Brain-derived neurotrophic factor (BDNF) is an essential facilitator of neuronal plasticity. By counteracting the adverse effects of excessive stress-induced glucocorticoid signaling, BDNF has been implicated as a resilience factor to psychopathology caused by chronic stress. Insights into the effects of acute stress on peripheral BDNF levels in humans are inconclusive. The short-term interplay between BDNF and cortisol in response to acute psychosocial stress remains unexplored. Furthermore, it is unknown whether mental training that is effective at reducing cortisol reactivity can also influence BDNF during acute stress. In the current study, we investigated serum BDNF levels during an acute psychosocial stress paradigm, the Trier Social Stress Test (TSST), in 301 healthy participants (178 women, mean age = 40.65) recruited as part of the ReSource Project, a large-scale mental training study consisting of three distinct 3-month training modules. Using a cross-sectional study design, we first examined the relationship between BDNF and salivary cortisol in a control group with no mental training. Subsequent analyses focused on differences in BDNF stress levels between control and mental training groups. We show that serum BDNF is indeed stress-sensitive, characterized by a significant post-stress increase and subsequent decline to recovery. While respective increases in BDNF and cortisol were not associated, we found two indications for an antagonistic relationship. Higher BDNF peaks after stress were associated with steeper cortisol recovery. On the other hand, the magnitude of the cortisol stress response was linked to steeper BDNF recovery after stress. BDNF levels were not modulated by any of the mental training modules. Providing novel evidence for the dynamics of BDNF and cortisol during acute stress, our findings may further inform research on the physiological mechanisms involved in stress chronification and the associated health risks.
Subscribe to Journal
Get full journal access for 1 year
only $43.69 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The datasets generated and/or analyzed for the current study are not publicly available due to ongoing analyses in the context of the large-scale ReSource Project. The data are available upon request for replication purposes.
Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24:677–736.
Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. In: Lewin GR, Carter BD, editors. Neurotrophic factors. Berlin, Heidelberg: Springer Berlin Heidelberg; 2014. p. 223–50.
Thoenen H. The changing scene of neurotrophic factors. Trends Neurosci. 1991;14:165–70.
Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev. 2012;64:238–58.
Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–27.
Castrén E, Rantamäki T. The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol. 2010;70:289–97.
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–49.
Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and anxiety. Nat Neurosci. 2007;10:1089–93.
McEwen BS. Protective and damaging effects of stress mediators: central role of the brain. Dialogues Clin Neurosci. 2006;8:367.
Björkholm C, Monteggia LM. BDNF—a key transducer of antidepressant effects. Neuropharmacology. 2016;102:72–9.
Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry. 1997;54:597–606.
Numakawa T, Odaka H, Adachi N. Actions of brain-derived neurotrophic factor and glucocorticoid stress in neurogenesis. Int J Mol Sci. 2017;18:2312.
Suri D, Vaidya V. Glucocorticoid regulation of brain-derived neurotrophic factor: relevance to hippocampal structural and functional plasticity. Neuroscience. 2013;239:196–213.
Jeanneteau FD, Lambert WM, Ismaili N, Bath KG, Lee FS, Garabedian MJ, Chao MV. BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus. Proc Natl Acad Sci USA. 2012;109:1305–10.
Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature. 2011;476:458–61.
Taliaz D, Loya A, Gersner R, Haramati S, Chen A, Zangen A. Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. J Neurosci. 2011;31:4475–83.
Tapia-Arancibia L, Rage F, Givalois L, Arancibia S. Physiology of BDNF: focus on hypothalamic function. Front Neuroendocrinol. 2004;25:77–107.
Jeanneteau FD, Chao MV. Are BDNF and glucocorticoid activities calibrated?. Neuroscience. 2013;239:173–95.
Jeanneteau FD, Garabedian MJ, Chao MV. Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect. Proc Natl Acad Sci USA. 2008;105:4862–7.
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.
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.
Rojas Vega S, Strüder HK, Wahrmann BV, Schmidt A, Bloch W, & Hollmann W. Acute BDNF and cortisol response to low intensity exercise and following ramp incremental exercise to exhaustion in humans. Brain Res. 2006;1121:59–65.
