Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Predictable maternal separation confers adult stress resilience via the medial prefrontal cortex oxytocin signaling pathway in rats

Abstract

Early-life stress is normally thought of as a major risk for psychiatric disorders, but many researchers have revealed that adversity early in life may enhance stress resilience later in life. Few studies have been performed in rodents to address the possibility that exposure to early-life stress may enhance stress resilience, and the underlying neural mechanisms are far from being understood. Here, we established a “two-hit” stress model in rats by applying two different early-life stress paradigms: predictable and unpredictable maternal separation (MS). Predictable MS during the postnatal period promotes resilience to adult restraint stress, while unpredictable MS increases stress susceptibility. We demonstrate that structural and functional impairments occur in glutamatergic synapses in pyramidal neurons of the medial prefrontal cortex (mPFC) in rats with unpredictable MS but not in rats with predictable MS. Then, we used differentially expressed gene (DEG) analysis of RNA sequencing data from the adult male PFC to identify a hub gene that is responsible for stress resilience. Oxytocin, a peptide hormone, was the highest ranked differentially expressed gene of these altered genes. Predictable MS increases the expression of oxytocin in the mPFC compared to normal raised and unpredictable MS rats. Conditional knockout of the oxytocin receptor in the mPFC was sufficient to generate excitatory synaptic dysfunction and anxiety behavior in rats with predictable MS, whereas restoration of oxytocin receptor expression in the mPFC modified excitatory synaptic function and anxiety behavior in rats subjected to unpredictable MS. These findings were further supported by the demonstration that blocking oxytocinergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the mPFC was sufficient to exacerbate anxiety behavior in rats exposed to predictable MS. Our findings provide direct evidence for the notion that predictable MS promotes stress resilience, while unpredictable MS increases stress susceptibility via mPFC oxytocin signaling in rats.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Maternal separation affects stress susceptibility and resilience in adult rats.
Fig. 2: Morphological changes in the mPFC and excitatory synaptic dysfunction in the mPFC pyramidal neurons of control and MS rats.
Fig. 3: Analysis of RNA-seq and oxytocin as a differential gene.
Fig. 4: Oxtr knock-down promotes RS induced anxiety-like behavior in PMS rats, and Oxtr overexpression attenuate RS induced anxiety-like behavior in UMS rats.
Fig. 5: PVN-mPFC OXT projections are necessary for anti-anxiety in PMS rats.

Similar content being viewed by others

Data availability

The RNA-seq datasets analyzed during the current study are available in the figshare repository, [https://doi.org/10.6084/m9.figshare.15170274].

References

  1. 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.

    Article  CAS  PubMed  Google Scholar 

  2. Nemeroff CB. Paradise lost: the neurobiological and clinical consequences of child abuse and neglect. Neuron. 2016;89:892–909.

    Article  CAS  PubMed  Google Scholar 

  3. Gunnar MR, Frenn K, Wewerka SS, Van Ryzin MJ. Moderate versus severe early life stress: associations with stress reactivity and regulation in 10-12-year-old children. Psychoneuroendocrinology. 2009;34:62–75.

    Article  PubMed  Google Scholar 

  4. Seery MD, Holman EA, Silver RC. Whatever does not kill us: cumulative lifetime adversity, vulnerability, and resilience. J Pers Soc Psychol. 2010;99:1025–41.

    Article  PubMed  Google Scholar 

  5. Schweizer S, Walsh ND, Stretton J, Dunn VJ, Goodyer IM, Dalgleish T. Enhanced emotion regulation capacity and its neural substrates in those exposed to moderate childhood adversity. Soc Cogn Affect Neurosci. 2016;11:272–81.

    Article  PubMed  Google Scholar 

  6. Harris MA, Brett CE, Starr JM, Deary IJ, McIntosh AM. Early-life predictors of resilience and related outcomes up to 66 years later in the 6-day sample of the 1947 Scottish mental survey. Soc Psychiatry Psychiatr Epidemiol. 2016;51:659–68.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Shapero BG, Hamilton JL, Stange JP, Liu RT, Abramson LY, Alloy LB. Moderate childhood stress buffers against depressive response to proximal stressors: a multi-wave prospective study of early adolescents. J Abnorm Child Psychol. 2015;43:1403–13.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ladd CO, Owens MJ, Nemeroff CB. Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology. 1996;137:1212–8.

    Article  CAS  PubMed  Google Scholar 

  9. Pena CJ, Kronman HG, Walker DM, Cates HM, Bagot RC, Purushothaman I, et al. Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. Science. 2017;356:1185–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Vetulani J. Early maternal separation a rodent model of depression and a prevailing human condition. Pharmacol Rep. 2013;65:1451–61.

