Skip to main content
SpringerLink
Log in

Cortisol effects on fear memory reconsolidation in women

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Previous work from our group has shown that cortisol enhances fear reconsolidation in men. Whether similar effects can be observed in women remains an open question.

Objectives

The effects of cortisol on the reconsolidation of fear memories were investigated in women. Based on results in men, we expected a specific enhancing effect of cortisol administration on the reactivated fear memory. In addition, possible interactions with oral contraceptive use were tested.

Methods

We incorporated a differential fear conditioning paradigm in a 3-day reconsolidation design. A fear memory, which was created on the first day, was reactivated on the second day following cortisol administration in the target group. One control group was given cortisol without reactivation, and the other participated in the reactivation session following placebo intake. On the third day, the return of fear for all stimuli following reinstatement was tested. Skin conductance response served as measure of conditioned response.

Results

In contrast to the hypothesis, cortisol in combination with reactivation did not enhance fear reconsolidation. No differences between the three experimental groups were apparent. In addition, hormonal contraceptive use had no effect on any of the learning phases and did not interact with the cortisol manipulation.

Conclusions

The lack of an effect in women might be the result of alternating concentrations of sex hormones during different phases of the menstrual cycle or following oral contraceptive use. Considering the higher vulnerability of women to stress-related mental disorders, further investigations in women are of great importance for both theory and treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

BMI:

Body mass index

CR:

Conditioned response

CS:

Conditioned stimulus/stimuli

FC:

Free cycling

GCs:

Glucocorticoids

HPA:

Hypothalamus-pituitary-adrenal

ITI:

Intertrial interval

OC:

Oral contraceptives

PTSD:

Post-traumatic stress disorder

SCR:

Skin conductance response

UCS:

Unconditioned stimulus

References

  • Abrari K, Rashidy-Pour A, Semnanian S, Fathollahi Y (2008) Administration of corticosterone after memory reactivation disrupts subsequent retrieval of a contextual conditioned fear memory: dependence upon training intensity. Neurobiol Learn Mem 89:178–184

    Article  CAS  PubMed  Google Scholar 

  • Akirav I, Maroun M (2013) Stress modulation of reconsolidation. Psychopharmacology (Berl) 226:747–761

    Article  CAS  Google Scholar 

  • Alberini CM (2011) The role of reconsolidation and the dynamic process of long-term memory formation and storage. Front Behav Neurosci 5

  • Alberini CM, LeDoux JE (2013) Memory reconsolidation. Curr Biol 23:R746–R750

    Article  CAS  PubMed  Google Scholar 

  • Altemus M, Redwine L, Leong YM, Yoshikawa T, Yehuda R, Detera-Wadleigh S et al (1997) Reduced sensitivity to glucocorticoid feedback and reduced glucocorticoid receptor mRNA expression in the luteal phase of the menstrual cycle. Neuropsychopharmacology 17:100–109

    Article  CAS  PubMed  Google Scholar 

  • Amiri S, Jafarian Z, Vafaei AA, Motaghed-Larijani Z, Samaei SA, Rashidy-Pour A (2015) Glucocorticoids inteact with cholinergic system in impairing memory reconsolidation of an inhibitory avoidance task in mice. Basic Clin Neurosci 6:155–162

    PubMed  PubMed Central  Google Scholar 

  • Beery AK, Zucker I (2011) Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 35:565–572

    Article  PubMed  Google Scholar 

  • Bos MGN, Schuijer J, Lodestijn F, Beckers T, Kindt M (2014) Stress enhances reconsolidation of declarative memory. Psychoneuroendocrinology

  • Bouton ME (2002) Context, ambiguity, and unlearning: sources of relapse after behavioral extinction. Biol Psychiatry 52:976–986

    Article  PubMed  Google Scholar 

  • Bouton ME (2004) Context and behavioral processes in extinction. Learn Mem 11:485–494

    Article  PubMed  Google Scholar 

  • Bouton ME, King DA (1983) Contextual control of the extinction of conditioned fear—tests for the associative value of the context. J Exp Psychol-Anim Behav Process 9:248–265