Szuhany KL, Bugatti M, Otto MW. A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor. J Psychiatr Res. 2015;60:56–64.
Kirschbaum C, Pirke KM, Hellhammer DH. The Trier Social Stress Test—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28:76–81.
Meng D, Wu T, Rao U, North CS, Xiao H, Javors MA, & Adinoff B. Serum NPY and BNDF response to a behavioral stressor in alcohol-dependent and healthy control participants. Psychopharmacology. 2011;218:59.
Sharma S, Graham R, Rohde R, & Ceballos N.A. Stress-induced change in serum BDNF is related to quantitative family history of alcohol use disorder and age at first alcohol use. Pharmacol Biochem Behav. 2017;153:12–17.
Gray J, Milner T, McEwen B. Dynamic plasticity: the role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors. Neuroscience. 2013;239:214–27.
Holsboer F, Ising M. Stress hormone regulation: biological role and translation into therapy. Annu Rev Psychol. 2009;61:81–109.
Jeanneteau F, Borie A, Chao MV, Garabedian MJ. Bridging the gap between BDNF and glucocorticoid effects on brain networks. Neuroendocrinology. 2018. https://doi.org/10.1159/000496392. PMID: 30572337.
Cain SW, Chang AM, Vlasac I, Tare A, Anderson C, Czeisler CA, & Saxena R. Circadian rhythms in plasma brain-derived neurotrophic factor differ in men and women. J Biol Rhythms. 2017;32:75–82.
Galante J, Galante I, Bekkers MJ, & Gallacher J. Effect of kindness-based meditation on health and well-being: a systematic review and meta-analysis. Journal of consulting and clinical psychology. 2014;82:1101.
Grossman P, Niemann L, Schmidt S, & Walach H. Mindfulness-based stress reduction and health benefits: a meta-analysis. Journal of psychosomatic research. 2004;57:35–43.
Khoury B, Sharma M, Rush SE, & Fournier C. Mindfulness-based stress reduction for healthy individuals: a meta-analysis. Journal of psychosomatic research. 2015;78:519–28.
Kabat-Zinn J. Wherever you go, there you are: Mindfulness meditation in everyday life. New York: Hyperion; 1994.
Segal ZV, Williams JMG, Teasdale JD. Mindfulness-based cognitive therapy for depression. New York, NY, US: Guilford Press; 2012.
Dahl CJ, Lutz A, Davidson RJ. Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice. Trends Cogn Sci. 2015;19:515–23.
Engert V, Kok BE, Papassotiriou I, Chrousos GP, & Singer T. Specific reduction in cortisol stress reactivity after social but not attention-based mental training. Sci Adv. 2017;3:e1700495.
Singer T, Kok BE, Bornemann B, Zurborg S, Bolz M, & Bochow C. The ReSource Project: background, design, samples, and measurements. Leipzig: Max Planck Institute for Human Cognitive and Brain Sciences; 2016.
Fan Y, Tang YY, Posner MI. Cortisol level modulated by integrative meditation in a dose‐dependent fashion. Stress Health. 2014;30:65–70.
Wittchen HU, Pfister H. DIA-X-Interviews: Manual für Screening-Verfahren und Interview. Frankfurt: Swets & Zeitlinger; 1997.
First MB, Gibbon M, Spitzer RL, Williams JBW, Benjamin LS. Structured clinical interview for DSM-IV Axis II personality disorders, (SCID-II). Washington, DC: American Psychiatric Press, Inc; 1997.
Wittchen HU, Zaudig M, Fydrich T. SKID—Strukturiertes Klinisches Interview für DSM-IV. Achse I und Achse II. Göttingen: Hogrefe; 1997.
Bus BAA, Molendijk ML, Penninx BJWH, Buitelaar JK, Kenis G, Prickaerts J, & Voshaar RO. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology. 2011;36:228–39.
Piccinni A, Marazziti D, Del Debbio A, Bianchi C, Roncaglia I, Mannari C, & Dell'Osso L. Diurnal variation of plasma brain‐derived neurotrophic factor (BDNF) in humans: an analysis of sex differences. Chronobiol Int. 2008;25:819–26.
Allen AP, Kennedy PJ, Cryan JF, Dinan TG, & Clarke G. Biological and psychological markers of stress in humans: focus on the Trier Social Stress Test. Neurosci Biobehav Rev. 2014;38:94–124.
