A study in mice provides clues about the common molecular origins of chronic stress and depression. The discovery could inform new treatments for mood disorders.
Millions of years ago, our ancestors evolved the physiological responses needed to survive in the face of sudden threats from rivals and predators.
The release of hormones, including epinephrine (adrenaline), noradrenaline (norepinephrine), and the steroid hormone cortisol, trigger these “fight-or-flight” stress responses.
However, sustained or chronic stress that does not resolve when the immediate threat passes is a major risk factor for the development of mood disorders such as anxiety and depression.
Traumatic experiences, for example, in military combat, can also damage the body’s ability to regulate its stress responses, causing post-traumatic stress disorder.
People with these mood disorders have abnormally high and sustained stress hormone levels, which puts them at an increased risk of developing cardiovascular disease.
Researchers at the Karolinska Institutet in Stockholm, Sweden, suspected that a protein called p11 plays a pivotal role in damping down stress responses in healthy brains after an acute threat has passed.
Their previous research found that p11 enhances the effect of the hormone serotonin, which regulates mood and has a calming effect.
Unusually low levels of p11 have been found in the brains of people with depression and in individuals who died by suicide.
Mice with reduced p11 levels also show depression and anxiety-like behaviors. In addition, three different classes of antidepressants that are effective in humans increase levels of this protein in the animals’ brains.
Now the Karolinska researchers have discovered that reduced p11 levels in the brains of mice make the animals more sensitive to stressful experiences.
The scientists also demonstrated that the protein controls activity in two distinct stress signaling pathways in the brain. It reduces not only the release of cortisol via one pathway but also adrenaline and noradrenaline via the other.
“We know that an abnormal stress response can precipitate or worsen depression and cause anxiety disorder and cardiovascular disease,” says first author Vasco Sousa. “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.”
The study, which appears in the journal Molecular Psychiatry, was a collaboration between the Karolinska Institutet and researchers at VU University in Amsterdam, The Netherlands.
To investigate the role of p11 in stress responses, the scientists bred “knockout” mice that lack the gene that makes this protein.
They compared their behavior with normal mice using a variety of standard tests. These suggested that those without p11 experienced heightened stress and anxiety.
For example, in one test, mice pups were separated from their mothers for 3 hours a day. The researchers found that pups lacking p11 produced more high-pitched distress calls, known as ultrasonic vocalizations, compared with normal pups.
In another test of anxiety-like behavior, the team gave the adult mice a choice of spending time in a brightly lit area or a dark space. Mice that were deficient in p11 chose to spend less time in the brightly lit area compared with normal mice.
In addition, their heart rates took longer to return to normal after a stress-provoking stimulus.
The scientists also monitored stress hormone levels in the animals, revealing hyperactivity in two distinct stress pathways in the mice that lacked p11.
One such pathway, called the sympathetic-adrenal-medullary (SAM) axis, is responsible for the immediate surge in adrenaline and noradrenaline that occurs in frightening situations, triggering physiological changes such as increased heart rate.
The other pathway, known as the hypothalamus-pituitary-adrenocortical (HPA) axis, responds slightly less quickly and leads to the release of cortisol. This stress hormone raises blood sugar levels, among other metabolic changes, and suppresses functions that the body does not need for the fight-or-flight response.
The findings could inform the development of more effective drugs for mood disorders, such as anxiety and depression, that redress chronic stress levels.
“One promising approach involves the administration of agents that enhance localized p11 expression, and several experiments are already being conducted in animal models of depression,” says Per Svenningsson, senior author of the new study.
“Another interesting approach which needs further investigation involves developing drugs that block the initiation of the stress hormone response in the brain.”
It is worth noting that all the research so far in this promising new field involves animal models of stress, anxiety, and depression, rather than human models.
While providing useful leads for drug development, animal lab studies may not reflect the complex interplay of social, environmental, and biological factors involved in the development of mental illness in people.