Male and Female Brains Respond Differently to Early-Life Stress

Researchers in Canada have shown that stress experienced early in life can alter the structure of specific brain cells in mice, resulting in behavioural changes that vary by sex. The findings, published in Nature Communications, offer new insight into the cellular mechanisms that regulate activity levels in rodents, especially in response to stress.

The study, led by Ciaran Murphy-Royal of the Research Centre of the University of Montreal Hospital (CRCHUM), focused on astrocytes – specialized glial cells in the brain – and their interaction with neurons in the lateral hypothalamus. This brain region is involved in managing sleep-wake cycles and is known to contribute to behaviours associated with alertness and energy expenditure.

Changes in activity and brain cell morphology

The researchers observed that adult mice subjected to stress during early development exhibited abnormal levels of corticosterone, a stress hormone in rodents. These elevated hormone levels were associated with changes in daily activity patterns that differed by sex. Female mice were less active during the night, while males were more active during the day.

At the cellular level, mice exposed to early-life stress had astrocytes with reduced size and fewer branches. These morphological changes were more pronounced in females. Astrocyte branches play a key role in communicating with neurons and other surrounding cells, and such structural alterations are often considered markers of dysfunction in neurological research.

These changes also affected a group of neurons known as orexin-producing neurons. Located in the same region of the brain, these neurons help regulate wakefulness and arousal. In males, these neurons showed increased activity, whereas in females, activity was suppressed.

Modelling early-life stress

To replicate early-life stress conditions, the researchers separated young mice from their mothers for 4 hours each day over 10 days. This developmental window corresponds to early childhood in humans, roughly between the ages of three and seven. This lack of maternal contact led to the behavioural and cellular changes seen later in the mice’s lives.

The team then explored whether these changes could be reversed. They genetically modified the mice to delete glucocorticoid receptors in astrocytes – receptors that normally bind to corticosterone. Without these receptors, the behavioural and neuronal changes associated with early-life stress were reduced, and the astrocytes regained some of their complexity, although not their original size.

Stress pathways in the brain

The findings suggest that astrocytes may respond to stress before neurons do. While the long-term implications for humans remain unclear, the results indicate that glial cells could be critical to understanding how early experiences shape brain function and behaviour.

“In our field of expertise, we believe that the changes in astrocyte morphology are a marker of dysfunction. In humans, we see these variations in diseases like Parkinson’s or Alzheimer’s.”

Dr. Ciaran Murphy-Royal.

Although further research is needed, especially in humans, the data point to astrocytes as a potential therapeutic target in the context of stress-related conditions. The researchers caution, however, that translating these findings to clinical applications will require more detailed study.

Reference: Depaauw-Holt LR, Duquenne M, Hamane S, et al. A divergent astrocytic response to stress alters activity patterns via distinct mechanisms in male and female mice. Nat Commun. 2025;16(1):6372. doi: 10.1038/s41467-025-61643-y

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