Dickerson SS, Kemeny ME. Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull. 2004;130:355–91.
Dressendorfer RA, Dressendörfer RA, Kirschbaum C, Rohde W, Stahl F, & Strasburger CJ. Synthesis of a cortisol-biotin conjugate and evaluation as a tracer in an immunoassay for salivary cortisol measurement. J Steroid Biochem Mol Biol. 1992;43:683–92.
Kudielka BM, Wüst S. Human models in acute and chronic stress: assessing determinants of individual hypothalamus–pituitary–adrenal axis activity and reactivity. Stress. 2010;13:1–14.
McEwen BS, Seeman T. Protective and damaging effects of mediators of stress: elaborating and testing the concepts of allostasis and allostatic load. Ann NY Acad Sci. 1999;896:30–47.
Hellhammer DH, Wüst S, Kudielka BM. Salivary cortisol as a biomarker in stress research. Psychoneuroendocrinology. 2009;34:163–71.
Kirschbaum C, Hellhammer DH. Salivary cortisol in psychoneuroendocrine research: recent developments and applications. Psychoneuroendocrinology. 1994;19:313–33.
Lippi G, Dipalo M, Buonocore R, Gnocchi C, Aloe R, & Delsignore R. Analytical evaluation of free testosterone and cortisol immunoassays in saliva as a reliable alternative to serum in sports medicine. J Clin Lab Anal. 2016;30:732–5.
Poll E-M, Kreitschmann-Andermahr I, Langejuergen Y, Stanzel S, Gilsbach JM, Gressner A, & Yagmur E. Saliva collection method affects predictability of serum cortisol. Clin Chim Acta. 2007;382:15–19.
Kok BE, Singer T. Effects of contemplative dyads on engagement and perceived social connectedness over 9 months of mental training: a randomized clinical trial. JAMA Psychiatry. 2017;74:126–34.
R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Austria. 2018. https://www.R-project.org.
Bates D, Maechler M, Bolker B, Walker S. lme4: Linear mixed-effects models using Eigen and S4. R package version 1.1–7. 2014 http://CRAN.R-project.org/package=lme4.
Miller R, Plessow F, Kirschbaum C, & Stalder T. Classification criteria for distinguishing cortisol responders from nonresponders to psychosocial stress: evaluation of salivary cortisol pulse detection in panel designs. Psychosom Med. 2013;75:832–40.
Egeland M, Zunszain PA, Pariante CM. Molecular mechanisms in the regulation of adult neurogenesis during stress. Nat Rev Neurosci. 2015;16:189.
Gold P. The organization of the stress system and its dysregulation in depressive illness. Mol psychiatry. 2015;20:32–47.
De Kloet ER, Joëls M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6:463.
Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, & Cullinan WE. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness. Front Neuroendocrinol. 2003;24:151–80.
Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10:397.
Pillai A, Kale A, Joshi S, Naphade N, Raju MSVK, Nasrallah H, & Mahadik SP. Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: correlation with plasma BDNF and psychopathology. Int J Neuropsychopharmacol. 2010;13:535–9.
McEwen BS, Gray JD, Nasca C. Recognizing resilience: Learning from the effects of stress on the brain. Neurobiol Stress. 2015;1:1–11.
Matthews KA, Gump BB, Owens JF. Chronic stress influences cardiovascular and neuroendocrine responses during acute stress and recovery, especially in men. Health Psychol. 2001;20:403.
Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev. 2000;21:55–89.
Burke HM, Davis MC, Otte C, & Mohr DC. Depression and cortisol responses to psychological stress: a meta-analysis. Psychoneuroendocrinology. 2005;30:846–56.
Marmigère F, Givalois L, Rage F, Arancibia S, & Tapia‐Arancibia L. Rapid induction of BDNF expression in the hippocampus during immobilization stress challenge in adult rats. Hippocampus. 2003;13:646–55.
Tang SW, Chu E, Hui T, Helmeste D, & Law C. Influence of exercise on serum brain-derived neurotrophic factor concentrations in healthy human subjects. Neurosci Lett. 2008;431:62–5.
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.
