Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Expert Review
  • Published:

Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders

Abstract

Brain-derived neurotrophic factor (BDNF) is widely accepted for its involvement in resilience and antidepressant drug action, is a common genetic locus of risk for mental illnesses, and remains one of the most prominently studied molecules within psychiatry. Stress, which arguably remains the “lowest common denominator” risk factor for several mental illnesses, targets BDNF in disease-implicated brain regions and circuits. Altered stress-related responses have also been observed in animal models of BDNF deficiency in vivo, and BDNF is a common downstream intermediary for environmental factors that potentiate anxiety- and depressive-like behavior. However, BDNF’s broad functionality has manifested a heterogeneous literature; likely reflecting that BDNF plays a hitherto under-recognized multifactorial role as both a regulator and target of stress hormone signaling within the brain. The role of BDNF in vulnerability to stress and stress-related disorders, such as posttraumatic stress disorder (PTSD), is a prominent example where inconsistent effects have emerged across numerous models, labs, and disciplines. In the current review we provide a contemporary update on the neurobiology of BDNF including new data from the behavioral neuroscience and neuropsychiatry literature on fear memory consolidation and extinction, stress, and PTSD. First we present an overview of recent advances in knowledge on the role of BDNF within the fear circuitry, as well as address mounting evidence whereby stress hormones interact with endogenous BDNF-TrkB signaling to alter brain homeostasis. Glucocorticoid signaling also acutely recruits BDNF to enhance the expression of fear memory. We then include observations that the functional common BDNF Val66Met polymorphism modulates stress susceptibility as well as stress-related and stress-inducible neuropsychiatric endophenotypes in both man and mouse. We conclude by proposing a BDNF stress–sensitivity hypothesis, which posits that disruption of endogenous BDNF activity by common factors (such as the BDNF Val66Met variant) potentiates sensitivity to stress and, by extension, vulnerability to stress-inducible illnesses. Thus, BDNF may induce plasticity to deleteriously promote the encoding of fear and trauma but, conversely, also enable adaptive plasticity during extinction learning to suppress PTSD-like fear responses. Ergo regulators of BDNF availability, such as the Val66Met polymorphism, may orchestrate sensitivity to stress, trauma, and risk of stress-induced disorders such as PTSD. Given an increasing interest in personalized psychiatry and clinically complex cases, this model provides a framework from which to experimentally disentangle the causal actions of BDNF in stress responses, which likely interact to potentiate, produce, and impair treatment of, stress-related psychiatric disorders.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The domain structure of BDNF, conservation of the NGF domain across species, and common BDNF coding polymorphisms in humans.
Fig. 2: The early developmental expression profile of BDNF (Bdnf) and TrkB (NTRK2) mRNA expression in the mouse brain.
Fig. 3: Schematic of the interaction of BDNF depletion and glucocorticoid stress hormones on contextual fear.
Fig. 4: Comparative overview of stress-related fear phenotypes in mice and humans.
Fig. 5: Schematic of the BDNF stress–sensitivity hypothesis proposed here per the preexisting and conjoint BDNF and stress literature.

Similar content being viewed by others

References

  1. Van der Kolk BA. The psychobiology of posttraumatic stress disorder. J Clin Psychiatry. 1997;58:16–24.

    Article  PubMed  Google Scholar 

  2. Notaras M, Hill R, van den Buuse M. The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy. Mol Psychiatry. 2015;20:916–30.

    Article  CAS  PubMed  Google Scholar 

  3. Notaras M, van den Buuse M. Brain-derived neurotrophic factor (BDNF): novel insights into regulation and genetic variation. Neuroscientist. 2019;25:434–54.

    Article  CAS  PubMed  Google Scholar 

  4. Cardenas-Aguayo M, Kazim S, Grundke-Iqbal I, Iqbal K. Neurogenic and neurotrophic effects of BDNF peptides in mouse hippocampal primary neuronal cell cultures. PloS ONE. 2013;8:e53596.

    Article  CAS  PubMed Central  Google Scholar 

  5. Björkholm C, Monteggia LM. BDNF—a key transducer of antidepressant effects. Neuropharmacology. 2016;102:72–9.

    Article  PubMed  CAS  Google Scholar 

  6. Barde Y-A, Edgar D, Thoenen H. Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1982;1:549–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lou H, Kim S-K, Zaitsev E, Snell CR, Lu B, Loh YP. Sorting and activity-dependent secretion of BDNF require interaction of a specific motif with the sorting receptor carboxypeptidase e. Neuron. 2005;45:245–55.

    Article  CAS  PubMed  Google Scholar 

  8. Minichiello L. TrkB signalling pathways in LTP and learning. Nat Rev Neurosci. 2009;10:850–60.

    Article  CAS  PubMed  Google Scholar 

  9. Mizui T, Ishikawa Y, Kumanogoh H, Lume M, Matsumoto T, Hara T, et al. BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met. Proc Natl Acad Sci USA. 2015;112:E3067–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Anastasia A, Deinhardt K, Chao MV, Will NE, Irmady K, Lee FS, et al. Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction. Nat Commun. 2013;4:2490.

    Article  PubMed  CAS  Google Scholar 

  11. Matsumoto T, Rauskolb S, Polack M, Klose J, Kolbeck R, Korte M, et al. Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci. 2008;11:131–3.

    Article  CAS  PubMed  Google Scholar 

  12. Yang J, Siao C-J, Nagappan G, Marinic T, Jing D, McGrath K, et al. Neuronal release of proBDNF. Nat Neurosci. 2009;12:113–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Hill R, Wu Y, Kwek P, van den Buuse M. Modulatory effects of sex steroid hormones on brain‐derived neurotrophic factor‐tyrosine kinase B expression during adolescent development in C57Bl/6 mice. J Neuroendocrinol. 2012;24:774–88.

    Article  CAS  PubMed  Google Scholar 

  14. Sohrabji F, Miranda RC, Toran-Allerand CD. Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor. Proc Natl Acad Sci USA. 1995;92:11110–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gibbs RB. Levels of trkA and BDNF mRNA, but not NGF mRNA, fluctuate across the estrous cycle and increase in response to acute hormone replacement. Brain Res. 1998;787:259–68.

