Post-retrieval oxytocin facilitates next day extinction of threat memory in humans
Memories can return to a labile state and become amenable to modification by pharmacological and behavioral manipulations after retrieval. This process may reduce the impact of aversive memories and provide a promising therapeutic technique for the treatment of anxiety disorders. A growing body of evidence suggests that the mammalian neuropeptide oxytocin (OT) plays a role in the regulation of emotional memories in animals. However, the effects of OT on threat memory in humans remain largely unknown.
This study aimed to investigate the effects of OT administration following threat memory retrieval on subsequent memory expression in human participants.
In a double-blind, randomized, placebo-controlled, between-subject design, 61 healthy human individuals completed a 3-day experiment. All the participants underwent threat conditioning on day 1. On day 2, the participants were randomized to receive an intranasal dose of OT (40 IU) or placebo after memory retrieval, or an intranasal dose of OT (40 IU) without retrieval. On day 3, the participants were tested for extinction and reinstatement.
On day 3, all groups showed equivalent stimulus discrimination during the early phase of extinction. However, the group that received OT following a memory reminder showed a greater decline in stimulus discrimination by the late phase of extinction relative to the two other groups.
The results indicate that OT did not block reconsolidation to prevent the return of threat memory but rather interacted with post-retrieval processes to facilitate next day extinction. The study provides novel preliminary evidence for the role of OT in human threat memory.
KeywordsOxytocin Fear conditioning Extinction Reactivation Reconsolidation
The authors thank Xiaoting Chen for the assistance with data collection and Xifu Zheng and Li Yang for the helpful discussions.
J.H., C.L., and D.S. designed the study. Z.W. and X.F. collected and scored the data. J.H. analyzed the data. D.S. contributed to data analysis; J.H. and D.S. wrote the first draft of the manuscript. All the authors contributed to the final version of the manuscript.
Funding was provided by the NIH MH105535 R01 grant and a Klingenstein-Simons Fellowship Award in the Neurosciences to D.S.; a grant from the National Natural Science Foundation of China (31871170) to C.L.; and the PhD Research Startup Foundation of Guangdong province to J.H.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Acheson D, Feifel D, de Wilde S, McKinney R, Lohr J, Risbrough V (2013) The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample. Psychopharmacology 229(1):199–208. https://doi.org/10.1007/s00213-013-3099-4 CrossRefPubMedPubMedCentralGoogle Scholar
- Agren T (2014) Human reconsolidation: a reactivation and update. Brain Res Bull 105:70–82. https://doi.org/10.1016/j.brainresbull.2013.12.010 CrossRefPubMedGoogle Scholar
- Maejima Y, Rita RS, Santoso P, Aoyama M, Hiraoka Y, Nishimori K, Gantulga D, Shimomura K, Yada T (2015) Nasal oxytocin administration reduces food intake without affecting locomotor activity and glycemia with c-fos induction in limited brain areas. Neuroendocrinology 101(1):35–44. https://doi.org/10.1159/000371636 CrossRefPubMedGoogle Scholar
- Peters S, Slattery DA, Uschold-Schmidt N, Reber SO, Neumann ID (2014) Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice. Psychoneuroendocrinology 42:225–236. https://doi.org/10.1016/j.psyneuen.2014.01.021 CrossRefPubMedGoogle Scholar
- Striepens N, Kendrick KM, Hanking V, Landgraf R, Wüllner U, Maier W, Hurlemann R (2013) Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci Rep 3(6163):3440. https://doi.org/10.1038/srep03440 CrossRefPubMedPubMedCentralGoogle Scholar
- Vervliet B, Craske MG, Hermans D (2013) Fear extinction and relapse: state of the art. Annu Rev Clin Psychol 9:215–248. https://doi.org/10.1146/annurev-clinpsy-050212-185542 CrossRefPubMedGoogle Scholar
- Warren VT, Anderson KM, Kwon C, Bosshardt L, Jovanovic T, Bradley B, Norrholm SD (2014) Human fear extinction and return of fear using reconsolidation update mechanisms: the contribution of on-line expectancy ratings. Neurobiol Learn Mem 113:165–173. https://doi.org/10.1016/j.nlm.2013.10.014 CrossRefPubMedGoogle Scholar