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 (nor epinephrine), 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.
Serotonin
signal boost
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.
Knockout
mice
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.
Source: Medical News Today
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