Abstract
Childhood and adolescent stress increase the risk of postpartum depression (PPD), often providing an increased probability of treatment refractoriness. Nevertheless, the mechanisms linking childhood and adolescent stress to PPD remain unclear. Here we investigated the longitudinal effects of adolescent stress on the hypothalamic–pituitary–adrenal axis and postpartum behaviors in mice and humans. Adolescent social isolation prolonged glucocorticoid elevation, leading to long-lasting postpartum behavioral changes in female mice. These changes were unresponsive to current PPD treatments but improved with post-delivery glucocorticoid receptor antagonist treatment. Childhood and adolescent stress significantly impacted hypothalamic–pituitary–adrenal axis dysregulation and PPD in human females. Repurposing glucocorticoid receptor antagonists for some cases of treatment-resistant PPD may be considered.
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Acknowledgements
We thank Corcept Therapeutics, especially H. Hunt and J. K. Belanoff for providing the GR antagonist CORT113176 and technical support for its use in an academic study. We also thank clinical study participants and staff members. We appreciate C. Erdly and D. Mallah for their technical help, and M. A. Landek-Salgado for scientific reading. This work was supported by the National Institutes of Health (MH-092443 (A.S.), MH-094268 Silvio O. Conte Center (A.S.), K99MH-094408 (M.N.), MH-105660 (A.S.), MH-107730 (A.S.), DA-040127 (A.S. and M.N.), and MH-116869 (M.N.)), NARSAD (A.S. and M.N.), Stanley (A.S.), S-R/RUSK (A.S.), JST PRESTO JPMJPR14M6 (M.N.), UAB Psychiatry startup funds (M.N.) and UAB Comprehensive Neuroscience Center Pilot Award (M.N. and S.K.).
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M.N. conceived and designed the project, and supervised S.L., D.J.W., J.F.-O., K.K. and A.A. for practical experiments with the help of S.K. and the guidance of A.S. Experiments were performed by M.N., S.L., D.J.W., J.F.-O., K.K. and A.A. Data were analyzed by M.N., K.Y., J.F.-O. and K.K. The first manuscript draft was written by M.N. and A.S. with input from all the authors. M.N. and A.S. revised and edited the manuscript for the final version. G.S.W. provided expertise of endocrinology in a translationally relevant manner. J.L.P. provided human plasma samples with participants’ information as well as expertise of postpartum mood disorders.
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Extended data
Extended Data Fig. 1 Experimental schedule of the preclinical study.
A, Virgin female mice were group-housed. B, Virgin female mice were isolated from 5 to 8 weeks of age. C, Virgin female mice were group-housed, mated with a male mouse, and gave birth to pups. D, Virgin female mice were isolated from 5 to 8 weeks of age, mated with a male mouse, and gave birth to pups. TST, tail suspension test; FST, forced swim test; SIT, three-chamber social interaction test. Different cohorts of mice subjected to behavioral tests at 0 week, 1 week, and 3 weeks postpartum were studied to avoid the repeated exposure to stressful behavioral procedures.
Extended Data Fig. 2 Long-lasting behavioral changes in the social interaction test in dams exposed to adolescent social isolation.
Sniffing time and indexes of sociability and social novelty recognition during the three-chamber social interaction test were measured at postpartum days 0, 7, and 21. No changes in sociability or social novelty recognition among the four groups were observed at postpartum day 0. Behavioral changes in social novelty recognition, but not sociability, were observed in stressed dams at postpartum days 7 and 21. Postpartum day 0/Unstressed virgins, N = 10; Postpartum day 0/Stressed virgins, N = 9; Postpartum day 0/Unstressed dams, N = 10; Postpartum day 0/Stressed dams, N = 9; Postpartum day 7/Unstressed virgins, N = 10; Postpartum day 7/Stressed virgins, N = 10; Postpartum day 7/Unstressed dams, N = 10; Postpartum day 7/Stressed dams, N = 11; Postpartum day 21/Unstressed virgins, N = 10; Postpartum day 21/Stressed virgins, N = 10; Postpartum day 21/Unstressed dams, N = 12; Postpartum day 21/Stressed dams, N = 11. Values are represented as mean ± SEM; **P < 0.01 and *P < 0.05. See Supplementary Table 1 for details on the statistical analyses.
Extended Data Fig. 3 No change in the levels of plasma estradiol, progesterone, oxytocin, and prolactin in mice exposed to adolescent social isolation.
