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Social experience in adolescence shapes prefrontal cortex structure and function in adulthood

Molecular Psychiatry (2024)Cite this article

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Abstract

During adolescence, the prefrontal cortex (PFC) undergoes dramatic reorganization. PFC development is profoundly influenced by the social environment, disruptions to which may prime the emergence of psychopathology across the lifespan. We investigated the neurobehavioral consequences of isolation experienced in adolescence in mice, and in particular, the long-term consequences that were detectable even despite normalization of the social milieu. Isolation produced biases toward habit-like behavior at the expense of flexible goal seeking, plus anhedonic-like reward deficits. Behavioral phenomena were accompanied by neuronal dendritic spine over-abundance and hyper-excitability in the ventromedial PFC (vmPFC), which was necessary for the expression of isolation-induced habits and sufficient to trigger behavioral inflexibility in socially reared controls. Isolation activated cytoskeletal regulatory pathways otherwise suppressed during adolescence, such that repression of constituent elements prevented long-term isolation-induced neurosequelae. Altogether, our findings unveil an adolescent critical period and multi-model mechanism by which social experiences facilitate prefrontal cortical maturation.

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Fig. 1: Social isolation during adolescence causes persistent reward-related behavioral effects despite re-socialization (RS) in adulthood or non-social environmental enrichment (EE).
Fig. 2: Social isolation during adolescence produces persistent dendritic spine over-abundance on deep-layer vmPFC neurons.
Fig. 3: Intrinsic and synaptic hyper-excitability among deep-layer vmPFC neurons following adolescent social isolation.
Fig. 4: vmPFC neuron activity bidirectionally modulates flexible decision making.
Fig. 5: Viral-mediated Rock2 knockdown (KD) in the vmPFC during adolescence, but not adulthood, blocks long-term behavioral deficits following social isolation.

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Individual data points are reported throughout. Data may be available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by NIH grants F30MH117873 (DCL), R01MH117103 (SLG), and P50MH100023 (SLG). The Emory National Primate Research Center is supported by the Office of Research Infrastructure Programs grant P30OD011132. The Emory Viral Vector Core is supported by NINDS Core Facilities grant P30NS055077. The Emory Integrated Genomics Core is a shared resource of Winship Cancer Institute of Emory University and NIH/NCI under grant P30CA138292. Additional research support was provided by The Marcus Foundation, Children’s Healthcare of Atlanta, and Emory University’s Pediatrics Integrated Cellular Imaging Core.

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Authors and Affiliations

  1. Medical Scientist Training Program, Emory University School of Medicine, Atlanta, GA, USA

    Dan C. Li

  2. Emory National Primate Research Center, Emory University, Atlanta, GA, USA

    Dan C. Li, Elizabeth A. Hinton, Jidong Guo, Kristopher A. Knight, Michelle K. Sequeira, Meghan E. Wynne, Niharika M. Dighe & Shannon L. Gourley

  3. Department of Pediatrics, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA

    Elizabeth A. Hinton, Michelle K. Sequeira, Niharika M. Dighe & Shannon L. Gourley

  4. Department of Psychiatry and Behavioral sciences, Emory University School of Medicine, Atlanta, GA, USA

    Jidong Guo & Shannon L. Gourley

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  1. Dan C. Li
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Contributions

Conceptualization: DCL, EAH, SLG. Methodology: DCL, EAH, JDG, SLG. Investigation: DCL, EAH, JDG, KAK, MKS, MEW, NMD. Formal Analysis: JDG, MEW, DCL. Writing: DCL, SLG. Supervision: SLG.

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Correspondence to Dan C. Li or Shannon L. Gourley.

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Li, D.C., Hinton, E.A., Guo, J. et al. Social experience in adolescence shapes prefrontal cortex structure and function in adulthood. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02540-6

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