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Nurture outpaces nature: fostering with an attentive mother alters social dominance in a mouse model of stress sensitivity

Molecular Psychiatry volume 28, pages 3816–3828 (2023)Cite this article

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Abstract

Maternal care is critical for epigenetic programming during postnatal brain development. Stress is recognized as a critical factor that may affect maternal behavior, yet owing to high heterogeneity in stress response, its impact varies among individuals. We aimed here to understand the connection between inborn stress vulnerability, maternal care, and early epigenetic programming using mouse populations that exhibit opposite poles of the behavioral spectrum (social dominance [Dom] and submissiveness [Sub]) and differential response to stress. In contrast to stress-resilient Dom dams, stress-vulnerable Sub dams exhibit significantly lower maternal attachment, serum oxytocin, and colonic Lactobacillus reuteri populations. Sub offspring showed a reduced hippocampal expression of key methylation genes at postnatal day (PND) 7 and a lack of developmentally-dependent increase in 5-methylcytosine (5-mC) at PND 21. In addition, Sub pups exhibit significant hypermethylation of gene promoters connected with glutamatergic synapses and behavioral responses. We were able to reverse the submissive endophenotype through cross-fostering Sub pups with Dom dams (Sub/D). Thus, Sub/D pups exhibited elevated hippocampal expression of DNMT3A at PND 7 and increased 5-mC levels at PND 21. Furthermore, adult Sub/D offspring exhibited increased sociability, social dominance, and hippocampal glutamate and monoamine levels resembling the neurochemical profile of Dom mice. We postulate that maternal inborn stress vulnerability governs epigenetic patterning sculpted by maternal care and intestinal microbiome diversity during early developmental stages and shapes the array of gene expression patterns that may dictate neuronal architecture with a long-lasting impact on stress sensitivity and the social behavior of offspring.

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Fig. 1: Sub dams exhibit poor maternal care, low serum oxytocin, and low Lactobacillus reuteri abundance in the intestinal microbiome, impacting pup behavior and hippocampal epigenetics machinery.
Fig. 2: Differential methylation patterns in hippocampi of dominant and submissive mice.
Fig. 3: Gene set enrichment analysis (GSEA).
Fig. 4: Cross-fostering with Dom mothers improves Sub pup methylation-related gene expression, development, and metabolic features.
Fig. 5: Cross-fostering of Sub mice produced improved social and anxiety-like/repetitive behaviors.
Fig. 6: Assessment of hippocampal neurochemistry and neurophysiology in cross-fostered mice.

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Acknowledgements

This work was supported by a grant from the Israel Science Foundation (Grant no 2069/17) supporting AP. AP and EL were supported by a grant from the Israel Ministry of Health. DS was supported by PBC post-doctoral fellowship grant.

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  1. Department of Molecular Biology, Faculty of Natural Sciences, Ariel University, Ramat HaGolan St 65, 4077625, Ariel, Israel

    Debpali Sur, Oryan Agranyoni, Naamah Cohen, Anastasia Bagaev, Kristina Karandasheva, Elena Shmerkin, Denis Gorobets, Brajesh Kumar Savita, Raphael Avneri, Mali-Salmon Divon, Elad Lax, Izhak Michaelevski & Albert Pinhasov

  2. Dr. Miriam and Sheldon G. Adelson School of Medicine, Ariel University, Ariel, Israel

    Michael Kirby, Mali-Salmon Divon & Albert Pinhasov

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Contributions

DS performed all the experiments and wrote the manuscript. AP conceived the idea. MK helped with study design, data analysis, statistics, and manuscript writing. OA, NC, AB, and BKS assisted in animal studies, histology, and behavioral experiments. ES assisted with HPLC. KK and RA conducted the bioinformatics analysis under the supervision of EL and MSD. DG performed in electrophysiology experiments and IM helped in interpretation and analysis of electrophysiological experiments.

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Correspondence to Albert Pinhasov.

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Sur, D., Agranyoni, O., Kirby, M. et al. Nurture outpaces nature: fostering with an attentive mother alters social dominance in a mouse model of stress sensitivity. Mol Psychiatry 28, 3816–3828 (2023). https://doi.org/10.1038/s41380-023-02273-y

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