    Article  CAS  PubMed  Google Scholar 

  16. Altar CA, Cai N, Bliven T, Juhasz M, Conner JM, Acheson AL, et al. Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature. 1997;389:856–60.

    Article  CAS  PubMed  Google Scholar 

  17. Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ. Induction of fear extinction with hippocampal-infralimbic BDNF. Science. 2010;328:1288–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Conner JM, Lauterborn JC, Yan Q, Gall CM, Varon S. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J Neurosci. 1997;17:2295–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sherry ST, Ward M-H, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mou Z, Hyde TM, Lipska BK, Martinowich K, Wei P, Ong C-J, et al. Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus. Cell Rep. 2015;13:1–8.

    Article  CAS  Google Scholar 

  21. Petryshen TL, Sabeti PC, Aldinger KA, Fry B, Fan JB, Schaffner S, et al. Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry. 2009;15:810–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314:140–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112:257–69.

    Article  CAS  PubMed  Google Scholar 

  24. Notaras M, Hill R, van den Buuse M. A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review. Neurosci Biobehav Rev. 2015;51:15–30.

    CAS  PubMed  Google Scholar 

  25. Chen Z-Y, Ieraci A, Teng H, Dall H, Meng C-X, Herrera DG, et al. Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway. J Neurosci. 2005;25:6156–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chiaruttini C, Vicario A, Li Z, Baj G, Braiuca P, Wu Y, et al. Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation. Proc Natl Acad Sci USA. 2009;106:16481–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Guo J, Ji Y, Ding Y, Jiang W, Sun Y, Lu B, et al. BDNF pro-peptide regulates dendritic spines via caspase-3. Cell Death Dis. 2016;7:e2264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kailainathan S, Piers TM, Yi JH, Choi S, Fahey MS, Borger E, et al. Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF). Pharmacol Res. 2016;104:97–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Giza JI, Kim J, Meyer HC, Anastasia A, Dincheva I, Zheng CI, et al. The BDNF Val66Met prodomain disassembles dendritic spines altering fear extinction circuitry and behavior. Neuron. 2018;99:163–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pluchino N, Russo M, Santoro AN, Litta P, Cela V, Genazzani AR. Steroid hormones and BDNF. Neuroscience. 2013;239:271–9.

    Article  CAS  PubMed  Google Scholar 

  31. Hojo Y, Murakami G, Mukai H, Higo S, Hatanaka Y, Ogiue-Ikeda M, et al. Estrogen synthesis in the brain–role in synaptic plasticity and memory. Mol Cell Endocrinol. 2008;290:31–43.

    Article  CAS  PubMed  Google Scholar 

  32. Fester L, Zhou L, Butow A, Huber C, von Lossow R, Prange-Kiel J, et al. Cholesterol-promoted synaptogenesis requires the conversion of cholesterol to estradiol in the hippocampus. Hippocampus. 2009;19:692–705.

    Article  CAS  PubMed  Google Scholar 

  33. Garcia-Segura LM. Aromatase in the brain: not just for reproduction anymore. J Neuroendocrinol. 2008;20:705–12.

    Article  CAS  PubMed  Google Scholar 

  34. Fester L, Prange-Kiel J, Jarry H, Rune GM. Estrogen synthesis in the hippocampus. Cell Tissue Res. 2011;345:285–94.

    Article  CAS  PubMed  Google Scholar 

  35. Foy MR. 17β-estradiol: effect on CA1 hippocampal synaptic plasticity. Neurobiol Learn Mem. 2001;76:239–52.

    Article  CAS  PubMed  Google Scholar 

  36. Parducz A, Perez J, Garcia-Segura L. Estradiol induces plasticity of GABAergic synapses in the hypothalamus. Neuroscience. 1993;53:395–401.

    Article  CAS  PubMed  Google Scholar 

  37. Tang Y, Janssen WGM, Hao J, Roberts JA, McKay H, Lasley B, et al. Estrogen replacement increases spinophilin-immunoreactive spine number in the prefrontal cortex of female rhesus monkeys. Cereb Cortex. 2004;14:215–23.

    Article  PubMed  Google Scholar 

  38. Carbone DL, Handa RJ. Sex and stress hormone influences on the expression and activity of brain-derived neurotrophic factor. Neuroscience. 2013;239:295–303.

    Article  CAS  PubMed  Google Scholar 

  39. Spencer-Segal JL, Tsuda MC, Mattei L, Waters EM, Romeo RD, Milner TA, et al. Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation. Neuroscience. 2012;202:131–46.

    Article  CAS  PubMed  Google Scholar 

  40. Spencer-Segal JL, Waters EM, Bath KG, Chao MV, McEwen BS, Milner TA. Distribution of phosphorylated TrkB receptor in the mouse hippocampal formation depends on sex and estrous cycle stage. J Neurosci. 2011;31:6780–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Caldeira MV, Melo CV, Pereira DB, Carvalho RF, Carvalho AL, Duarte CB. BDNF regulates the expression and traffic of NMDA receptors in cultured hippocampal neurons. Mol Cell Neurosci. 2007;35:208–19.

    Article  CAS  PubMed  Google Scholar 

  42. Smith CC, Vedder LC, McMahon LL. Estradiol and the relationship between dendritic spines, NR2B containing NMDA receptors, and the magnitude of long-term potentiation at hippocampal CA3–CA1 synapses. Psychoneuroendocrinology. 2009;34:S130–S42.

    Article  CAS  PubMed  Google Scholar 

  43. Segal M, Murphy D. Estradiol induces formation of dendritic spines in hippocampal neurons: functional correlates. Horm Behav. 2001;40:156–9.

    Article  CAS  PubMed  Google Scholar 

  44. McEwen BS, Woolley CS. Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain. Exp Gerontol. 1994;29:431–6.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang S, Jonklaas J, Danielsen M. The glucocorticoid agonist activities of mifepristone (RU486) and progesterone are dependent on glucocorticoid receptor levels but not on EC50 values. Steroids. 2007;72:600–8.

