Scientists have identified sex differences in the effects of early stress on the brain

Stress before birth and in the first days of life caused sex-dependent changes in behavior, brain activity, and gene function in adult mice. In males, the researchers found a decrease in behavioral flexibility and a weakening of functional coherence between brain regions, while in females, flexibility remained, and the connectivity of neural networks increased after social interaction. The results are published in the journal Proceedings of the National Academy of Sciences (PNAS). About how scientists conducted the experiment and why its results cannot yet be directly transferred to humans, see the "Izvestia" material.

How Scientists Modeled early Stress

Exposure to severe or prolonged stress during development is considered one of the risk factors for anxiety disorders and depression in adulthood. However, the mechanisms linking early adverse conditions with subsequent mental disorders have not been fully studied. Researchers from the Max Planck Institute of Psychiatry, McGill University and the University of Côte d'Azur decided to test whether the developing brain's response to stress depends on biological sex.

The main experimental part of the work was carried out on CD1 mice. Scientists have created a model combining stress effects during pregnancy and after the birth of offspring. This approach has been designated PNELS — prenatal and early life stress, that is, prenatal stress and stress at an early age.

During a certain period, pregnant females were injected with corticosterone, a hormone involved in the stress response in rodents. After birth, the cubs were kept in cages from the second to the ninth day of life with a limited amount of litter and nest building material. The control animals were kept under standard conditions.

On the ninth day, all the cubs were transferred to regular cages. Behavioral and neurobiological studies began when the mice reached young adulthood— about eight weeks old. The experiment included control and stressed animals of both sexes. Separate groups of mice were used for different analysis methods, so the same sample did not go through all the procedures sequentially.

This model allows us to study the consequences of a specific combination of hormonal effects before birth and adverse conditions shortly after it. However, it cannot be completely equated with childhood psychological trauma in humans, which can include violence, loss of loved ones, neglect of the child's needs and other difficult social circumstances.

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How has the position of the animals in the group changed?

In a separate experiment, the researchers studied social hierarchy. Mice were placed in groups of four in an environment close to natural conditions and monitored for four days and four nights.

Animals of both sexes that were exposed to early stress occupied a subordinate position in the social hierarchy. Statistical analysis confirmed that experimental exposure was a significant predictor of a lower rank.

This result turned out to be common for males and females. However, other behavioral and neurobiological effects of stress varied markedly by gender. The authors believe that a superficially similar result — for example, a subordinate position — can be formed through various changes in brain function. Therefore, the same behavior does not necessarily mean the same biological mechanism.

How has the attitude towards remuneration changed?

To study motivation and reward sensitivity, mice were offered sweet pellets. In this part of the study, each experimental group included 12 animals.

The males exposed to early stress consumed fewer freely available sucrose granules than the control animals. The authors compared this with anhedony—like behavior-a decrease in interest in reward. However, depression cannot be diagnosed in mice in the same sense as in humans, so it is correct to talk about depression-like symptoms.

In the females, the reaction was the opposite: the stressed animals ate more sweet pellets than the females from the control group. The researchers interpreted this as evidence of differences in reward sensitivity.

In a more complex task, the mice had to press their noses on a specific sensor to get a pellet. The overall accuracy of the task did not differ significantly between the groups. The authors only recorded a downward trend in accuracy, mainly related to males at one stage.

At night, stressed males performed relatively many actions, but the accuracy of their selection decreased. This allowed the researchers to suggest an increase in impulsivity. However, impulsivity was not measured by a separate specialized test, so this conclusion remains an interpretation of the observed behavior.

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What did the analysis of nerve cell activity show?

The scientists studied the c-Fos protein, which is used as a marker of recent nerve cell activity. This part of the experiment included eight animals of each sex in the control and stress groups. The analysis was conducted after a brief social interaction. Unlike MRI, which reflected accumulated activity over about a week, c-Fos allowed for a short-term "snapshot" of the brain's response to a specific situation.

Regional analysis showed that after early stress, males had increased activity in some cortical and limbic regions. At the same time, functional coherence between different parts of the brain decreased. In the females, the researchers found the opposite configuration: in some thalamic and hypothalamic regions, activity was lower, but the strength and density of functional connections between the regions increased.

In this case, functional connectivity refers to the statistical consistency of activity in different areas. The study did not show that a certain number of nerve connections physically appeared or disappeared in the animals.

The authors concluded that males and females can use different network strategies to adapt to early stress. At the same time, some of the global c-Fos indicators did not reach statistical significance, and the most pronounced differences were found at the level of individual areas and their interrelationships.

What changes have been found in the work of genes

The next step was the sequencing of RNA in 10 brain regions associated with stress and mental disorders. The method allowed us to determine which genes became more active after early exposure or, conversely, decreased their activity.

Most of the changes were regional in nature. In males, 93.7% of the genes with altered expression were unique to one area of the brain. In females, this indicator reached 98.2%. The researchers paid special attention to the nucleus accumbens and the nucleus of the terminal stripe bed. The former is involved in reward and motivation processing, the latter is associated with stress and anxiety reactions.

It was in these two areas that the direction of changes in a number of genes differed in males and females. In males, energy metabolism and maintenance of cellular balance prevailed among the activated processes. In females, oppositely directed changes were associated with synaptic transmission, plasticity, and development of the nervous system.

This does not mean that all the genes had the opposite reaction. In most of the studied areas, scientists have found similar trends of change. The most noticeable discrepancy related to individual brain regions and certain groups of genes.

What did the comparison with human data show?

To verify the possible applicability of the results to humans, the scientists used a previously published dataset. It contained information about gene expression in postmortem brain samples of men and women with major depressive disorder.

Data from the prefrontal cortex and the nucleus accumbens were compared. In terms of overlapping genes, the direction of changes in men and women differed, as did in male and female mice.

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However, the overall overlap between the species turned out to be weak. In the original article, the authors explicitly point out that the correlation of transcriptomic profiles of mice and humans was close to zero, and the overlap was limited, depending on gender and brain region.

In addition, the human samples referred to major depressive disorder, rather than a specially formed group of people with documented stress or trauma at an early age. Therefore, the comparison does not prove that childhood trauma changes the brains of men and women exactly as it did in mice.

The authors believe that human datasets specifically dedicated to adverse early childhood experiences will be needed to verify the results. The study did not include brain scans of living patients and did not track the development of mental disorders after childhood trauma.

How the results may affect psychiatry

The study does not offer a ready-made method for the diagnosis or treatment of anxiety disorders and depression. His results form hypotheses about which areas of the brain and molecular processes should be studied further.

The authors draw attention to the historical orientation of many preclinical studies on male laboratory animals. If the stress response really depends on gender, using only one group may hide significant mechanisms or create an incomplete picture.

In the future, the differences found may help in the search for biomarkers and the development of more accurate treatment approaches. To do this, the results need to be confirmed in other models, and then in studies involving people with a documented history of early adverse events.

Thus, the work shows not that men and women inevitably react to childhood trauma in the opposite way, but that in a certain mouse model, the same early stress exposure triggered different behavioral, network, and molecular changes. The extent to which these mechanisms are reproduced in humans has yet to be established.