    Article  PubMed  Google Scholar 

  11. Biggio F, Pisu MG, Garau A, Boero G, Locci V, Mostallino MC, et al. Maternal separation attenuates the effect of adolescent social isolation on HPA axis responsiveness in adult rats. Eur Neuropsychopharmacol. 2014;24:1152–61.

    Article  CAS  PubMed  Google Scholar 

  12. Wetulani J. Early maternal separation a rodent model of depression and a prevailing human condition. Pharmacol Rep. 2013;65:1451–62.

    Article  Google Scholar 

  13. Miller SM. Predictability and human stress: toward a clarification of evidence and theory. Adv Exp Soc Psychol. 1981;14:203–56.

    Article  Google Scholar 

  14. Corbett BF, Luz S, Arner J, Pearson-Leary J, Sengupta A, Taylor D, et al. Sphingosine-1-phosphate receptor 3 in the medial prefrontal cortex promotes stress resilience by reducing inflammatory processes. Nat Commun. 2019;10:3146.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Plotsky PM, Meaney MJ. Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Mol Brain Res. 1993;18:195–200.

    Article  CAS  PubMed  Google Scholar 

  16. Risher WC, Ustunkaya T, Singh Alvarado J, Eroglu C. Rapid Golgi analysis method for efficient and unbiased classification of dendritic spines. PLoS ONE. 2014;9:e107591.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bourne J, Harris KM. Do thin spines learn to be mushroom spines that remember? Curr Opin Neurobiol. 2007;17:381–6.

    Article  CAS  PubMed  Google Scholar 

  18. Boku S, Toda H, Nakagawa S, Kato A, Inoue T, Koyama T, et al. Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter. Biol Psychiatry. 2015;77:335–44.

    Article  CAS  PubMed  Google Scholar 

  19. Daniels WM, Pietersen CY, Carstens ME, Stein DJ. Maternal separation in rats leads to anxiety-like behavior and a blunted ACTH response and altered neurotransmitter levels in response to a subsequent stressor. Metab Brain Dis. 2004;19:3–14.

    Article  CAS  PubMed  Google Scholar 

  20. Authement ME, Kodangattil JN, Gouty S, Rusnak M, Symes AJ, Cox BM, et al. Histone deacetylase inhibition rescues maternal deprivation-induced GABAergic metaplasticity through restoration of AKAP signaling. Neuron. 2015;86:1240–52.

    Article  CAS  PubMed  Google Scholar 

  21. Liu C, Hao S, Zhu M, Wang Y, Zhang T, Yang Z. Maternal separation induces different autophagic responses in the hippocampus and prefrontal cortex of adult rats. Neuroscience. 2018;374:287–94.

    Article  CAS  PubMed  Google Scholar 

  22. Franklin TB, Linder N, Russig H, Thony B, Mansuy IM. Influence of early stress on social abilities and serotonergic functions across generations in mice. PLoS ONE. 2011;6:e21842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Uchida S, Hara K, Kobayashi A, Funato H, Hobara T, Otsuki K, et al. Early life stress enhances behavioral vulnerability to stress through the activation of REST4-mediated gene transcription in the medial prefrontal cortex of rodents. J Neurosci. 2010;30:15007–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shalev U, Kafkafi N. Repeated maternal separation does not alter sucrose-reinforced and open-field behaviors.pdf. Pharmacol Biochem Behav. 2002;73:115–22.

    Article  CAS  PubMed  Google Scholar 

  25. Marmendal M, Roman E, Eriksson CJ, Nylander I, Fahlke C. Maternal separation alters maternal care, but has minor effects on behavior and brain opioid peptides in adult offspring. Dev Psychobiol. 2004;45:140–52.

    Article  CAS  PubMed  Google Scholar 

  26. Macri S, Mason GJ, Wurbel H. Dissociation in the effects of neonatal maternal separations on maternal care and the offspring’s HPA and fear responses in rats. Eur J Neurosci. 2004;20:1017–24.

    Article  PubMed  Google Scholar 

  27. de Jongh R, Geyer MA, Olivier B, Groenink L. The effects of sex and neonatal maternal separation on fear-potentiated and light-enhanced startle. Behav Brain Res. 2005;161:190–6.

    Article  PubMed  Google Scholar 

  28. Roman E, Gustafsson L, Berg M, Nylander I. Behavioral profiles and stress-induced corticosteroid secretion in male Wistar rats subjected to short and prolonged periods of maternal separation. Horm Behav. 2006;50:736–47.

    Article  CAS  PubMed  Google Scholar 

  29. Kaneko WM, Riley EP, Ehlers CL. Behavioral and electrophysiological effects of early repeated maternal separation. Depression. 1994;2:43–53.