    Article  CAS  PubMed  Google Scholar 

  46. Singh M, Su C. Progesterone, brain-derived neurotrophic factor and neuroprotection. Neuroscience. 2013;239:84–91.

    Article  CAS  PubMed  Google Scholar 

  47. Aguirre C, Jayaraman A, Pike C, Baudry M. Progesterone inhibits estrogen‐mediated neuroprotection against excitotoxicity by down‐regulating estrogen receptor‐β. J Neurochem. 2010;115:1277–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Aguirre CC, Baudry M. Progesterone reverses 17β‐estradiol‐mediated neuroprotection and BDNF induction in cultured hippocampal slices. Eur J Neurosci. 2009;29:447–54.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Schroeder A, Notaras M, Du X, Hill R. On the developmental timing of stress: delineating sex-specific effects of stress across development on adult behavior. Brain Sci. 2018;8:121.

    Article  PubMed Central  CAS  Google Scholar 

  50. Miranda RC, Sohrabji F, Toran-Allerand D. Interactions of estrogen with the neurotrophins and their receptors during neural development. Horm Behav. 1994;28:367–75.

    Article  CAS  PubMed  Google Scholar 

  51. Toran-Allerand CD. Mechanisms of estrogen action during neural development: mediation by interactions with the neurotrophins and their receptors? J Steroid Biochem. 1996;56:169–78.

    Article  CAS  Google Scholar 

  52. Fan X, Warner M, Gustafsson JÅ. Estrogen receptor β expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons. Proc Nat Acad Sci. 2006;103:19338–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Orikasa C, McEwen BS, Hayashi H, Sakuma Y, Hayashi S. Estrogen receptor alpha, but not beta, is expressed in the interneurons of the hippocampus in prepubertal rats: an in situ hybridization study. Dev Brain Res. 2000;120:245–54.

    Article  CAS  Google Scholar 

  54. Fan X, Kim HJ, Warner M, Gustafsson JÅ. Estrogen receptor β is essential for sprouting of nociceptive primary afferents and for morphogenesis and maintenance of the dorsal horn interneurons. Proc Nat Acad Sci USA. 2007;104:13696–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Blurton‐Jones M, Tuszynski MH. Estrogen receptor‐beta colocalizes extensively with parvalbumin‐labeled inhibitory neurons in the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized adult rats. J Comp Neurol. 2002;452:276–87.

    Article  PubMed  Google Scholar 

  56. Murphy DD, Cole NB, Greenberger V, Segal M. Estradiol increases dendritic spine density by reducing GABA neurotransmission in hippocampal neurons. J Neurosci. 1998;18:2550–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wu YC, Du X, van den Buuse M, Hill RA. Sex differences in the adolescent developmental trajectory of parvalbumin interneurons in the hippocampus: a role for estradiol. Psychoneuroendocrinology. 2014;45:167–78.

    Article  CAS  PubMed  Google Scholar 

  58. Du X, Serena K, Hwang W, Grech A, Wu Y, Schroeder A, et al. Prefrontal cortical parvalbumin and somatostatin expression and cell density increase during adolescence and are modified by BDNF and sex. Mol Cell Neurosci. 2018;88:177–88.

    Article  CAS  PubMed  Google Scholar 

  59. Schroeder A, Hudson M, Du X, Wu YC, Nakamura J, van den Buuse M, et al. Estradiol and raloxifene modulate hippocampal gamma oscillations during a spatial memory task. Psychoneuroendocrinology. 2017;78:85–92.

    Article  CAS  PubMed  Google Scholar 

  60. Wu YC, Du X, van den Buuse M, Hill R. Analyzing the influence of BDNF heterozygosity on spatial memory response to 17β-estradiol. Transl Psychiatry. 2015;5:e498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Jones NC, Hudson M, Foreman J, Rind G, Hill RA, Manning EE, et al. Brain‐derived neurotrophic factor haploinsufficiency impairs high‐frequency cortical oscillations in mice. Eur J Neurosci. 2018;48:2816–25.

    Article  PubMed  Google Scholar 

  62. Karpova NN, Pickenhagen A, Lindholm J, Tiraboschi E, Kulesskaya N, Ágústsdóttir A, et al. Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science. 2011;334:1731–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Courtin J, Chaudun F, Rozeske RR, Karalis N, Gonzalez-Campo C, Wurtz H, et al. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature. 2014;505:92–6.

    Article  PubMed  CAS  Google Scholar 

  64. Mueller EM, Panitz C, Hermann C, Pizzagalli DA. Prefrontal oscillations during recall of conditioned and extinguished fear in humans. J Neurosci. 2014;34:7059–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Grech AM, Du X, Murray SS, Xiao J, Hill RA. Sex-specific spatial memory deficits in mice with a conditional TrkB deletion on parvalbumin interneurons. Behav Brain Res. 2019;372:111984. in press

    Article  CAS  PubMed  Google Scholar 

  66. Lucas EK, Jegarl A, Clem RL. Mice lacking TrkB in parvalbumin-positive cells exhibit sexually dimorphic behavioral phenotypes. Behav Brain Res. 2014;274:219–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Scharfman HE, MacLusky NJ. Differential regulation of BDNF, synaptic plasticity and sprouting in the hippocampal mossy fiber pathway of male and female rats. Neuropharmacology. 2014;76:696–708.

    Article  CAS  PubMed  Google Scholar 

  68. Monson CM, Shnaider P. Theory underlying trauma-focused interventions. In: Treating PTSD with cognitive-behavioral therapies: interventions that work. Washington: American Psychological Association; 2014.

  69. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:1048–60.

    Article  CAS  PubMed  Google Scholar 

  70. Bountress KE, Bacanu SA, Tomko RL, Korte KJ, Hicks T, Sheerin C, et al. The effects of a BDNF Val66Met polymorphism on posttraumatic stress disorder: a meta-analysis. Neuropsychobiol. 2017;76:136–42.