    Article  CAS  PubMed  Google Scholar 

  • Cahill L (2012) A half-truth is a whole lie: on the necessity of investigating sex influences on the brain. Endocrinology 153:2541–2543

    Article  PubMed  PubMed Central  Google Scholar 

  • Cahill L, Prins B, Weber M, McGaugh JL (1994) Beta-adrenergic activation and memory for emotional events. Nature 371:702–704

    Article  CAS  PubMed  Google Scholar 

  • Cahill L, Gorski L, Le K (2003) Enhanced human memory consolidation with post-learning stress: interaction with the degree of arousal at encoding. Learn Mem 10:270–274

    Article  PubMed  PubMed Central  Google Scholar 

  • Cai WH, Blundell J, Han J, Greene RW, Powell CM (2006) Postreactivation glucocorticoids impair recall of established fear memory. J Neurosci 26:9560–9566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chadwick KD, Burkman RT, Tornesi BM, Mahadevan B (2012) Fifty years of “the pill”: risk reduction and discovery of benefits beyond contraception, reflections, and forecast. Toxicol Sci 125:2–9

    Article  CAS  PubMed  Google Scholar 

  • Coccoz V, Maldonado H, Delorenzi A (2011) The enhancement of reconsolidation with a naturalistic mild stressor improves the expression of a declarative memory in humans. Neuroscience 185:61–72

    Article  CAS  PubMed  Google Scholar 

  • Coccoz V, Sandoval AV, Stehberg J, Delorenzi A (2013) The temporal dynamics of enhancing a human declarative memory during reconsolidation. Neuroscience 246:397–408

    Article  CAS  PubMed  Google Scholar 

  • Cordero MI, Kruyt ND, Merino JJ, Sandi C (2002) Glucocorticoid involvement in memory formation in a rat model for traumatic memory. Stress 5:73–79

    Article  CAS  PubMed  Google Scholar 

  • Craske M (1999) Anxiety disorders: psychological approaches to theory and treatment. Westview Press, Boulder

    Google Scholar 

  • de Kloet ER, Oitzl MS, Joels M (1999) Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci 22:422–426

    Article  PubMed  Google Scholar 

  • de Quervain DJ, Margraf J (2008) Glucocorticoids for the treatment of post-traumatic stress disorder and phobias: a novel therapeutic approach. Eur J Pharmacol 583:365–371

    Article  PubMed  Google Scholar 

  • de Quervain DJ, Aerni A, Schelling G, Roozendaal B (2009) Glucocorticoids and the regulation of memory in health and disease. Front Neuroendocrinol 30:358–370

    Article  PubMed  Google Scholar 

  • Debiec J, LeDoux JE, Nader K (2002) Cellular and systems reconsolidation in the hippocampus. Neuron 36:527–538

    Article  CAS  PubMed  Google Scholar 

  • Dudai Y (2004) The neurobiology of consolidations, or, how stable is the engram? Annu Rev Psychol 55:51–86

    Article  PubMed  Google Scholar 

  • Ferree NK, Kamat R, Cahill L (2011) Influences of menstrual cycle position and sex hormone levels on spontaneous intrusive recollections following emotional stimuli. Conscious Cogn 20:1154–1162

    Article  PubMed  PubMed Central  Google Scholar 

  • Ferree NK, Wheeler M, Cahill L (2012) The influence of emergency contraception on post-traumatic stress symptoms following sexual assault. J Forensic Nurs 8:122–130

    Article  PubMed  PubMed Central  Google Scholar 

  • Forcato C, Fernandez RS, Pedreira ME (2014) Strengthening a consolidated memory: the key role of the reconsolidation process. J Physiol Paris 108:323–333

    Article  PubMed  Google Scholar 

  • Golkar A, Bellander M, Olsson A, Ohman A (2012) Are fear memories erasable?-reconsolidation of learned fear with fear-relevant and fear-irrelevant stimuli. Front Behav Neurosci 6:80

    Article  PubMed  PubMed Central  Google Scholar 

  • Guimaraes FS, Hellewell J, Hensman R, Wang M, Deakin JFW (1991) Characterization of a psychophysiological model of classical fear conditioning in healthy-volunteers—influence of gender, instruction, personality and placebo. Psychopharmacology 104:231–236