    Article  Google Scholar 

  30. Enthoven L, Oitzl MS, Koning N, van der Mark M, de Kloet ER. Hypothalamic-pituitary-adrenal axis activity of newborn mice rapidly desensitizes to repeated maternal absence but becomes highly responsive to novelty. Endocrinology. 2008;149:6366–77.

    Article  CAS  PubMed  Google Scholar 

  31. Simpson JR, Drevets WC, Snyder AZ, Gusnard DA, Raichle ME. Emotion-induced changes in human medial prefrontal cortex: II. During anticipatory anxiety. PNAS. 2001;98:688–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhao XH, Wang PJ, Li CB, Hu ZH, Xi Q, Wu WY, et al. Altered default mode network activity in patient with anxiety disorders: an fMRI study. Eur J Radio. 2007;63:373–8.

    Article  Google Scholar 

  33. Covington HE III, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci. 2010;30:16082–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Giacobbe P, Mayberg HS, Lozano AM. Treatment resistant depression as a failure of brain homeostatic mechanisms: implications for deep brain stimulation. Exp Neurol. 2009;219:44–52.

    Article  PubMed  Google Scholar 

  35. Bewernick BH, Hurlemann R, Matusch A, Kayser S, Grubert C, Hadrysiewicz B, et al. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry. 2010;67:110–6.

    Article  PubMed  Google Scholar 

  36. Perova Z, Delevich K, Li B. Depression of excitatory synapses onto parvalbumin interneurons in the medial prefrontal cortex in susceptibility to stress. J Neurosci. 2015;35:3201–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang M, Perova Z, Arenkiel BR, Li B. Synaptic modifications in the medial prefrontal cortex in susceptibility and resilience to stress. J Neurosci. 2014;34:7485–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Missig G, Ayers LW, Schulkin J, Rosen JB. Oxytocin reduces background anxiety in a fear-potentiated startle paradigm. Neuropsychopharmacology. 2010;35:2607–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Windle RJ, Kershaw YM, Shanks N, Wood SA, Lightman SL, Ingram CD. Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity. J Neurosci. 2004;24:2974–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, et al. Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci. 2005;25:11489–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rotzinger S, Lovejoy DA, Tan LA. Behavioral effects of neuropeptides in rodent models of depression and anxiety. Peptides. 2010;31:736–56.

    Article  CAS  PubMed  Google Scholar 

  42. Sabihi S, Durosko NE, Dong SM, Leuner B. Oxytocin in the prelimbic medial prefrontal cortex reduces anxiety-like behavior in female and male rats. Psychoneuroendocrinology. 2014;45:31–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li K, Nakajima M, Ibanez-Tallon I, Heintz N. A cortical circuit for sexually dimorphic oxytocin-dependent anxiety behaviors. Cell. 2016;167:60–72 e11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jurek B, Neumann ID. The oxytocin receptor: from intracellular signaling to behavior. Physiol Rev. 2018;98:1805–908.

    Article  CAS  PubMed  Google Scholar 

  45. Audigier S, Barberis C. Pharmacological characterization of two specific binding sites for neurohypophyseal hormones in hippocampal synaptic plasma membranes of the rat. EMBO J. 1985;4:1407–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Langer SZ. Presynaptic autoreceptors regulating transmitter release. Neurochem Int. 2008;52:26–30.

    Article  CAS  PubMed  Google Scholar 

  47. Vaidyanathan R, Hammock EAD. Oxytocin receptor gene loss influences expression of the oxytocin gene in C57BL/6J mice in a sex- and age-dependent manner. J Neuroendocrinol. 2020;32:e12821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Blank T, Detje CN, Spiess A, Hagemeyer N, Brendecke SM, Wolfart J, et al. Brain endothelial- and epithelial-specific interferon receptor chain 1 drives virus-induced sickness behavior and cognitive impairment. Immunity. 2016;44:901–12.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (31900730), Shanghai Science and Technology Committee (20XD1423100, 19YF14420000), Shanghai Municipal Education Commission (2021-01-07-00-02-E0086), Shanghai Municipal Health Commission (2019ZB0201).

Author information

Authors and Affiliations

Authors

Contributions

ZW and DDS conceived the study design. DDS performed all in vitro electrophysiology experiments, immunohistochemistry experiments and behavioral tests, with the help of YDZ and YYR; YDZ and SYP analyzed the behavioral test and electrophysiology experiments; DDS wrote the paper. ZW and TFY reviewed and edited the paper.

Corresponding author

Correspondence to Zhen Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, DD., Zhang, YD., Ren, YY. et al. Predictable maternal separation confers adult stress resilience via the medial prefrontal cortex oxytocin signaling pathway in rats. Mol Psychiatry 26, 7296–7307 (2021). https://doi.org/10.1038/s41380-021-01293-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01293-w

This article is cited by

Search

Quick links