    Article  CAS  Google Scholar 

  71. Zhang L, Benedek D, Fullerton C, Forsten R, Naifeh J, Li X, et al. PTSD risk is associated with BDNF Val66Met and BDNF overexpression. Mol Psychiatry. 2013;19:8–10.

    Article  PubMed  CAS  Google Scholar 

  72. Felmingham KL, Dobson-Stone C, Schofield PR, Quirk GJ, Bryant RA. The brain-derived neurotrophic factor Val66Met polymorphism predicts response to exposure therapy in posttraumatic stress disorder. Biol Psychiatry. 2013;73:1059–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Boschen MJ, Neumann DL, Waters AM. Relapse of successfully treated anxiety and fear: theoretical issues and recommendations for clinical practice. Aust NZ J Psychiatry. 2009;43:89–100.

    Article  Google Scholar 

  74. Chhatwal JP, Stanek-Rattiner L, Davis M, Ressler KJ. Amygdala BDNF signaling is required for consolidation but not encoding of extinction. Nat Neurosci. 2006;9:870–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Notaras M, Hill R, Gogos J, Van Den Buuse M. BDNF Val66Met genotype determines hippocampus-dependent behavior via sensitivity to glucocorticoid signaling. Mol Psychiatry. 2016;21:730–2.

    Article  CAS  PubMed  Google Scholar 

  76. Cao L, Dhilla A, Mukai J, Blazeski R, Lodovichi C, Mason CA, et al. Genetic modulation of BDNF signaling affects the outcome of axonal competition in vivo. Curr Biol. 2007;17:911–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sakata K, Martinowich K, Woo NH, Schloesser RJ, Jimenez DV, Ji Y, et al. Role of activity-dependent BDNF expression in hippocampal–prefrontal cortical regulation of behavioral perseverance. Proc Natl Acad Sci USA. 2013;110:15103–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mizuno K, Dempster E, Mill J, Giese K. Long‐lasting regulation of hippocampal Bdnf gene transcription after contextual fear conditioning. Genes Brain Behav. 2012;11:651–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lubin FD, Roth TL, Sweatt JD. Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci. 2008;28:10576–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Psotta L, Lessmann V, Endres T. Impaired fear extinction learning in adult heterozygous BDNF knock-out mice. Neurobiol Learn Mem. 2013;103:34–8.

    Article  CAS  PubMed  Google Scholar 

  81. Pattwell SS, Bath KG, Perez-Castro R, Lee FS, Chao MV, Ninan I. The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex. J Neurosci. 2012;32:2410–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS, et al. A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science. 2010;327:863–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Asthana MK, Brunhuber B, Mühlberger A, Reif A, Schneider S, Herrmann MJ. Preventing the return of fear using reconsolidation update mechanisms depends on the met-allele of the brain derived neurotrophic factor Val66Met polymorphism. Int J Neuropsychopharmacol. 2016;19:pyv137.

    PubMed  Google Scholar 

  84. Heldt SA, Stanek L, Chhatwal JP, Ressler KJ. Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry. 2007;12:656–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hoover WB, Vertes RP. Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct Funct. 2007;212:149–79.

    Article  PubMed  Google Scholar 

  86. Rosas-Vidal LE, Do-Monte FH, Sotres-Bayon F, Quirk GJ. Hippocampal–prefrontal BDNF and memory for fear extinction. Neuropsychopharmacology. 2014;39:2161–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Fanselow MS, Dong HW. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron. 2010;65:7–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sakata K, Woo NH, Martinowich K, Greene JS, Schloesser RJ, Shen L, et al. Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex. Proc Natl Acad Sci USA. 2009;106:5942–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Lee JL, Everitt BJ, Thomas KL. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science. 2004;304:839–43.

    Article  CAS  PubMed  Google Scholar 

  90. Radiske A, Rossato JI, Köhler CA, Gonzalez MC, Medina JH, Cammarota M. Requirement for BDNF in the reconsolidation of fear extinction. J Neurosci. 2015;35:6570–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kirtley A, Thomas KL. The exclusive induction of extinction is gated by BDNF. Learn Mem. 2010;17:612–9.

    Article  CAS  PubMed  Google Scholar 

  92. Choi DC, Maguschak KA, Ye K, Jang SW, Myers KM, Ressler KJ. Prelimbic cortical BDNF is required for memory of learned fear but not extinction or innate fear. Proc Natl Acad Sci USA. 2010;107:2675–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, Barad M. Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem. 2007;14:268–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20:6969–78.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Marek R, Xu L, Sullivan RKP, Sah P. Excitatory connections between the prelimbic and infralimbic medial prefrontal cortex show a role for the prelimbic cortex in fear extinction. Nat Neurosci. 2018;21:654–8.

    Article  CAS  PubMed  Google Scholar 

  96. Vasquez JH, Leong KC, Gagliardi CM, Harland B, Apicella AJ, Muzzio IA. Pathway specific activation of ventral hippocampal cells projecting to the prelimbic cortex diminishes fear renewal. Neurobiol Learn Mem. 2019;161:63–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Pitts BL, Whealin JM, Harpaz-Rotem I, Duman RS, Krystal JH, Southwick SM, et al. BDNF Val66Met polymorphism and posttraumatic stress symptoms in US military veterans: protective effect of physical exercise. Psychoneuroendocrinology. 2019;100:198–202.

    Article  CAS  PubMed  Google Scholar 

  98. Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR, et al. Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry. 2009;14:681–95.

    Article  CAS  PubMed  Google Scholar 

  99. Felmingham KL, Zuj DV, Hsu KCM, Nicholson E, Palmer MA, Stuart K, et al. The BDNF Val66Met polymorphism moderates the relationship between posttraumatic stress disorder and fear extinction learning. Psychoneuroendocrinology. 2018;91:142–8.

    Article  CAS  PubMed  Google Scholar 

  100. Robertson DAF, Beattie JE, Reid IC, Balfour DJK. Regulation of corticosteroid receptors in the rat brain: the role of serotonin and stress. Eur J Neurosci. 2005;21:1511–20.

