Stress and BDNF Signal Transduction: Implications for Stress-Related Psychiatric Disorders

  • Shigeru Morinobu
  • Masashi Nibuya
  • Ronald S. Duman


It is well known that stress is a major risk factor for psychiatric disorders, such as major depression and posttraumatic stress disorder (PTSD). These illnesses can have some common symptoms, such as psychogenic amnesia, diminished interest, and impaired concentration, suggesting that the underlying pathophysiology of depression and PTSD may have common features (Friedman and Yehuda 1995). Clinical studies have provided support for this possibility. Brain imaging studies have demonstrated that the volume of the hippocampus is decreased in patients with major depression (Sheline et al. 1996) or patients with PTSD (Bremner et al. 1995). These findings suggest that atrophy or death of neurons in the hippocampus may contribute to the pathogenesis of depression and PTSD. In support of this hypothesis, basic research studies have demonstrated that chronic stress causes atrophy or, in extreme cases, death of hippocampal neurons in rats and nonhuman primates.


Nerve Growth Factor Brain Derive Neurotrophic Factor Posttraumatic Stress Disorder Chronic Restraint Stress Brain Derive Neurotrophic Factor Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Berzaghi MP, Cooper J, Castren E, Zafra F, Sofroniew M, Thoenen H, Lindholm D (1993) Cholinergic regulation of brain-derived neurotrophic factor (BDNF) but not neurotrophin-3 (NT-3) mRNA levels in the developing rat hippocampus. J Neurosci 13: 3818–3826Google Scholar
  2. Bremner JD, Randall P, Scott T, Bronen RA, Seibyl JP, Southwick SM, Delaney RC, McCarthy G, Charney DS, Innis RB (1995) MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry 152: 973–981PubMedGoogle Scholar
  3. Condorelli DF, DellAlbani PD, Mudö G, Timmusk T, Belluardo N (1994) Expression of neurotrophins and their receptors in primary astroglial culture: induction by cyclic AMP-elevating agents. J Neurochem 63: 509–516PubMedCrossRefGoogle Scholar
  4. Friedman MJ, Yehuda R (1995) Post-traumatic stress disorder and comorbidity. In: Friedman MJ, Charney DS, Deutch AY (eds) Neurobiology and clinical consequences of stress. Lippincott-Raven, Philadelphia, pp 429–445Google Scholar
  5. Glass DJ, Yancopoulos GD (1993) The neurotrophins and their receptors. Trends Cell Biol 3: 262–268PubMedCrossRefGoogle Scholar
  6. Hosoda K, Duman RS (1993) Regulation of ß-adrenergic receptor mRNA and ligand binding by antidepressant treatments and norepinephrine depletion in rat frontal cortex. J Neurochem 60: 1335–1343PubMedCrossRefGoogle Scholar
  7. Hyman C, Juhasz M, Jackson C, Wright P, Ip NY, Lindsay RM (1994) Overlapping and distinct actions of the neurotrophins BDNF, NT-3, and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon. J Neurosci 14:335– 347Google Scholar
  8. Maisonpierre PC, Belluscio L, Squinto S, Ip NY, Furth ME, Lindsay RM, Yancopoulos GD (1990) Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science 247: 1446–1451PubMedCrossRefGoogle Scholar
  9. Mamounas LA, Blue ME, Siuciak J A, Altar CA (1995) Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J Neurosci 15: 7929–7939PubMedGoogle Scholar
  10. Martin-Iverson MT, Todd KG, Altar CA (1994) Brain-derived neurotrophic factor and neurotrophin-3 activate striatal dopamine and serotonin metabolism and related behaviors: interactions with amphetamine. J Neurosci 14: 1262–1270PubMedGoogle Scholar
  11. Nestler RJ, Terwilliger RZ, Duman RS (1989) Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem 53: 1644–1647PubMedCrossRefGoogle Scholar
  12. Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and TrkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15: 7539–7547PubMedGoogle Scholar
  13. Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein ( CREB) in rat hippocampus. J Neurosci 16: 2365–2372Google Scholar
  14. Phillips HS, Heins JM, Winslow JW (1990) Widespread expression of BDNF but not NT-3 by target areas of basal forebrain cholinergic neurons. Science 250: 2914–2919Google Scholar
  15. Sapolsky RM, Uno H, Robert CS, Finsh CE (1990) Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J Neurosci 10: 2897–2902PubMedGoogle Scholar
  16. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW (1996) Hippocampal atrophy in recurrent major depression. Proc Natl Sci USA 93: 3908–3913CrossRefGoogle Scholar
  17. Siuciak JA, Lewis D, Wiegand SJ, Lindsay RM (1994) Brain derived neurotrophic factor ( BDNF) produces an anti-depressant like effect in two animal models of depression. Soc Neurosci Abstr 20: 1106Google Scholar
  18. 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: 1768–1777PubMedGoogle Scholar
  19. Uno H, Tarara R, Else JG, Suleman MA, Sapolsky RM (1989) Hippocampal damage associated with prolonged and fatal stress in primates. J Neurosci 9: 1705–1711PubMedGoogle Scholar
  20. Watanabe Y, Gould E, McEwen BS (1992) Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 588: 341–345PubMedCrossRefGoogle Scholar
  21. Wooley CS, Gould E, McEwen BS (1990) Exposure to excess glucocorticoid alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 588:341– 345Google Scholar
  22. Zafra F, Hengerer B, Thoenen H, Lindholm D (1990) Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO 11: 3545–3550Google Scholar
  23. Zafra F, Castren E, Thoenen H, Lindholm D (1991) Interplay between glutamate and y-aminobutyric acid transmitter systems in the physiological regulation of brain–derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc Natl Acad Sci USA 88: 10037–10041PubMedCrossRefGoogle Scholar
  24. Zafra F, Lindholm D, Castren E, Hartikka J, Thoenen H (1992) Regulation of brain–derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. J Neurosci 12: 4793–4799PubMedGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 1998

Authors and Affiliations

  • Shigeru Morinobu
    • 1
  • Masashi Nibuya
    • 2
  • Ronald S. Duman
    • 3
  1. 1.Department of NeuropsychiatryYamagata University School of MedicineYamagataJapan
  2. 2.Department of PsychiatryJichi Medical School School of MedicineMinamikawachi, Kawachi, TochigiJapan
  3. 3.Division of Molecular Psychiatry, Department of PsychiatryYale University School of MedicineNew HavenUSA

Personalised recommendations