    Article  CAS  PubMed  Google Scholar 

  • Hwang MJ, Zsido RG, Song H, Pace-Schott EF, Miller KK, Lebron-Milad K et al (2015) Contribution of estradiol levels and hormonal contraceptives to sex differences within the fear network during fear conditioning and extinction. BMC Psychiatry 15:295

    Article  PubMed  PubMed Central  Google Scholar 

  • Joels M (2006) Corticosteroid effects in the brain: U-shape it. Trends Pharmacol Sci 27:244–250

    Article  CAS  PubMed  Google Scholar 

  • Joels M, Baram TZ (2009) The neuro-symphony of stress. Nat Rev Neurosci 10:459–466

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kandel ER (2001) The molecular biology of memory storage: a dialog between genes and synapses. Biosci Rep 21:565–611

    Article  CAS  PubMed  Google Scholar 

  • Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE (2005) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication (vol 62, pg 593, 2005). Arch Gen Psychiatr 62:768

  • Kindt M, Soeter M (2013) Reconsolidation in a human fear conditioning study: a test of extinction as updating mechanism. Biol Psychol 92:43–50

    Article  PubMed  Google Scholar 

  • Kindt M, Soeter M, Vervliet B (2009) Beyond extinction: erasing human fear responses and preventing the return of fear. Nat Neurosci 12:256–258

    Article  CAS  PubMed  Google Scholar 

  • Kirschbaum C, Hellhammer DH (1994) Salivary cortisol in psychoneuroendocrine research: recent developments and applications. Psychoneuroendocrinology 19:313–333

    Article  CAS  PubMed  Google Scholar 

  • Kirschbaum C, Kudielka BM, Gaab J, Schommer NC, Hellhammer DH (1999) Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. Psychosom Med 61:154–162

    Article  CAS  PubMed  Google Scholar 

  • Kuhlmann S, Wolf OT (2005) Cortisol and memory retrieval in women: influence of menstrual cycle and oral contraceptives. Psychopharmacology (Berl) 183:65–71

    Article  CAS  Google Scholar 

  • Kukolja J, Schlapfer TE, Keysers C, Klingmuller D, Maier W, Fink GR et al (2008) Modeling a negative response bias in the human amygdala by noradrenergic-glucocorticoid interactions. J Neurosci 28:12868–12876

    Article  CAS  PubMed  Google Scholar 

  • Likis FE (2002) Contraceptive applications of estrogen. J Midwifery Womens Health 47:139–156

    Article  PubMed  Google Scholar 

  • Maeng LY, Milad MR (2015) Sex differences in anxiety disorders: interactions between fear, stress, and gonadal hormones. Horm Behav

  • McGaugh JL (1966) Time-dependent processes in memory storage. Science 153:1351–1358

    Article  CAS  PubMed  Google Scholar 

  • Meir Drexler S, Merz CJ, Hamacher-Dang TC, Marquardt V, Fritsch N, Otto T et al (2014) Effects of postretrieval-extinction learning on return of contextually controlled cued fear. Behav Neurosci 128:474–481

    Article  PubMed  Google Scholar 

  • Meir Drexler S, Merz CJ, Hamacher-Dang TC, Tegenthoff M, Wolf OT (2015) Effects of cortisol on reconsolidation of reactivated fear memories. Neuropsychopharmacology 40:3036–3043

    Article  CAS  Google Scholar 

  • Merlo E, Milton AL, Goozee ZY, Theobald DE, Everitt BJ (2014) Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and molecular evidence. J Neurosci 34:2422–2431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Merz CJ, Wolf OT (2015) Stress and emotional learning in humans: evidence for sex differences. In: Shansky R (ed) Sex differences in the central nervous system. Elsevier, Oxford, pp 149–170

    Google Scholar 

  • Merz CJ, Tabbert K, Schweckendiek J, Klucken T, Vaitl D, Stark R et al (2012) Oral contraceptive usage alters the effects of cortisol on implicit fear learning. Horm Behav 62:531–538