Jiang R, Babyak MA, Brummett BH, Siegler IC, Kuhn CM, & Williams RB. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism interacts with gender to influence cortisol responses to mental stress. Psychoneuroendocrinology. 2017;79:13–9.
Shalev I, Lerer E, Israel S, Uzefovsky F, Gritsenko I, Mankuta D, & Kaitz M. BDNF Val66Met polymorphism is associated with HPA axis reactivity to psychological stress characterized by genotype and gender interactions. Psychoneuroendocrinology. 2009;34:382–8.
Tsuru J, Tanaka Y, Ishitobi Y, Maruyama Y, Inoue A, Kawano A, & Masuda K. Association of BDNF Val66Met polymorphism with HPA and SAM axis reactivity to psychological and physical stress. Neuropsychiatr Dis Treat. 2014;10:2123.
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, & Lu B. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112:257–69.
Cahn BR, Goodman MS, Peterson CT, Maturi R, & Mills PJ. Yoga, meditation and mind-body health: increased BDNF, cortisol awakening response, and altered inflammatory marker expression after a 3-month yoga and meditation retreat. Front Hum Neurosci. 2017;11:315.
Gold SM, Schulz KH, Hartmann S, Mladek M, Lang UE, Hellweg R, & Heesen C. Basal serum levels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls. J Neuroimmunol. 2003;138:99–105.
Vega SR, Strüder HK, Wahrmann BV, Schmidt A, Bloch W, & Hollmann W. Acute BDNF and cortisol response to low intensity exercise and following ramp incremental exercise to exhaustion in humans. Brain Res. 2006;1121:59–65.
Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, & Aznar S. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol. 2011;14:347–53.
Sartorius A, Hellweg R, Litzke J, Vogt M, Dormann C, Vollmayr B, & Gass P. Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats. Pharmacopsychiatry. 2009;42:270–6.
Lang UE, Hellweg R, Seifert F, Schubert F, & Gallinat J. Correlation between serum brain-derived neurotrophic factor level and an in vivo marker of cortical integrity. Biol psychiatry. 2007;62:530–5.
Kancheva R, Hill M, Novak Z, Chrastina J, Kancheva L, & Starka L. Neuroactive steroids in periphery and cerebrospinal fluid. Neuroscience. 2011;191:22–7.
Mason BL, Pariante CM, Jamel S, & Thomas SA. Central nervous system (CNS) delivery of glucocorticoids is fine-tuned by saturable transporters at the blood-CNS barriers and nonbarrier regions. Endocrinology. 2010;151:5294–305.
Arango-Lievano M, Lambert WM, Bath KG, Garabedian MJ, Chao MV, & Jeanneteau, F. Neurotrophic-priming of glucocorticoid receptor signaling is essential for neuronal plasticity to stress and antidepressant treatment. Proc Natl Acad Sci USA. 2015;112:15737.
We are thankful to the members of the Social Neuroscience Department involved in the ReSource Project over many years, in particular to Astrid Ackermann, Christina Bochow, Matthias Bolz, and Sandra Zurborg for managing the large-scale longitudinal study, to Elisabeth Murzik, Nadine Otto, Sylvia Tydecks, and Kerstin Träger for help with recruiting and data archiving, to Henrik Grunert for technical assistance, and to Hannes Niederhausen and Torsten Kästner for data management. Thank you also to the research assistants and students, especially Anna Koester, whose help with data collection was indispensable.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Linz, R., Puhlmann, L.M.C., Apostolakou, F. et al. Acute psychosocial stress increases serum BDNF levels: an antagonistic relation to cortisol but no group differences after mental training. Neuropsychopharmacol. 44, 1797–1804 (2019). https://doi.org/10.1038/s41386-019-0391-y
Non-pharmacological and pharmacological approaches for psychiatric disorders: Re-appraisal and insights from zebrafish models
Pharmacology Biochemistry and Behavior (2020)
Acute increases in brain-derived neurotrophic factor in plasma following physical exercise relates to subsequent learning in older adults
Scientific Reports (2020)
Aging & Mental Health (2020)
Biochemical Mechanisms and Translational Relevance of Hippocampal Vulnerability to Distant Focal Brain Injury: The Price of Stress Response
Biochemistry (Moscow) (2019)