    Article  CAS  PubMed  Google Scholar 

  101. Buret L, van den Buuse M. Corticosterone treatment during adolescence induces down-regulation of reelin and NMDA receptor subunit GLUN2C expression only in male mice: implications for schizophrenia. Int J Neuropsychopharmacol. 2014;17:1221–32.

    Article  CAS  PubMed  Google Scholar 

  102. Floriou-Servou A, von Ziegler L, Stalder L, Sturman O, Privitera M, Rassi A, et al. Distinct proteomic, transcriptomic, and epigenetic stress responses in dorsal and ventral hippocampus. Biol Psychiatry. 2018;84:531–41.

    Article  CAS  PubMed  Google Scholar 

  103. Quirk GJ, Mueller D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology. 2008;33:56–72.

    Article  PubMed  Google Scholar 

  104. De Kloet CS, Vermetten E, Geuze E, Lentjes EGWM, Heijnen CJ, Stalla GK, et al. Elevated plasma corticotrophin-releasing hormone levels in veterans with posttraumatic stress disorder. Prog Brain Res. 2007;167:287–91.

    Article  CAS  Google Scholar 

  105. Meewisse ML, Reitsma JB, De Vries GJ, Gersons BPR, Olff M. Cortisol and post-traumatic stress disorder in adults: systematic review and meta-analysis. Br J Psychiatry. 2007;191:387–92.

    Article  PubMed  Google Scholar 

  106. Yehuda R. Status of glucocorticoid alterations in post‐traumatic stress disorder. Ann N. Y. Acad Sci. 2009;1179:56–69.

    Article  CAS  PubMed  Google Scholar 

  107. Yehuda R, Southwick S, Krystal J, Bremner D, Charney D, Mason J. Enhanced suppression of cortisol following dexamethasone administration in posttraumatic stress disorder. Am J Psychiatry. 1993;150:83–6.

    Article  CAS  PubMed  Google Scholar 

  108. Newport DJ, Heim C, Bonsall R, Miller AH, Nemeroff CB. Pituitary-adrenal responses to standard and low-dose dexamethasone suppression tests in adult survivors of child abuse. Biol Psychiatry. 2004;55:10–20.

    Article  CAS  PubMed  Google Scholar 

  109. Duval F, Crocq MA, Guillon MS, Mokrani MC, Monreal J, Bailey P, et al. Increased adrenocorticotropin suppression following dexamethasone administration in sexually abused adolescents with posttraumatic stress disorder. Psychoneuroendocrinology. 2004;29:1281–9.

    Article  CAS  PubMed  Google Scholar 

  110. Najarian LM, Fairbanks LA. Basal cortisol, dexamethasone suppression of cortisol, and MHPG in adolescents after the 1988 earthquake in Armenia. Am J Psychiatry. 1996;153:929–34.

    Article  PubMed  Google Scholar 

  111. Yehuda R, Halligan SL, Grossman R, Golier JA, Wong C. The cortisol and glucocorticoid receptor response to low dose dexamethasone administration in aging combat veterans and holocaust survivors with and without posttraumatic stress disorder. Biol Psychiatry. 2002;52:393–403.

    Article  CAS  PubMed  Google Scholar 

  112. Galatzer-Levy IR, Ma S, Statnikov A, Yehuda R, Shalev A. Utilization of machine learning for prediction of post-traumatic stress: a re-examination of cortisol in the prediction and pathways to non-remitting PTSD. Transl Psychiatry. 2017;7:e0.

    Article  CAS  PubMed  Google Scholar 

  113. Yehuda R, Bierer L, Schmediler J, Aferiat D, Breslau I, Dolan S. Low cortisol and risk for PTSD in adult offspring of holocaust survivors. Am J Psychiatry. 2000;157:1252–9.

    Article  CAS  PubMed  Google Scholar 

  114. Yehuda R, Blair W, Labinsky E, Bierer L. Effects of parental PTSD on the cortisol response to dexamethasone administration in their adult offspring. Am J Psychiatry. 2007;2007:163–6.

    Article  Google Scholar 

  115. Yehuda R, Bierer LM. Transgenerational transmission of cortisol and PTSD risk. Prog Brain Res. 2007;167:121–35.

    Article  Google Scholar 

  116. Youssef N, Lockwood L, Su S, Hao G, Rutten B. The effects of trauma, with or without PTSD, on the transgenerational DNA methylation alterations in human offsprings. Brain Sci. 2018;8:E83.

    Article  PubMed  CAS  Google Scholar 

  117. Short AK, Yeshurun S, Powell R, Perreau VM, Fox A, Kim JH, et al. Exercise alters mouse sperm small noncoding RNAs and induces a transgenerational modification of male offspring conditioned fear and anxiety. Transl Psychiatry. 2017;7:e1114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Rodgers AB, Bale TL. Germ cell origins of posttraumatic stress disorder risk: the transgenerational impact of parental stress experience. Biol Psychiatry. 2015;78:307–14.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Schelling G, Briegel J, Roozendaal B, Stoll C, Rothenhausler HB, Kapfhammer HP. The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder in survivors. Biol Psychiatry. 2001;50:978–85.

    Article  CAS  PubMed  Google Scholar 

  120. De Quervain D. Glucocorticoid‐induced inhibition of memory retrieval: implications for posttraumatic stress disorder. Ann N. Y. Acad Sci. 2006;1071:216–20.

    Article  PubMed  CAS  Google Scholar 

  121. Schelling G. Effects of stress hormones on traumatic memory formation and the development of posttraumatic stress disorder in critically ill patients. Neurobiol Learn Mem. 2002;78:596–609.

    Article  CAS  PubMed  Google Scholar 

  122. Schelling G, Kilger E, Roozendaal B, de Quervain D, Briegel J, Dagge A, et al. Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study. Biol Psychiatry. 2004;55:627–33.

    Article  CAS  PubMed  Google Scholar 

  123. Schelling G, Roozendaal B, Krauseneck T, Schmoelz M, De Quervain D, Briegel J. Efficacy of hydrocortisone in preventing posttraumatic stress disorder following critical illness and major surgery. Ann N. Y. Acad Sci. 2006;1071:46–53.

