psychopharmacol. 7:24S–35SCrossRefPubMedGoogle Scholar
  2. Béquet F, Gomez-Merino D, Berthelot M, Guezennec CY (2001) Exercise-induced changes in brain glucose and serotonin revealed by microdialysis in rat hippocampus: effect of glucose supplementation. Acta Physiol Scand 173:223–230CrossRefPubMedGoogle Scholar
  3. Borer KT, Bestervelt LL, Mannheim M, Brosamer MB, Thompson M, Swamy U, Piper WN (1992) Stimulation by voluntary exercise of adrenal glucocorticoid secretion in mature female hamsters. Physiol Behav 51:713–718CrossRefPubMedGoogle Scholar
  4. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000) Hippocampal volume reduction in major depression. Am J Psychiatry 157:115–118CrossRefPubMedGoogle Scholar
  5. Chen MJ, Russo-Neustadt AA (2005) Exercise activates the phosphatidylinositol 3-kinase pathway. Mol. Brain Res. 135:181–193CrossRefPubMedGoogle Scholar
  6. Craft LL (2005) Exercise and clinical depression: examining two psychological mechanisms. Psychol. Sport Exerc. 6:151–171CrossRefGoogle Scholar
  7. Daley A (2008) Exercise and Depression: A review of reviews. J. Clin. Psychol. Med. Settings 15:140–147CrossRefPubMedGoogle Scholar
  8. Davies KJ, Quintanilha AT, Brooks GA, Packer L (1982) Free radicals and tissue damage produced by exercise. Biochem Biophys Res Commun 107:1198–205CrossRefPubMedGoogle Scholar
  9. Dimeo F, Bauer M, Varahram I, Proest G, Halter U (2001) Benefits from aerobic exercise in patients with major depression: a pilot study. Br J Sports Med 35:114–117CrossRefPubMedGoogle Scholar
  10. Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME (1997) Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386:824–827CrossRefPubMedGoogle Scholar
  11. Duman RS (2002) Pathophysiology of depression: the concept of synaptic plasticity. Eur. Psychiatry 17(suppl 3):306–310CrossRefPubMedGoogle Scholar
  12. Duman CH, Schlesinger L, Russell DS, Duman RS (2008) Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice. Brain Res 1199:148–158PubMedGoogle Scholar
  13. Duman CH, Schlesinger L, Terwilliger R, Russell DS, Newton SS, Duman RS (2009) Peripheral insulin-like growth factor-I produces antidepressant-like behavior and contributes to the effect of exercise. Behav Brain Res 198:366–371CrossRefPubMedGoogle Scholar
  14. El Khoury A, Gruber SHM, Mork A, Mathe AA (2006) Adult life behavioral consequences of early maternal separation are alleviated by escitalopram treatment in a rat model of depression. Prog Neuropsychopharmacol Biol Psychiatry 30:533–540Google Scholar
  15. Engesser-Cesar C, Anderson AJ, Cotman CW (2007) Wheel running and fluoxetine antidepressant treatment have differential effects in the hippocampus and the spinal cord. Neuroscience 144:1033–1044CrossRefPubMedGoogle Scholar
  16. Fabricius K, Wörtwein G, Pakkenberg B (2008) The impact of maternal separation on adult mouse behaviour and on the total neuron number in the mouse hippocampus. Brain Struct. Funct. 212:403–416CrossRefPubMedGoogle Scholar
  17. Fava M, Davison KG (1996) Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 19:179–200CrossRefPubMedGoogle Scholar
  18. Ferris LT, Williams JS, Shen C-L (2007) The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function. Med Sci Sports Exerc 39:728–34CrossRefPubMedGoogle Scholar
  19. Gilmer WS, McKinney WT (2003) Early experience and depressive disorders: human and non-human primate studies. J. Affect. Disord. 75:97–113CrossRefPubMedGoogle Scholar
  20. Gomez-Merino D, Béquet F, Berthelot M, Chennaoui M, Guezennec CY (2001) Site-dependant effects of an acute intensive exercise on extracellular 5-HT and 5-HIAA levels in rat brain. Neurosci Lett 301:143–146CrossRefPubMedGoogle Scholar
  21. Gould E, Tanapat P, Rydel T, Hastings N (2000) Regulation of hippocampal neurogenesis in adulthood. Biol Psychiatry 48:715–720CrossRefPubMedGoogle Scholar
