Working with mice, Johns Hopkins researchers have established a link between elevated levels of a stress hormone in adolescence — a critical time for brain development — and genetic changes that, in young adulthood, cause severe mental illness in those predisposed to it.
The findings, reported in the journal Science, could have wide-reaching implications in both the prevention and treatment of schizophrenia, severe depression and other mental illnesses.
"We have discovered a mechanism for how environmental factors, such as stress hormones, can affect the brain's physiology and bring about mental illness," says study leader Akira Sawa, M.D., Ph.D., a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. "We've shown in mice that stress in adolescence can affect the expression of a gene that codes for a key neurotransmitter related to mental function and psychiatric illness. While many genes are believed to be involved in the development of mental illness, my gut feeling is environmental factors are critically important to the process."
Sawa, director of the Johns Hopkins Schizophrenia Center, and his team set out to simulate social isolation associated with the difficult years of adolescents in human teens. They found that isolating healthy mice from other mice for three weeks during the equivalent of rodent adolescence had no effect on their behavior. But, when mice known to have a genetic predisposition to characteristics of mental illness were similarly isolated, they exhibited behaviors associated with mental illness, such as hyperactivity. They also failed to swim when put in a pool, an indirect correlate of human depression. When the isolated mice with genetic risk factors for mental illness were returned to group housing with other mice, they continued to exhibit these abnormal behaviors, a finding that suggests the effects of isolation lasted into the equivalent of adulthood.
"Genetic risk factors in these experiments were necessary, but not sufficient, to cause behaviors associated with mental illness in mice," Sawa says. "Only the addition of the external stressor — in this case, excess cortisol related to social isolation — was enough to bring about dramatic behavior changes."
The investigators not only found that the "mentally ill" mice had elevated levels of cortisol, known as the stress hormone because it's secreted in higher levels during the body's fight-or-flight response. They also found that these mice had significantly lower levels of the neurotransmitter dopamine in a specific region of the brain involved in higher brain function, such as emotional control and cognition. Changes in dopamine in the brains of patients with schizophrenia, depression and mood disorders have been suggested in clinical studies, but the mechanism for the clinical impact remains elusive.