    Article  CAS  PubMed  Google Scholar 

  124. Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34:S186–S95.

    Article  CAS  PubMed  Google Scholar 

  125. Davies TH, Ning YM, Sánchez ER. A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. J Biol Chem. 2002;277:4597–600.

    Article  CAS  PubMed  Google Scholar 

  126. Storer CL, Dickey CA, Galigniana MD, Rein T, Cox MB. FKBP51 and FKBP52 in signaling and disease. Trends Endocrinol Metab. 2011;22:481–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Jääskeläinen T, Makkonen H, Palvimo JJ. Steroid up-regulation of FKBP51 and its role in hormone signaling. Curr Opin Pharmacol. 2011;11:326–31.

    Article  PubMed  CAS  Google Scholar 

  128. Matosin N, Halldorsdottir T, Binder EB. Understanding the molecular mechanisms underpinning gene by environment interactions in psychiatric disorders: the FKBP5 model. Biol Psychiatry. 2018;83:821–30.

    Article  CAS  PubMed  Google Scholar 

  129. Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299:1291–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Farrer LA, et al. Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacology. 2010;35:1684–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Yehuda R, Cai G, Golier JA, Sarapas C, Galea S, Ising M, et al. Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks. Biol Psychiatry. 2009;66:708–11.

    Article  CAS  PubMed  Google Scholar 

  132. Yehuda R, Daskalakis NP, Bierer LM, Bader HN, Klengel T, Holsboer F, et al. Holocaust exposure induced intergenerational effects on FKBP5 methylation. Biol Psychiatry. 2016;80:372–80.

    Article  CAS  PubMed  Google Scholar 

  133. Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, et al. Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nat Neurosci. 2012;16:33–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Galatzer-Levy IR, Andero R, Sawamura T, Jovanovic T, Papini S, Ressler KJ, et al. A cross species study of heterogeneity in fear extinction learning in relation to FKBP5 variation and expression: Implications for the acute treatment of posttraumatic stress disorder. Neuropharmacology. 2017;116:188–95.

    Article  CAS  PubMed  Google Scholar 

  135. Sawamura T, Klengel T, Armario A, Jovanovic T, Norrholm SD, Ressler KJ, et al. Dexamethasone treatment leads to enhanced fear extinction and dynamic Fkbp5 regulation in amygdala. Neuropsychopharmacology. 2015;41:832–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10:434–45.

    Article  CAS  PubMed  Google Scholar 

  137. Murakami S, Imbe H, Morikawa Y, Kubo C, Senba E. Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly. Neurosci Res. 2005;53:129–39.

    Article  CAS  PubMed  Google Scholar 

  138. Grønli J, Bramham C, Murison R, Kanhema T, Fiske E, Bjorvatn B, et al. Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper. Pharm Biochem Behav. 2006;85:842–9.

    Article  CAS  Google Scholar 

  139. Xu Y, Ku B, Tie L, Yao H, Jiang W, Ma X, et al. Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB. Brain Res. 2006;1122:56–64.

    Article  CAS  PubMed  Google Scholar 

  140. Choy KHC, de Visser Y, Nichols NR, van den Buuse M. Combined neonatal stress and young‐adult glucocorticoid stimulation in rats reduce BDNF expression in hippocampus: Effects on learning and memory. Hippocampus. 2008;18:655–67.

    Article  CAS  PubMed  Google Scholar 

  141. Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. 1995;15:1768–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Gourley SL, Kedves AT, Olausson P, Taylor JR. A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF. Neuropsychopharmacology. 2009;34:707–16.

    Article  CAS  PubMed  Google Scholar 

  143. Jeanneteau FD, Lambert WM, Ismaili N, Bath KG, Lee FS, Garabedian MJ, et al. BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus. Proc Natl Acad Sci USA. 2012;109:1305–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Rage F, Givalois L, Marmigere F, Tapia-Arancibia L, Arancibia S. Immobilization stress rapidly modulates BDNF mRNA expression in the hypothalamus of adult male rats. Neuroscience. 2002;112:309–18.

    Article  CAS  PubMed  Google Scholar 

  145. Tapia-Arancibia L, Rage F, Givalois L, Arancibia S. Physiology of BDNF: focus on hypothalamic function. Front Neuroendocrinol. 2004;25:77–107.

    Article  CAS  PubMed  Google Scholar 

  146. Lambert WM, Xu CF, Neubert TA, Chao MV, Garabedian MJ, Jeanneteau FD. Brain-derived neurotrophic factor signaling rewrites the glucocorticoid transcriptome via glucocorticoid receptor phosphorylation. Mol Cell Biol. 2013;33:3700–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Jeanneteau F, Garabedian MJ, Chao MV. Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect. Proc Natl Acad Sci USA. 2008;105:4862–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Notaras M, Du X, Gogos J, Van Den Buuse M, Hill R. The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair. Transl Psychiatry. 2017;7:e1233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Hill RA, van den Buuse M. Sex-dependent and region-specific changes in TrkB signaling in BDNF heterozygous mice. Brain Res. 2011;1384:51–60.

    Article  CAS  PubMed  Google Scholar 

  150. Numakawa T, Kumamaru E, Adachi N, Yagasaki Y, Izumi A, Kunugi H. Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-γ signaling for glutamate release via a glutamate transporter. Proc Natl Acad Sci USA. 2009;106:647–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kumamaru E, Numakawa T, Adachi N, Kunugi H. Glucocorticoid suppresses BDNF-stimulated MAPK/ERK pathway via inhibiting interaction of Shp2 with TrkB. FEBS Lett. 2011;585:3224–8.

    Article  CAS  PubMed  Google Scholar 

  152. Daskalakis NP, De Kloet ER, Yehuda R, Malaspina D, Kranz TM. Early life stress effects on glucocorticoid—BDNF interplay in the hippocampus. Front Mol Neurosci. 2015;8:68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Jeanneteau F, Chao MV. Are BDNF and glucocorticoid activities calibrated? Neuroscience. 2013;239:173–95.

