Researchers at Karolinska Institutet in Sweden report on a new protein that could tie stress to depression and anxiety.

The team has identified a protein in the brains of mice that regulates the release of both serotonin and cortisol, which are the feel-good hormone and stress hormone, respectively. This protein, p11, was previously discovered by the same team, who showed that it plays a key role in the functioning of serotonin. The present study showed that mice lacking p11 show depression- and anxiety-like behaviour, which was treatable in part with antidepressants.

The findings could help us better understand the biochemical mechanisms behind depression and anxiety, and to develop new medicine to treat them.

P11 giveth, p11 taketh away

“We know that an abnormal stress response can precipitate or worsen a depression and cause anxiety disorder and cardiovascular disease,” says first author Vasco Sousa, researcher at the Department of Clinical Neuroscience, Karolinska Institutet. “Therefore, it is important to find out whether the link between p11 deficiency and stress response that we see in mice can also be seen in patients.”

Individuals that have experienced trauma or episodes of very severe stress are known to sometimes develop an abnormal (i.e. excessive) response to stress in the future. Those who also suffer from anxiety or depression are more likely to show such responses. However, in order to find out how to help them, we must first understand how our bodies create and regulate stress.

The authors report previously observing that depressed patients and suicide victims tend to have lower-than-average levels of the p11 protein in their brains. In order to find if there’s a link there, they engineered lab mice to produce low levels of p11. Further testing confirmed that these animals showed behavior consistent with depression and anxiety.

Mice with p11 deficiency also showed a stronger reaction to stress, exhibiting higher heart rates and more anxiety-related behavior when presented with a stressful situation, than unaltered mice.

The protein is directly involved in the initial release of cortisol in mice, the team explains, as it dictates the activity of neurons in the hypothalamus, an area of the brain heavily involved in controlling hormone levels in the body. It also — through its activity in a completely separate pathway in the brainstem — dictates the release of adrenaline and noradrenaline (also known as epinephrine and norepinephrine), two other hormones involved in the stress response.

Keeping p11 levels in the brain in check could thus be a promising avenue to treat patients suffering from depression, anxiety, and those who are struggling with chronic anxiety and stress from past experiences. This is especially heartening news as many such patients report that currently-available antidepressants are not effective in managing or treating their conditions.

“One promising approach involves administration of agents that enhance localised p11 expression, and several experiments are already being conducted in animal models of depression,” says Per Svenningsson, professor at the Department of Clinical Neuroscience, Karolinska Institutet, who led the study.

“Another interesting approach which needs further investigation involves developing drugs that block the initiation of the stress hormone response in the brain.”

The paper “P11 deficiency increases stress reactivity along with HPA axis and autonomic hyperresponsiveness” has been published in the journal Molecular Psychiatry.