    Article  CAS  PubMed  Google Scholar 

  • Milad MR, Goldstein JM, Orr SP, Wedig MM, Klibanski A, Pitman RK et al (2006) Fear conditioning and extinction: influence of sex and menstrual cycle in healthy humans. Biol Psychiatry 59:143S

    Google Scholar 

  • Milad MR, Igoe SA, Lebron-Milad K, Novales JE (2009) Estrous cycle phase and gonadal hormones influence conditioned fear extinction. Neuroscience 164:887–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Milad MR, Zeidan MA, Contero A, Pitman RK, Klibanski A, Rauch SL et al (2010) The influence of gonadal hormones on conditioned fear extinction in healthy humans. Neuroscience 168:652–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Misanin JR, Miller RR, Lewis DJ (1968) Retrograde amnesia produced by electroconvulsive shock after reactivation of a consolidated memory trace. Science 160:554–555

    Article  CAS  PubMed  Google Scholar 

  • Nader K, Schafe GE, LeDoux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722–726

    Article  CAS  PubMed  Google Scholar 

  • Nikzad S, Vafaei AA, Rashidy-Pour A, Haghighi S (2011) Systemic and intrahippocampal administrations of the glucocorticoid receptor antagonist RU38486 impairs fear memory reconsolidation in rats. Stress Int J Biol Stress 14:459–464

    Article  CAS  Google Scholar 

  • Otte C, Hart S, Neylan TC, Marmar CR, Yaffe K, Mohr DC (2005) A meta-analysis of cortisol response to challenge in human aging: importance of gender. Psychoneuroendocrinology 30:80–91

    Article  CAS  PubMed  Google Scholar 

  • Pitman RK (1989) Post-traumatic stress disorder, hormones, and memory. Biol Psychiatry 26:221–223

    Article  CAS  PubMed  Google Scholar 

  • Pitman RK, Milad MR, Igoe SA, Vangel MG, Orr SP, Tsareva A et al (2011) Systemic mifepristone blocks reconsolidation of cue-conditioned fear; propranolol prevents this effect. Behav Neurosci 125:632–638

    Article  PubMed  Google Scholar 

  • Rescorla RA (2004) Spontaneous recovery. Learn Mem 11:501–509

    Article  PubMed  Google Scholar 

  • Rescorla RA, Heth CD (1975) Reinstatement of fear to an extinguished conditioned stimulus. J Exp Psychol 104:88–96

    Google Scholar 

  • Rombold F, Wingenfeld K, Renneberg B, Hellmann-Regen J, Otte C, Roepke S (2015) Does the noradrenergic system influence intrusive memories? An experimental approach with a trauma film paradigm. Psychoneuroendocrinology 61:24

    Article  PubMed  Google Scholar 

  • Roozendaal B (2002) Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval. Neurobiol Learn Mem 78:578–595

    Article  CAS  PubMed  Google Scholar 

  • Schiller D, Delgado MR (2010) Overlapping neural systems mediating extinction, reversal and regulation of fear. Trends Cogn Sci 14:268–276

    Article  PubMed  Google Scholar 

  • Schiller D, Monfils MH, Raio CM, Johnson DC, LeDoux JE, Phelps EA (2010) Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463:49-U51

    Article  Google Scholar 

  • Sevenster D, Beckers T, Kindt M (2012) Retrieval per se is not sufficient to trigger reconsolidation of human fear memory. Neurobiol Learn Mem 97:338–345

    Article  PubMed  Google Scholar 

  • Sevenster D, Beckers T, Kindt M (2013) Prediction error governs pharmacologically induced amnesia for learned fear. Science 339:830–833

    Article  CAS  PubMed  Google Scholar 

  • Soeter M, Kindt M (2015) An abrupt transformation of phobic behavior after a post-retrieval amnesic agent. Biol Psychiatry

  • Soldin OP, Mattison DR (2009) Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 48:143–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki A, Josselyn SA, Frankland PW, Masushige S, Silva AJ, Kida S (2004) Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci 24:4787–4795

