Neuroscientists at Harvard Medical School and its affiliate
McLean Hospital have shown that long-term exposure to stress hormone in mice
directly results in the anxiety that often comes with depression. After years of
circumstantial evidence linking stress and depression, this evidence may be the
"smoking gun" of what, for some, causes some types of mood disorders. The
research appears in the April issue of Behavioral Neuroscience, which
is published by the American Psychological Association.
The findings are important for understanding the causes and
improving the treatment of depression. Scientists already knew that many people
with depression have high levels of cortisol, a human stress hormone, but it
wasn’t clear whether that was a cause or effect. Now it appears likely that
long-term exposure to cortisol actually contributes to the symptoms of
depression.
Paul Ardayfio, PhD candidate, and Kwang-Soo Kim, PhD, of the
Molecular Neurobiology Laboratory at McLean Hospital, made their discovery by
exposing mice to both short-term and long-term durations of stress hormone,
which in rodents is corticosterone. In humans, usually ongoing, chronic stress,
such as caring for a spouse with dementia, rather than acute stress, has been
associated with depression.
Using 58 mice, the researchers gave the hormone in drinking
water so as not to confound the results with the stress of injection. Chronic
doses were 17 to 18 days of exposure; acute doses were 24 hours of exposure.
Compared with mice given stress hormone for a day, mice given
stress hormone for more than two weeks took significantly longer to emerge from
a small dark compartment into a brightly lit open field, a common behavioral
test of anxiety in animals. In other words, they seemed more fearful and were
less willing to explore the new environment. Chronic but not acute treatment
also dulled reactions to a startling stimulus, another sign their nervous
systems were overwhelmed.
To the best of the authors’ knowledge, this was the first
experiment to compare the effects of chronic corticosterone with the effects of
acute corticosterone on anxiety-like behavior.
Given four related lines of evidence, the findings were not a
complete surprise. First, more than half the people with Cushing’s disease, in
which a disordered adrenal system releases too much cortisol, have depression
and anxiety. Second, the "anxious-retarded" subtype of depression is commonly
associated with disruption of that same hormonal system. Third, people getting
corticosteroid therapy for inflammatory and other disorders have increased
mood-related side effects, including anxiety and depression. Fourth, higher
glucocorticoid levels for chronic periods have been linked to increased activity
in anxiety-related brain regions such as the amygdala in both rodents and
humans.
Now the pieces fit together around a central axiom: Stress
hormone can cause anxiety, which appears with depression. Having found this
causal link in a controlled laboratory setting, the authors say, "Our results
suggest that chronically high levels of cortisol, which occurs in Cushing’s
disease and some subtypes of depression, can increase anxiety on the one hand
and dull responses to external stimuli on the other." The difference between the
responses to acute and chronic hormone exposure strengthen the view that
very-short-term or acute exposure, they add, "may be adaptive, whereas chronic
exposure has detrimental effects on brain and behavior."
Ardayfio and Kim say that outlining the relationship between
physiological disruptions and subsequent behavior may help researchers to design
new psychiatric drugs that treat the causes of disease rather than peripheral
disease-related phenomena. The authors speculate that drugs that reverse or
block the deleterious effects of chronically elevated stress hormones may help
guard against some types of anxiety symptoms in depression, citing preclinical
evidence in rats.
Article: "Anxiogenic-like Effect of Chronic Corticosterone in
the Light-Dark Emergence Task in Mice," Paul Ardayfio, PhD candidate, and
Kwang-Soo Kim, PhD, McLean Hospital and Harvard Medical School; Behavioral
Neuroscience, Vol. 120, No. 2.
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