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Early-life prefrontal cortex inhibition and early-life stress lead to long-lasting behavioral, transcriptional, and physiological impairments

Molecular Psychiatry (2024)Cite this article

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Abstract

Early-life stress has been linked to multiple neurodevelopmental and neuropsychiatric deficits. Our previous studies have linked maternal presence/absence from the nest in developing rat pups to changes in prefrontal cortex (PFC) activity. Furthermore, we have shown that these changes are modulated by serotonergic signaling. Here we test whether changes in PFC activity during early life affect the developing cortex leading to behavioral alterations in the adult. We show that inhibiting the PFC of mouse pups leads to cognitive deficits in the adult comparable to those seen following maternal separation. Moreover, we show that activating the PFC during maternal separation can prevent these behavioral deficits. To test how maternal separation affects the transcriptional profile of the PFC we performed single-nucleus RNA-sequencing. Maternal separation led to differential gene expression almost exclusively in inhibitory neurons. Among others, we found changes in GABAergic and serotonergic pathways in these interneurons. Interestingly, both maternal separation and early-life PFC inhibition led to changes in physiological responses in prefrontal activity to GABAergic and serotonergic antagonists that were similar to the responses of more immature brains. Prefrontal activation during maternal separation prevented these changes. These data point to a crucial role of PFC activity during early life in behavioral expression in adulthood.

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Fig. 1: DREADDs expression and response to CNO in early life.
Fig. 2: Maternal separation leads to cognitive deficits.
Fig. 3: Early-life PFC inhibition leads to cognitive deficits.
Fig. 4: Early-life PFC excitation blocks cognitive deficits induced by maternal separation.
Fig. 5: Transcriptome-based cell classification and differential comparison by age and rearing in the mouse PFC.
Fig. 6: Maternal separation affected pathways related to development, glutamatergic/GABAergic and serotonergic function, in interneurons.
Fig. 7: PFC responses to GABAergic and serotonergic modulation.
Fig. 8: PFC responses to GABAergic and serotonergic modulation.

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Data availability

snRNA-seq data have been deposited in the NCBI Gene Expression Omnibus (GEO) database and are publicly accessible through GEO accession number GSE254342.

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Acknowledgements

This work has been supported by the National Institute of Child Health and Human Development (R01HD095966 and R01HD110541). We thank Catarina Cunha for setting up and training in the VSD experiments.

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Author notes

  1. These authors contributed equally: Edênia C. Menezes, Heather Geiger.

Authors and Affiliations

  1. Emotional Brain Institute, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, 10962, USA

    Edênia C. Menezes, Fabiula F. Abreu, Lital Rachmany, Donald A. Wilson, Melissa J. Alldred, Francisco X. Castellanos & Cátia M. Teixeira

  2. Department of Child and Adolescent Psychiatry, New York University Grossman School of Medicine, New York, NY, 10016, USA

    Edênia C. Menezes, Fabiula F. Abreu, Lital Rachmany, Donald A. Wilson, Francisco X. Castellanos & Cátia M. Teixeira

  3. New York Genome Center, New York, NY, 10013, USA

    Heather Geiger, Rui Fu & André Corvelo

  4. Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, 10016, USA

    Melissa J. Alldred

  5. Department of Psychology, Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, T2N 1N4, Canada

    Derya Sargin

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Contributions

CMT designed the experiments and supervised the project. ECM, CMT, LR, and FA performed the behavioral manipulations, physiological experiments, and analyzed the data. DAW set up the in vivo recordings. MJA performed the pathway analysis. HG, RF, and AC designed, performed, and analyzed the snRNA sequencing experiments. DS designed and supervised the patch-clamp experiments. CMT and FXC wrote the paper with contributions from all co-authors.

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Correspondence to Cátia M. Teixeira.

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Menezes, E.C., Geiger, H., Abreu, F.F. et al. Early-life prefrontal cortex inhibition and early-life stress lead to long-lasting behavioral, transcriptional, and physiological impairments. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02499-4

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