Perinatal SSRI exposure impacts innate fear circuit activation and behavior in mice and humans
Before assuming its role in the mature brain, serotonin modulates early brain development across phylogenetically diverse species. In mice and humans, early-life SSRI exposure alters the offspring's brain structure and is associated with anxiety and depression-related behaviors beginning in puberty. However, the impact of early-life SSRI exposure on brain circuit function is unknown. To address this question, we examined how developmental SSRI exposure changes fear-related brain activation and behavior in mice and humans. SSRI-exposed mice showed increased defense responses to a predator odor, and stronger fMRI amygdala and extended fear-circuit activation. Likewise, adolescents exposed to SSRIs in utero exhibited higher anxiety and depression symptoms than unexposed adolescents and also had greater activation of the amygdala and other limbic structures when processing fearful faces. These findings demonstrate that increases in anxiety and fear-related behaviors as well as brain circuit activation following developmental SSRI exposure are conserved between mice and humans. These findings have potential implications for the clinical use of SSRIs during human pregnancy and for designing interventions that protect fetal brain development.
Authors
- Kiyohito Iigaya (ORCID: https://orcid.org/0000-0002-4748-8432)
- Myrna M. Weissman (ORCID: https://orcid.org/0000-0003-3490-3075)
- Jay A. Gingrich (ORCID: https://orcid.org/0000-0002-7890-0389)
- Praveen Kulkarni (ORCID: https://orcid.org/0000-0003-1134-4442)
- Mark S. Ansorge (ORCID: https://orcid.org/0000-0002-1467-0107)
- Giulia Zanni (ORCID: https://orcid.org/0000-0003-0384-3954)
- Ardesheer Talati (ORCID: https://orcid.org/0000-0001-5708-1372)
- Alexander L. Kesin
- Milenna T. van Dijk (ORCID: https://orcid.org/0000-0002-7936-2746)
- Ariel L. Rose
- Claudia I. Lugo-Candelas (ORCID: https://orcid.org/0000-0002-8388-9479)
- Craig F. Ferris (ORCID: https://orcid.org/0000-0001-9744-5214)
- Nicolò Pini (ORCID: https://orcid.org/0000-0002-0839-6033)
- Pradyumna Sepúlveda (ORCID: https://orcid.org/0000-0003-0159-6777)
- Priscila Dib Gonçalves (ORCID: https://orcid.org/0000-0002-7684-0554)
- Alexandra S. MacKay
- Martha Caffrey Cagliostro
Institutions
- Northeastern University (US)
- Allen Institute for Brain Science (US)
- New York Psychoanalytic Society and Institute (US)
- New York State Psychiatric Institute
- Columbia University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-06
- DOI
- https://doi.org/10.1038/s41467-025-58785-4
- Citations
- 9
- Primary Topic
- Stress Responses and Cortisol
- Type
- article
- Field-Weighted Citation Impact
- 10.01
Funders
- American Foundation for Suicide Prevention
- National Institutes of Health
- National Institute of Mental Health