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.
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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
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.
Nemeroff CB. Paradise lost: the neurobiological and clinical consequences of child abuse and neglect. Neuron. 2016;89:892–909.
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.
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.
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.
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.
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.
Ladd CO, Owens MJ, Nemeroff CB. Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology. 1996;137:1212–8.
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.
Vetulani J. Early maternal separation a rodent model of depression and a prevailing human condition. Pharmacol Rep. 2013;65:1451–61.
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.
Wetulani J. Early maternal separation a rodent model of depression and a prevailing human condition. Pharmacol Rep. 2013;65:1451–62.
Miller SM. Predictability and human stress: toward a clarification of evidence and theory. Adv Exp Soc Psychol. 1981;14:203–56.
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.
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.
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.
Bourne J, Harris KM. Do thin spines learn to be mushroom spines that remember? Curr Opin Neurobiol. 2007;17:381–6.
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.
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.
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.
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.
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.
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.
Shalev U, Kafkafi N. Repeated maternal separation does not alter sucrose-reinforced and open-field behaviors.pdf. Pharmacol Biochem Behav. 2002;73:115–22.
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.
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.
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.
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.
Kaneko WM, Riley EP, Ehlers CL. Behavioral and electrophysiological effects of early repeated maternal separation. Depression. 1994;2:43–53.
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.
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.
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.
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.
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.
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.
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.
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.
Missig G, Ayers LW, Schulkin J, Rosen JB. Oxytocin reduces background anxiety in a fear-potentiated startle paradigm. Neuropsychopharmacology. 2010;35:2607–16.
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.
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.
Rotzinger S, Lovejoy DA, Tan LA. Behavioral effects of neuropeptides in rodent models of depression and anxiety. Peptides. 2010;31:736–56.
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.
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.
Jurek B, Neumann ID. The oxytocin receptor: from intracellular signaling to behavior. Physiol Rev. 2018;98:1805–908.
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.
Langer SZ. Presynaptic autoreceptors regulating transmitter release. Neurochem Int. 2008;52:26–30.
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.
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.
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).
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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.
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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
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DOI: https://doi.org/10.1038/s41380-021-01293-w
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