    Article  CAS  PubMed  Google Scholar 

  154. Numakawa T, Adachi N, Richards M, Chiba S, Kunugi H. Brain-derived neurotrophic factor and glucocorticoids: reciprocal influence on the central nervous system. Neuroscience. 2013;239:157–72.

    Article  CAS  PubMed  Google Scholar 

  155. Yu H, Wang DD, Wang Y, Liu T, Lee FS, Chen ZY. Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. J Neurosci. 2012;32:4092–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Notaras MJ, Hill RA, Gogos JA, van den Buuse M. BDNF Val66Met genotype interacts with a history of simulated stress exposure to regulate sensorimotor gating and startle reactivity. Schizophr Bull. 2017;43:665–72.

    PubMed  Google Scholar 

  157. Lehto K, Mäestu J, Kiive E, Veidebaum T, Harro J. BDNF Val66Met genotype and neuroticism predict life stress: a longitudinal study from childhood to adulthood. Eur Neuropsychopharmacol. 2016;26:562–9.

    Article  CAS  PubMed  Google Scholar 

  158. Bukh JD, Bock C, Vinberg M, Werge T, Gether U, Vedel Kessing L. Interaction between genetic polymorphisms and stressful life events in first episode depression. J Affect Disord. 2009;119:107–15.

    Article  PubMed  CAS  Google Scholar 

  159. Alemany S, Arias B, Aguilera M, Villa H, Moya J, Ibanez MI, et al. Childhood abuse, the BDNF-Val66Met polymorphism and adult psychotic-like experiences. Br J Psychiatry. 2011;199:38–42.

    Article  PubMed  Google Scholar 

  160. Armbruster D, Müller-Alcazar A, Strobel A, Lesch KP, Kirschbaum C, Brocke B. BDNF val 66 met genotype shows distinct associations with the acoustic startle reflex and the cortisol stress response in young adults and children. Psychoneuroendocrinology. 2016;66:39–46.

    Article  CAS  PubMed  Google Scholar 

  161. Chau CMY, Cepeda IL, Devlin AM, Weinberg J, Grunau RE. The Val66Met brain-derived neurotrophic factor gene variant interacts with early pain exposure to predict cortisol dysregulation in 7-year-old children born very preterm: implications for cognition. Neuroscience. 2015;342:188–99.

    Article  PubMed  CAS  Google Scholar 

  162. Alexander N, Osinsky R, Schmitz A, Mueller E, Kuepper Y, Hennig J. The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress. Psychoneuroendocrinology. 2010;35:949–53.

    Article  CAS  PubMed  Google Scholar 

  163. Shalev I, Lerer E, Israel S, Uzefovsky F, Gritsenko I, Mankuta D, et al. BDNF Val66Met polymorphism is associated with HPA axis reactivity to psychological stress characterized by genotype and gender interactions. Psychoneuroendocrinology. 2009;34:382–8.

    Article  CAS  PubMed  Google Scholar 

  164. Bath KG, Chuang J, Spencer-Segal JL, Amso D, Altemus M, McEwen BS, et al. Variant brain-derived neurotrophic factor (Valine66Methionine) polymorphism contributes to developmental and estrous stage-specific expression of anxiety-like behavior in female mice. Biol Psychiatry. 2012;72:499–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Spencer JL, Waters EM, Milner TA, Lee FS, McEwen BS. BDNF variant Val66Met interacts with estrous cycle in the control of hippocampal function. Proc Natl Acad Sci USA. 2010;107:4395–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Revest JM, Le Roux A, Roullot-Lacarrière V, Kaouane N, Vallée M, Kasanetz F, et al. BDNF-TrkB signaling through Erk1/2 MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoids. Mol Psychiatry. 2014;19:1001–9.

    Article  CAS  PubMed  Google Scholar 

  167. Furmaga H, Carreno FR, Frazer A. Vagal nerve stimulation rapidly activates brain-derived neurotrophic factor receptor TrkB in rat brain. PLoS ONE. 2012;7:e34844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Ninan I, Bath KG, Dagar K, Perez-Castro R, Plummer MR, Lee FS, et al. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus. J Neurosci. 2010;30:8866–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Mizui T, Ishikawa Y, Kumanogoh H, Kojima M. Neurobiological actions by three distinct subtypes of brain-derived neurotrophic factor: multi-ligand model of growth factor signaling. Pharmacol Res 2016;105:93–8.

    Article  CAS  PubMed  Google Scholar 

  170. Kumamaru E, Numakawa T, Adachi N, Yagasaki Y, Izumi A, Niyaz M, et al. Glucocorticoid prevents brain-derived neurotrophic factor-mediated maturation of synaptic function in developing hippocampal neurons through reduction in the activity of mitogen-activated protein kinase. Mol Endocrinol. 2008;22:546–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Klug M, Hill RA, Choy KHC, Kyrios M, Hannan AJ, van den Buuse M. Long-term behavioral and NMDA receptor effects of young-adult corticosterone treatment in BDNF heterozygous mice. Neurobiol Dis 2012;46:722–31.

    Article  CAS  PubMed  Google Scholar 

  172. Hashimoto T, Fukui K, Takeuchi H, Yokota S, Kikuchi Y, Tomita H, et al. Effects of the BDNF Val66Met polymorphism on gray matter volume in typically developing children and adolescents. Cereb Cortex. 2016;26:1795–803.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Scharfman HE, Goodman JH, Sollas AL, Croll SD. Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. Exp Neurol. 2002;174:201–14.

    Article  CAS  PubMed  Google Scholar 

  174. Nakagawa T, Ono‐Kishino M, Sugaru E, Yamanaka M, Taiji M, Noguchi H. Brain‐derived neurotrophic factor (BDNF) regulates glucose and energy metabolism in diabetic mice. Diabetes Metab Res Rev. 2002;18:185–91.

