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.
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Van der Kolk BA. The psychobiology of posttraumatic stress disorder. J Clin Psychiatry. 1997;58:16–24.
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.
Notaras M, van den Buuse M. Brain-derived neurotrophic factor (BDNF): novel insights into regulation and genetic variation. Neuroscientist. 2019;25:434–54.
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.
Björkholm C, Monteggia LM. BDNF—a key transducer of antidepressant effects. Neuropharmacology. 2016;102:72–9.
Barde Y-A, Edgar D, Thoenen H. Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1982;1:549–53.
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.
Minichiello L. TrkB signalling pathways in LTP and learning. Nat Rev Neurosci. 2009;10:850–60.
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.
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.
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.
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.
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.
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.
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.
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.
Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ. Induction of fear extinction with hippocampal-infralimbic BDNF. Science. 2010;328:1288–90.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Pluchino N, Russo M, Santoro AN, Litta P, Cela V, Genazzani AR. Steroid hormones and BDNF. Neuroscience. 2013;239:271–9.
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.
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.
Garcia-Segura LM. Aromatase in the brain: not just for reproduction anymore. J Neuroendocrinol. 2008;20:705–12.
Fester L, Prange-Kiel J, Jarry H, Rune GM. Estrogen synthesis in the hippocampus. Cell Tissue Res. 2011;345:285–94.
Foy MR. 17β-estradiol: effect on CA1 hippocampal synaptic plasticity. Neurobiol Learn Mem. 2001;76:239–52.
Parducz A, Perez J, Garcia-Segura L. Estradiol induces plasticity of GABAergic synapses in the hypothalamus. Neuroscience. 1993;53:395–401.
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.
Carbone DL, Handa RJ. Sex and stress hormone influences on the expression and activity of brain-derived neurotrophic factor. Neuroscience. 2013;239:295–303.
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.
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.
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.
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.
Segal M, Murphy D. Estradiol induces formation of dendritic spines in hippocampal neurons: functional correlates. Horm Behav. 2001;40:156–9.
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.
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.
Singh M, Su C. Progesterone, brain-derived neurotrophic factor and neuroprotection. Neuroscience. 2013;239:84–91.
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.
Aguirre CC, Baudry M. Progesterone reverses 17β‐estradiol‐mediated neuroprotection and BDNF induction in cultured hippocampal slices. Eur J Neurosci. 2009;29:447–54.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
Monson CM, Shnaider P. Theory underlying trauma-focused interventions. In: Treating PTSD with cognitive-behavioral therapies: interventions that work. Washington: American Psychological Association; 2014.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Lubin FD, Roth TL, Sweatt JD. Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci. 2008;28:10576–86.
Psotta L, Lessmann V, Endres T. Impaired fear extinction learning in adult heterozygous BDNF knock-out mice. Neurobiol Learn Mem. 2013;103:34–8.
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.
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.
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.
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.
Hoover WB, Vertes RP. Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct Funct. 2007;212:149–79.
Rosas-Vidal LE, Do-Monte FH, Sotres-Bayon F, Quirk GJ. Hippocampal–prefrontal BDNF and memory for fear extinction. Neuropsychopharmacology. 2014;39:2161–9.
Fanselow MS, Dong HW. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron. 2010;65:7–19.
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.
Lee JL, Everitt BJ, Thomas KL. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science. 2004;304:839–43.
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.
Kirtley A, Thomas KL. The exclusive induction of extinction is gated by BDNF. Learn Mem. 2010;17:612–9.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Quirk GJ, Mueller D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology. 2008;33:56–72.
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.
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.
Yehuda R. Status of glucocorticoid alterations in post‐traumatic stress disorder. Ann N. Y. Acad Sci. 2009;1179:56–69.
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.
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.
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.
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.
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.
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.
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.
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.
Yehuda R, Bierer LM. Transgenerational transmission of cortisol and PTSD risk. Prog Brain Res. 2007;167:121–35.
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.
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.
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.
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.
De Quervain D. Glucocorticoid‐induced inhibition of memory retrieval: implications for posttraumatic stress disorder. Ann N. Y. Acad Sci. 2006;1071:216–20.
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.
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.
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.
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.
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.
Storer CL, Dickey CA, Galigniana MD, Rein T, Cox MB. FKBP51 and FKBP52 in signaling and disease. Trends Endocrinol Metab. 2011;22:481–90.
Jääskeläinen T, Makkonen H, Palvimo JJ. Steroid up-regulation of FKBP51 and its role in hormone signaling. Curr Opin Pharmacol. 2011;11:326–31.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Tapia-Arancibia L, Rage F, Givalois L, Arancibia S. Physiology of BDNF: focus on hypothalamic function. Front Neuroendocrinol. 2004;25:77–107.
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.
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.
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.
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.
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.
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.
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.
Jeanneteau F, Chao MV. Are BDNF and glucocorticoid activities calibrated? Neuroscience. 2013;239:173–95.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Du X, Hill R. 7, 8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders. Neurochem Int. 2015;89:170–80.
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.
Vaynman S, Ying Z, Gómez‐Pinilla F. Exercise induces BDNF and synapsin I to specific hippocampal subfields. J Neurosci Res. 2004;76:356–62.
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.
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.
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.
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.
UniProt-Consortium. UniProt: a hub for protein information. Nucleic Acids Res. 2015;43:D204–D12.
Meakin SO, Shooter EM. The nerve growth factor family of receptors. Trends Neurosci. 1992;15:323–31.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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Notaras, M., van den Buuse, M. Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-019-0639-2