    Article  CAS  PubMed  Google Scholar 

  • Tabbert K, Merz CJ, Klucken T, Schweckendiek J, Vaitl D, Wolf OT et al (2011) Influence of contingency awareness on neural, electrodermal and evaluative responses during fear conditioning. Soc Cogn Affect Neurosci 6:495–506

    Article  PubMed  Google Scholar 

  • ter Horst JP, de Kloet ER, Schachinger H, Oitzl MS (2012) Relevance of stress and female sex hormones for emotion and cognition. Cell Mol Neurobiol 32:725–735

    Article  PubMed  Google Scholar 

  • Tollenaar MS, Elzinga BM, Spinhoven P, Everaerd W (2009) Psychophysiological responding to emotional memories in healthy young men after cortisol and propranolol administration. Psychopharmacology 203:793–803

    Article  CAS  PubMed  Google Scholar 

  • Wiemers US, Wolf OT (2015) Cortisol broadens memory of a non-stressful social interaction. Psychopharmacology (Berl) 232:1727–1733

    Article  CAS  Google Scholar 

  • Wood NE, Rosasco ML, Suris AM, Spring JD, Marin MF, Lasko NB et al (2015) Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies. Psychiatry Res 225:31–39

    Article  PubMed  Google Scholar 

  • Yang C, Liu JF, Chai BS, Fang Q, Chai N, Zhao LY et al (2013) Stress within a restricted time window selectively affects the persistence of long-term memory. Plos One 8

  • Yehuda R (2002) Post-traumatic stress disorder. N Engl J Med 346:108–114

    Article  CAS  PubMed  Google Scholar 

  • Yehuda R (2004) Risk and resilience in posttraumatic stress disorder. J Clin Psychiatry 65(Suppl 1):29–36

    CAS  PubMed  Google Scholar 

  • Yehuda R, Antelman SM (1993) Criteria for rationally evaluating animal models of posttraumatic stress disorder. Biol Psychiatry 33:479–486

    Article  CAS  PubMed  Google Scholar 

  • Yehuda R, LeDoux J (2007) Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56:19–32

    Article  CAS  PubMed  Google Scholar 

  • Zeidan MA, Igoe SA, Linnman C, Vitalo A, Levine JB, Klibanski A et al (2011) Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats. Biol Psychiatry 70:920–927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao LY, Zhang XL, Shi J, Epstein D, Lu L (2009) Psychosocial stress after reactivation of drug-related memory impairs later recall in abstinent heroin addicts. Psychopharmacology 203:599–608

    Article  CAS  PubMed  Google Scholar 

  • Zorawski M, Cook CA, Kuhn CM, LaBar KS (2005) Sex, stress, and fear: individual differences in conditioned learning. Cogn Affect Behav Neurosci 5:191–201

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Tobias Otto for technical support and Malte Dewies and Christoph Fraenz for their help in data collection and recruitment. The work was funded by project P5 of the German Research Foundation (DFG) Research Unit 1581 “Extinction Learning: Neural Mechanisms, Behavioral Manifestations, and Clinical Implications.” The DFG had no role in study design, data collection, analysis and interpretation, writing of the manuscript, or in the decision to submit the paper for publication.

Author information

Authors and Affiliations

  1. Department of Cognitive Psychology, Institute of Cognitive Neuroscience, Ruhr-University Bochum, Universitätsstraße 150, 44801, Bochum, Germany

    Shira Meir Drexler, Christian J. Merz, Tanja C. Hamacher-Dang & Oliver T. Wolf

  2. International Graduate School of Neuroscience, Ruhr-University Bochum, 44801, Bochum, Germany

    Shira Meir Drexler & Oliver T. Wolf

Authors
  1. Shira Meir Drexler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian J. Merz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tanja C. Hamacher-Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Oliver T. Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oliver T. Wolf.

Ethics declarations

Conflict of interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meir Drexler, S., Merz, C.J., Hamacher-Dang, T.C. et al. Cortisol effects on fear memory reconsolidation in women. Psychopharmacology 233, 2687–2697 (2016). https://doi.org/10.1007/s00213-016-4314-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4314-x

Keywords

Search

Navigation