Levels of estradiol, progesterone, oxytocin, and prolactin in plasma were measured at four-time points (virgin, late pregnancy, 0 week postpartum, and 1 week postpartum). No differences in the levels of estradiol, progesterone, oxytocin, and prolactin were observed between unstressed and stressed mice at any time point. N = 9–20 (precise values detailed in Supplementary Table 1). Values are represented as mean ± SEM. See Supplementary Table 1 for details on the statistical analyses.
Extended Data Fig. 4 Positive correlation between plasma corticosterone levels and immobility time in the tail suspension and forced swim tests at 1 week and 3 weeks after delivery.
The levels of plasma corticosterone (CORT) were positively correlated with immobility time in the tail suspension test (TST) and forced swim test (FST) at 1 week and 3 weeks after delivery. 1 week postpartum/Unstressed dams, N = 9; 1 week postpartum/Stressed dams, N = 10; 3 weeks postpartum/Unstressed dams, N = 12; 3 weeks postpartum/Stressed dams, N = 11. Spearman and Pearson rank correlation coefficients were examined for the data at 1 week and 3 weeks postpartum, respectively. See Supplementary Table 1 for details on the statistical analyses.
Extended Data Fig. 5 Dose-response effects of a SSRI, a GABAA receptor modulator, or a GR antagonist on behavioral changes in dams exposed to adolescent social isolation.
A–C, Stressed dams were treated with a SSRI fluoxetine (18, 36, 52 mg/kg, p.o.) (A), a GABAA receptor modulator ganaxolone (10, 20, 30 mg/kg, i.p.) (B), or a GR antagonist CORT113176 (40, 80, 160 mg/kg, p.o.) (C) once daily from postpartum day 0 to 24 h prior to sampling at postpartum day 9. Post-delivery treatment with only the GR antagonist at 40 and 80 mg/kg ameliorated the behavioral changes in the tail suspension test on postpartum day 7 in stressed dams. Post-delivery treatment with only the GR antagonist at 80 mg/kg ameliorated the behavioral changes in forced swim test on postpartum day 8 in stressed dams N = 12. Values are represented as mean ± SEM; **P < 0.01 and *P < 0.05. See Supplementary Table 1 for details on the statistical analyses.
Extended Data Fig. 6 No effect of a GR antagonist, a SSRI, and an allopregnanolone analog on body weight.
A, CORT113176 (80 mg/kg, p.o., once daily from gestation day 14 to 24 h prior to behavioral testing), a selective GR antagonist, did not affect body weight after the forced swim test at postpartum day 8 in either group. B, Post-delivery treatment with a SSRI fluoxetine (18 mg/kg, p.o.), a GABAA receptor modulator ganaxolone (10 mg/kg, i.p.), or CORT113176 (80 mg/kg, p.o.) once daily from postpartum day 0 to 24 h prior to behavioral testing did not affect body weight after the forced swim test at postpartum day 8 in any of the groups. N = 12. Values are represented as mean ± SEM. See Supplementary Table 1 for details on the statistical analyses.
Extended Data Fig. 7 No effect of a GR antagonist on blood glucose levels and weight of the thymus, spleen, and visceral fat.
A, After fasting for 6 hours, glucose (2 g/kg) was administered intraperitoneally and blood glucose levels at 0, 30, 60, 90, and 120 minutes were examined on postnatal day 8. CORT113176 (80 mg/kg, p.o., once daily from postpartum day 0 to 24 h prior to the blood glucose testing at postpartum day 8), a selective GR antagonist, did not affect blood glucose levels in either group. B-D, Thymus, spleen, and visceral fat weights were measured after blood glucose testing at postpartum day 8. CORT113176 (80 mg/kg, p.o., once daily from postpartum day 0 to 24 h prior to the blood glucose testing at postpartum day 8) had no effect on weight of the thymus (B), spleen (C), and visceral fat (D) in any groups. Unstressed/Vehicle, N = 6; Unstressed/GR antagonist, N = 6; Stressed/Vehicle, N = 6; Stressed/GR antagonist, N = 7. Values are represented as mean ± SEM. See Supplementary Table 1 for details on the statistical analyses.
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Supplementary Table 1: Statistical results.
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Niwa, M., Lockhart, S., Wood, D.J. et al. Prolonged HPA axis dysregulation in postpartum depression associated with adverse early life experiences: a cross-species translational study. Nat. Mental Health 2, 593–604 (2024). https://doi.org/10.1038/s44220-024-00217-1
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DOI: https://doi.org/10.1038/s44220-024-00217-1
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