A research in mice offers clues about the common molecular causes of depression and chronic stress. The discovery could inform new treatments for mood disorders.
Millions of years ago, in the face of unexpected challenges from rivals and predators, our ancestors developed the physiological responses needed to survive.
These ‘fight-or – flight’ stress responses are activated by the release of hormones, including epinephrine ( adrenaline), noradrenaline (norepinephrine), and the steroid hormone cortisol.
Nevertheless, a significant risk factor for the development of mood disorders such as anxiety and depression is sustained or chronic stress that does not relieve after the immediate threat passes.
In military action, for instance, stressful events can also impair the capacity of the body to control its stress responses, triggering post-traumatic stress disorder.
People with these mood disorders have hormone levels of stress that are abnormally elevated and sustained, which puts them at increased risk of developing cardiovascular disease.
Researchers at the Karolinska Institutet in Stockholm , Sweden, hypothesized that after an immediate threat has passed, a protein called p11 plays a crucial role in dampening stress responses in healthy brains.
Serotonin signal boost
In the brains of people with depression and in people who died by suicide, extremely low levels of p11 were identified.
Depression and anxiety-like symptoms are also demonstrated by mice with decreased p11 levels. Moreover, the levels of this protein in the brains of animals are increased by three separate types of antidepressants that are effective in humans.
The Karolinska researchers have now found that decreased levels of p11 in the brains of mice make the animals more vulnerable to traumatic experiences.
The researchers have showed that in two separate stress signaling pathways in the brain, the protein regulates activity. This decreases not only the release of cortisol through one path, but also the release of adrenaline and noradrenaline through the other.
We know that depression can be precipitated or exacerbated by an irregular stress response and cause anxiety disorder and cardiovascular disease, “says Vasco Sousa, first author.” “It is therefore important to find out if patients can also see the connection between p11 deficiency and the stress response we see in mice.”
The report, published in the journal Molecular Psychiatry, was a collaboration between researchers at VU University in Amsterdam, The Netherlands, and the Karolinska Institutet.
The researchers bred “knockout” mice that lack the gene that makes this protein to investigate the role of p11 in stress responses.
Using a number of standard tests, they compared their behavior with normal mice. They indicated that those without p11 were experiencing increased stress and anxiety.
Mice pups, for instance, were separated from their mothers for 3 hours a day in one test. The researchers found that , compared with normal pups, pups lacking p11 produced more high-pitched distress calls, known as ultrasonic vocalizations.
The team gave the adult mice a choice of spending time in a brightly lit area or a dark space in another test of anxiety-like behaviour. Compared with normal mice, mice that were deficient in p11 chose to spend less time in the brightly lit region.
Moreover, after a stress-provoking stimulation, their heart rates took longer to return to normal.
Stress hormone levels in the animals were also controlled by the researchers, showing hyperactivity in two different stress pathways in the mice that lacked p11.
The rapid surge of adrenaline and noradrenaline that occurs of terrifying conditions, causing physiological changes such as increased heart rate, is responsible for one such mechanism, called the sympathetic-adrenal-medullary (SAM) axis.
The other pathway, referred to as the axis of the hypothalamus-pituitary-adrenocortical (HPA), reacts slightly less rapidly and contributes to cortisol release. Among other metabolic changes, this stress hormone increases blood sugar levels and suppresses functions that the body does not require for the fight-or – flight response.
The results could guide the production of more effective medications to correct chronic stress levels for mood disorders , such as anxiety and depression.
Per Svenningsson, senior author of the new study, says: “A promising approach involves the administration of agents that enhance localized p11 expression, and several experiments are already being carried out in animal models of depression.”
“The development of drugs that inhibit the activation of the stress hormone response in the brain is another fascinating approach that needs further study.”
It is worth noting that, rather than human models, all the research so far in this promising new field includes animal models of stress, anxiety , and depression.
Animal laboratory research, while providing useful leads for drug production, do not reflect the dynamic interplay of social, environmental, and biological factors involved in the development of human mental illness.