  22. Griesbach GS, Hovda DA, Gomez-Pinilla F, Sutton RL (2008) Voluntary exercise or amphetamine treatment, but not the combination, increases hippocampal brain-derived neurotrophic for and synapsin 1 following cortical contusion injury in rats. Neuroscience 154:530–540CrossRefPubMedGoogle Scholar
  23. Hall FS, Sundstrom JM, Lerner J, Pert A (2001) Enhanced corticosterone release after a modified forced swim test in Fawn hooded rats is independent of rearing experience. Pharmacol Biochem Behav 69:629–634CrossRefPubMedGoogle Scholar
  24. Henningan A, O’Callaghan RM, Kelly AM (2007) Neurotrophins and their receptors: roles in plasticity, neurodegeneration and neuroprotection. Biochem Soc Trans 35:424–427CrossRefGoogle Scholar
  25. Hu XH, Bull SA, Hunkeler EM, Ming E, Lee JY, Fireman B, Markson LE (2004) Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J. Clin. Psychiatry 65:959–65PubMedGoogle Scholar
  26. Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642CrossRefPubMedGoogle Scholar
  27. Husain MM, McDonald WM, Doraiswamy PM, Figiel GS, Na C, Escalona PR, Boyko OB, Nemeroff CB, Krishnan KR (1991) A magnetic resonance imaging study of putamen nuclei in major depression. Psychiatry Res 40:95–99CrossRefPubMedGoogle Scholar
  28. Johnson RA, Rhodes JS, Jeffrey SL, Garland T, Mitchell GS (2003) Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running. Neuroscience 121:1–7CrossRefPubMedGoogle Scholar
  29. Kelly K, Posternak M, Alpert JE (2008) Toward achieving optimal response: understand and managing antidepressant side effects. Dialogues Clin. Neurosci. 10:409–418PubMedGoogle Scholar
  30. Kendler KS, Karkowski LM, Prescott CA (1999) Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 156:837–841PubMedGoogle Scholar
  31. Krishnan KR, McDonald WM, Escalona PR, Doraiswamy PM, Na C, Husain MM, Figiel GS, Boyko OB, Ellinwood EH, Nemeroff CB (1992) Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations. Arch Gen Psychiatry 49:553–557PubMedGoogle Scholar
  32. Kuma H, Miki T, Matsumoto Y, Gu H, Li H, Kusaka T, Satriotomo I, Okamoto H, Yokoyama T, Bedi K, Onishi S, Suwaki H, Takeuchi Y (2004) Early maternal deprivation induces alterations in brain-derived neurotrophic factor expression in the developing rat hippocampus. Neurosci Lett 372:68–73CrossRefPubMedGoogle Scholar
  33. Lee HJ, Kim JW, Yim SV, Kim MJ, Kim SA, Kim YJ, Kim CJ, Chung JH (2001) Fluoxetine enhances cell proliferation and prevents apoptosis in dentate gyrus of maternally separated rats. Mol. Psychiatry 6:725–728CrossRefGoogle Scholar
  34. Lou S, Liu J, Chang H, Chen P (2008) Hippocampal neurogenesis and gene expression depend on exercise intensity in juvenile rats. Brain Res 1210:48–55CrossRefPubMedGoogle Scholar
  35. Manni L, Micera A, Pistillo L, Aloe L (1998) Neonatal handling in EAE-susceptible rats alters NGF levels and mast cell distribution in the brain. Int J Dev Neurosci 16:1–8CrossRefPubMedGoogle Scholar
  36. Marais L, van Rensburg SJ, van Zyl JM, Stein DJ, Daniels WM (2008) Maternal separation of rat pups increases the risk of developing depressive-like behavior after subsequent chronic stress by altering corticosterone and neurotrophin levels in the hippocampus. Neurosci Res 61:106–112CrossRefPubMedGoogle Scholar
  37. Mattson MP, Maudsley S, Martin B (2004) BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27:589–594CrossRefPubMedGoogle Scholar
  38. Mattson MP, Novell MA, Furukawa K, Markesbery WR (1995) Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of [Ca2+] and neurotoxicity, and increase antioxidant enzyme activities in hippocampal neurons. J. Neurochem. 65:1740–1751PubMedCrossRefGoogle Scholar
  39. McEwen B (2000) Effects of adverse experiences for brain structure and function. Biol Psychiatry 48:766–777CrossRefGoogle Scholar
  40. Min YK, Chung SH, Lee JS, Kim SS, Shin HD, Lim BV, Shin MC, Jang MH, Kim EH, Kim CJ (2003) Red ginseng inhibits exercise-induced increase in 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in dorsal raphe of rats. J. Pharmacol. Sci. 93:218–221CrossRefPubMedGoogle Scholar
