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Early life stress (ELS) can have surprising benefits for female mice, leading to improved emotional regulation and cognitive function. A groundbreaking study identifies a critical protein, FKBP51, as playing a key role in this adaptive process. The uncovering of sex-specific mechanisms through which ELS can build resilience helps researchers to understand the development of psychiatric disorders and identify potential therapeutic targets.
While early life stress is often linked to increased vulnerability to psychiatric disorders like depression and anxiety, this study led by Lotte van Doeselaar and Mathias Schmidt from the Max-Planck-Institute of Psychiatry demonstrates that in female mice, moderate stress can actually build resilience. The researchers found that female mice exposed to ELS exhibited reduced anxiety and enhanced memory performance in stressful situations. However, this beneficial effect was absent in mice lacking FKBP51 in their glutamatergic forebrain neurons, highlighting the protein's crucial role.
"Our findings suggest that FKBP51 acts as a mediator, allowing female mice to adapt and thrive in the face of future challenges," explains Lotte van Doeselaar, the study's first author. "This is a significant departure from the traditional view of early life stress as solely detrimental."
The study recently published in Nature Communications also uncovered sex-specific differences. While female mice showed pronounced behavioral and brain changes, male mice exhibited less dramatic effects, suggesting that the mechanisms of stress adaptation differ between sexes.
Furthermore, the researchers identified a transcription factor, TCF4, as a potential downstream effector of FKBP51. Overexpression of TCF4 in female mice mimicked the beneficial effects of ELS, indicating its role in promoting resilience.
"Psychiatric disorders are a major global health concern, and understanding the biological underpinnings is essential for developing effective treatments," says Mathias Schmidt, the study's senior author. "Our research sheds light on the complex interplay between genes and environment, and how early experiences can shape long-term mental health." This study leads researchers one step closer to developing interventions that promote mental well-being.
PD Dr. Mathias Schmidt (mschmidt@psych.mpg.de)
Lotte van Doeselaar et al.: FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice, Nature Communications, doi: 10.1038/s41467-025-57952-x
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