Multilevel sex-influenced neurobiological signatures of early life adversity
Stress exposure early in life is an established risk factor for adult psychiatric illness, yet these disorders-including anxiety disorders and depression-show significant sex differences in prevalence, symptomatology, and treatment response. The biology underlying these differences remains largely unexplored and may contribute to the clinical heterogeneity in anxiety and depression. Here, we characterize the lasting impact of developmental stress on adulthood neurobiology and behavior in mice by combining analyses of multiple levels of brain function, including whole-brain c-Fos mapping, manganese-enhanced MRI, and transcriptomics with advanced behavioral phenotyping. Across levels of investigation, we find distinct and often opposite effects of developmental stress based on sex. These results together showcase the strong influence of sex on how early life adversity affects the onset of stress-related disorders. This work emphasizes the necessity of considering sex when investigating developmental and neurobiological underpinnings of stress-related disorders and displays a vast range of lasting effects of developmental stress on the brain, which provides a valuable resource for future studies aiming to improve psychiatric treatments.
Authors
- Stoyo Karamihalev (ORCID: https://orcid.org/0000-0002-1774-1548)
- Shiladitya Mitra (ORCID: https://orcid.org/0000-0002-0741-9424)
- Elisabeth B. Binder (ORCID: https://orcid.org/0000-0001-7088-6618)
- Darina Czamara (ORCID: https://orcid.org/0000-0001-7381-904X)
- Patrícia Pelufo Silveira (ORCID: https://orcid.org/0000-0001-8626-2519)
- Patrícia Maidana Miguel (ORCID: https://orcid.org/0000-0001-7427-0159)
- Susann Sauer
- Bonnie Alberry (ORCID: https://orcid.org/0000-0003-1713-821X)
- Veronika Kovářová
- Mathias V. Schmidt (ORCID: https://orcid.org/0000-0002-3788-2268)
- Christina Beer (ORCID: https://orcid.org/0000-0003-4832-9270)
- Michael Czisch (ORCID: https://orcid.org/0000-0002-3682-631X)
- Tibor Štark (ORCID: https://orcid.org/0000-0001-8118-9914)
- Sowmya Narayan (ORCID: https://orcid.org/0000-0003-3675-1685)
- Joeri Bordes (ORCID: https://orcid.org/0000-0003-2909-2976)
- Simone Röh
- Carlo Castoldi
- Beatrice Dal Bianco
- Bianca Silva
Institutions
- Inserm (FR)
- Douglas Mental Health University Institute (CA)
- Cognitive Neuroimaging Lab (FR)
- Max Planck Institute of Psychiatry (DE)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-08-27
- DOI
- https://doi.org/10.1073/pnas.2603982123
- Primary Topic
- Stress Responses and Cortisol
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Alzheimer's Association
- Deutsche Forschungsgemeinschaft
- Fondazione Cariplo
- Associazione Italiana Ricerca Alzheimer
- HORIZON EUROPE Framework Programme
- European Research Council