  41. Mirescu C, Peters JD, Gould E (2004) Early life experience alters response of adult neurogenesis to stress. Nat Neurosci 7:841–846CrossRefPubMedGoogle Scholar
  42. Ogonovsky H, Berkes I, Kumagai S, Kaneko T, Tahara S, Goto S, Radák Z (2005) The effects of moderate-, strenuous- and over-training on oxidative stress markers, DNA repair and memory, in rat brain. Neurochem Int 46:635–640CrossRefGoogle Scholar
  43. Paykel ES (2001) Stress and affective disorders in humans. Semin. Clin. Neuropsychiatry 6:4–11CrossRefPubMedGoogle Scholar
  44. Toldy A, Stadler K, Sasvari M, Jakus J, Jung KJ, Chung HY, Berkes I, Nyakas C, Radak Z (2005) The effect of exercise and nettle supplementation on oxidative stress markers in the rat brain. Brain Res Bull 65:487–493CrossRefPubMedGoogle Scholar
  45. Trivedi MH, Grannemann BD, Chambliss HO, Jordan AN (2006) Exercise as and augmentation strategy for treatment of major depression. J. Psychiatr. Pract. 12:205–213CrossRefPubMedGoogle Scholar
  46. Radak Z, Chung HY, Goto S (2005) Exercise and hormesis: oxidative stress-related adaptation for successful aging. Biogerontol. 6:71–75CrossRefGoogle Scholar
  47. Radak Z, Toldy A, Szabo Z, Siamilis S, Nyakas C, Silye G, Jakus J, Goto S (2006) The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain. Neurochem Int 49:387–392CrossRefPubMedGoogle Scholar
  48. Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW (2000) Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 101:305–312CrossRefPubMedGoogle Scholar
  49. Russo-Neustadt A, Ha T, Ramirez R, Kesslak JP (2001) Physical activity-antidepressant treatment combination: impact on brain-derived neurotrophic factor and behaviour in and animal model. Behav Brain Res 120:87–95CrossRefPubMedGoogle Scholar
  50. Sapolsky RM (1985a) A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults. J. Neurosci 5:1228–1232PubMedGoogle Scholar
  51. Sapolsky RM (1985b) Glucocorticoid toxicity in the hippocampus: temporal aspects of neuronal vulnerability. Brain Res 359:300–305CrossRefPubMedGoogle Scholar
  52. Sapolsky RM, Krey LC, McEwen BC (1985) Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J. Neurosci. 5:1222–1227PubMedGoogle Scholar
  53. Sheline Y, Sanghavi M, Mintun M, Gado M (1999) Depression duration but not age predicts hippocampal volume loss in women with recurrent major depression. J. Neurosci. 19:5034–5043PubMedGoogle Scholar
  54. Shirayama Y, Chen ACH, Duman RS (2000) Antidepressant-like effects of BDNF and NT-3 in behavioral models of depression. Abstr. Soc, Neurosci 26Google Scholar
  55. Siucak JA, Lewis DR, Wiegand SR, Lindsay R (1996) Antidepressant-like effects of brain derived neurotrophic factor (BDNF). Pharmcol. Biochem. Behav. 56:131–137CrossRefGoogle Scholar
  56. Soya H, Nakamura T, Deocaris CC, Kimpara A, Iimura M, Fujikawa T, Chang H, McEwen BS, Nishijima T (2007) BDNF induction with mild exercise in the rat hippocampus. Biochem Biophys Res Commun 358:961–967CrossRefPubMedGoogle Scholar
  57. Van Rensburg S, Van Zyl JM, Potocnik FC, Daniels WM, Uys J, Marais L, Hon D, Van der Walt BJ, Erasmus RT (2006) The effect of stress on the antioxidative potential of serum: implications for Alzheimer's disease. Metab Brain Dis 21:171–9CrossRefPubMedGoogle Scholar
  58. Vaynman S, Ying Z, Gomez-Pinilla F (2003) Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience 122:647–657CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Lelanie Marais
    • 1
  • Dan J. Stein
    • 2
  • Willie M. U. Daniels
    • 3
  1. 1.Division of Medical PhysiologyStellenbosch UniversityTygerbergSouth Africa
  2. 2.Department of PsychiatryUniversity of Cape TownCape TownSouth Africa
  3. 3.Discipline of Human PhysiologyUniversity of Kwazulu-NatalDurbanSouth Africa

Personalised recommendations