    Article  CAS  PubMed  Google Scholar 

  175. Poduslo JF, Curran GL. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Mol Brain Res. 1996;36:280–6.

    Article  CAS  PubMed  Google Scholar 

  176. Du X, Hill R. 7, 8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders. Neurochem Int. 2015;89:170–80.

    Article  CAS  PubMed  Google Scholar 

  177. Massa SM, Yang T, Xie Y, Shi J, Bilgen M, Joyce JN, et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Investig. 2010;120:1774–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Vaynman S, Ying Z, Gómez‐Pinilla F. Exercise induces BDNF and synapsin I to specific hippocampal subfields. J Neurosci Res. 2004;76:356–62.

    Article  CAS  PubMed  Google Scholar 

  179. Vaynman S, Ying Z, Gomez‐Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci. 2004;20:2580–90.

    Article  PubMed  Google Scholar 

  180. Patki G, Li L, Allam F, Solanki N, Dao AT, Alkadhi K, et al. Moderate treadmill exercise rescues anxiety and depression-like behavior as well as memory impairment in a rat model of posttraumatic stress disorder. Physiol Behav. 2014;130:47–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Voisey J, Lawford B, Bruenig D, Harvey W, Morris CP, Young RM, et al. Differential BDNF methylation in combat exposed veterans and the association with exercise. Gene. 2019;698:107–12.

    Article  CAS  PubMed  Google Scholar 

  182. Finn RD, Coggill P, Eberhardt RY, Eddy SR, Mistry J, Mitchell AL, et al. The Pfam protein families database: towards a more sustainable future. Nucleic Acids Res. 2016;44:D279–D85.

    Article  CAS  PubMed  Google Scholar 

  183. UniProt-Consortium. UniProt: a hub for protein information. Nucleic Acids Res. 2015;43:D204–D12.

    Article  CAS  Google Scholar 

  184. Meakin SO, Shooter EM. The nerve growth factor family of receptors. Trends Neurosci. 1992;15:323–31.

    Article  CAS  PubMed  Google Scholar 

  185. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445:168–76.

    Article  CAS  PubMed  Google Scholar 

  186. Lee HJ, Kang RH, Lim SW, Paik JW, Choi MJ, Lee MS. No association between the brain‐derived neurotrophic factor gene Val66Met polymorphism and post‐traumatic stress disorder. Stress Health. 2006;22:115–9.

    Article  Google Scholar 

  187. Zhang H, Ozbay F, Lappalainen J, Kranzler HR, van Dyck CH, Charney DS, et al. Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer's disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. Am J Med Genet B Neuropsychiatr Genet. 2006;141:387–93.

    Article  CAS  Google Scholar 

  188. Valente NLM, Vallada H, Cordeiro Q, Miguita K, Bressan RA, Andreoli SB, et al. Candidate-gene approach in posttraumatic stress disorder after urban violence: association analysis of the genes encoding serotonin transporter, dopamine transporter, and BDNF. J Mol Neurosci. 2011;44:59–67.

    Article  CAS  PubMed  Google Scholar 

  189. Pivac N, Kozaric-Kovacic D, Grubisic-Ilic M, Nedic G, Rakos I, Nikolac M, et al. The association between brain-derived neurotrophic factor Val66Met variants and psychotic symptoms in posttraumatic stress disorder. World J Biol Psychiatry. 2012;13:306–11.

    Article  PubMed  Google Scholar 

  190. Li RH, Fan M, Hu MS, Ran MS, Fang DZ. Reduced severity of posttraumatic stress disorder associated with Val allele of Val66Met polymorphism at brain‐derived neurotrophic factor gene among Chinese adolescents after Wenchuan earthquake. Psychophysiology. 2016;53:705–11.

    Article  PubMed  Google Scholar 

  191. van den Heuvel L, Suliman S, Malan-Müller S, Hemmings S, Seedat S. Brain-derived neurotrophic factor Val66met polymorphism and plasma levels in road traffic accident survivors. Anxiety Stress Coping. 2016;29:1–14.

    Article  Google Scholar 

  192. Lyoo IK, Kim JE, Yoon SJ, Hwang J, Bae S, Kim DJ. The neurobiological role of the dorsolateral prefrontal cortex in recovery from trauma: longitudinal brain imaging study among survivors of the South Korean subway disaster. JAMA Psychiatry. 2011;68:701–13.

    Google Scholar 

  193. Dretsch MN, Williams K, Emmerich T, Crynen G, Ait-Ghezala G, Chaytow H, et al. Brain-derived neurotropic factor polymorphisms, traumatic stress, mild traumatic brain injury, and combat exposure contribute to postdeployment traumatic stress. Brain Behav. 2016;6:e00392.

    Article  PubMed  Google Scholar 

  194. Bruenig D, Lurie J, Morris CP, Harvey W, Lawford B, Young RM, et al. A case-control study and meta-analysis reveal BDNF Val66Met is a possible risk factor for PTSD. Neural Plasticity. 2016;2016:6979435.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Tudor L, Konjevod M, Nikolac Perkovic M, Svob Strac D, Nedic Erjavec G, Uzun S, et al. Genetic variants of the brain-derived neurotrophic factor and metabolic indices in veterans with posttraumatic stress disorder. Front Psychiatry. 2018;9:637.

    Article  PubMed  PubMed Central  Google Scholar 

  196. Guo JC, Yang YJ, Zheng JF, Guo M, Wang XD, Gao YS, et al. Functional rs6265 polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in posttraumatic stress disorder among Chinese patients with hepatocellular carcinoma. J Cell Biochem. 2019;120:10434–43.

    Article  CAS  PubMed  Google Scholar 

  197. Guo JC, Yang YJ, Guo M, Wang XD, Juan Y, Gao YS, et al. Correlations of four genetic single-nucleotide polymorphisms in brain-derived neurotrophic factor with posttraumatic stress disorder. Psychiatry Investig. 2018;15:407–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Michael Notaras or Maarten van den Buuse.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Notaras, M., van den Buuse, M. Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders. Mol Psychiatry 25, 2251–2274 (2020). https://doi.org/10.1038/s41380-019-0639-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-019-0639-2

This article is cited by

Search

Quick links