Early life stress (ELS) can have long-lasting effects on mental health, increasing the risk of developing anxiety disorders and post-traumatic stress disorder (PTSD). Importantly, women are disproportionately affected by PTSD, highlighting the need to understand how biological sex influences responses to trauma.

A study published in Communications Biology has revealed, with the help of machine learning tools, striking differences in how males and females respond to stress, both in behavior as well as in brain metabolism and stress hormone regulation.

Childhood stress, such as neglect or adversity, is a known risk factor for developing mental disorders later in life. Researchers at the Max Planck Institute of Psychiatry (MPI) in Munich, led by Joeri Bordes and Mathias Schmidt, used a mouse model of ELS to investigate how it affects fear learning and memory in males and females.

They found that ELS led to heightened fear responses, different in males and females: Males exhibit passive fear coping strategies (freezing), while females show active fear coping strategies (darting, or escaping-like behaviors). ELS impacts males and females at different times, with females experiencing more acute effects and males enduring longer-lasting changes. Females exhibit elevated stress hormone (corticosterone) levels immediately after early life stress exposure, while males do not.

The researchers also examined the metabolic processes in brain regions associated with fear and stress, including the amygdala and hippocampus. They discovered sex-specific and stress-dependent changes in brain metabolism: ELS triggered sex-specific alterations in critical metabolic pathways, processes essential for energy production, DNA repair, and neuronal communication. These findings suggest that early stress reprograms how the brain manages energy and signaling, potentially increasing vulnerability to mental disorders later in life.

Implications for mental health

“Our findings emphasize the importance of considering sex differences in the neurobiological pathways underlying trauma-related behaviors,” says Bordes, lead author of the study. “This knowledge could pave the way for the development of sex-specific interventions for individuals who have experienced early life stress.”

This research provides crucial new information about the complex relationship between ELS, sex, and fear. By understanding these sex-specific effects, researchers hope to develop more effective treatments for trauma-related disorders. Potential therapies targeting specific metabolic pathways could be tailored to meet the different needs of males and females.

“By understanding how stress affects the brain differently in males and females, we move closer to building a world where mental health care is more effective, equitable, and tailored to individual needs,” hopes MPI Research Group Leader Schmidt.