Anxiogenic-like effect of chronic corticosterone in the light-dark emergence task in mice

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.

Full text of the article is available from the APA Public Affairs Office and at http://www.apa.org/releases/beh_06v120n2.pdf