Childhood abuse and neglect may reprogram the brain to be more sensitive to stress, according to a study of the brains of people who died by suicide. The research, reported in Nature Neuroscience in March, also suggests that this programming process might be reversible with drugs even in adults, potentially offering a new way to treat depression and related disorders.
“We know that adult cells are capable of this modification,” says principal investigator Michael Meaney of McGill University in Montreal.
Researchers in Meaney’s lab examined the brains of 12 people who died by suicide and had a history of childhood abuse, defined as sexual contact, severe physical abuse or severe neglect. They also studied the brains of two control groups—12 suicides with no history of childhood abuse and 12 age-matched controls who had died suddenly for other reasons, such as by accident.
In each group, the researchers measured gene expression levels for a brain-cell receptor called the glucocorticoid receptor. Hormones stimulated by stressful events bind to these receptors on neurons in the frontal lobes of the brain, activating a signaling pathway that in turn dampens the production of stress hormones. In other words, glucocorticoid receptors on forebrain neurons serve as part of a “negative feedback” system to keep stress responses from getting out of control.
Meaney and his colleagues found a key difference between the people with a history of abuse and the two control groups: The former had significantly lower expression of the messenger RNA—a key part of the translation process from gene to protein—for the glucocorticoid receptor gene, as well as for a key genetic element known to promote the gene’s expression.
Previous studies in rodents, by Meaney’s lab among others, have shown that the reduction of these feedback elements, which can occur as a result of maternal neglect, lowers the brain’s ability to temper the stress response.
“This study provides a nice validation that this is not only important in animal model systems but has direct relevance for human psychiatric pathology,” says Louis Muglia of Vanderbilt University, who wasn’t connected with Meaney’s study but has done work in this area.
Chemical change might be reversible
The “epigenetic” (environmentally triggered) programming of the stress response, so that it effectively becomes larger for a given stressor, is widely assumed to represent an ancient evolutionary adaptation. An inherently active stress response could be “critical for survival in a persistently threatening environment,” Meaney says.
In the modern world, this greater stress responsivity is also associated with depression, schizophrenia and other mental illnesses. But in this study and in a 2004 study with rats, Meaney’s group found that the suppression of the glucocorticoid receptor in childhood seemed to result from a chemical process that, in principle, drugs could undo. In fact, in the previous rat study, Meaney’s group did reverse this suppression due to “epigenetic marks” by using a chemical called a histone deacetylase inhibitor. (Better rat parental care had a similar effect.)
To Meaney there is now good evidence from animal and cell-culture studies that “even in cells that are no longer in the early stages of development, epigenetic marks can be reversed.”
This work, though, is still in early days. And, as Muglia points out, an epigenetic-mark-reversal therapy to restore glucocorticoid receptor expression—and therefore a healthy stress response—might have to be targeted narrowly to the appropriate brain regions to avoid unacceptable side effects.
Existing drugs may affect these epigenetic mechanisms. Some antidepressants, for example, increase glucocorticoid receptor expression, “so one mechanism by which they might exert their efficacy is through this pathway,” says Muglia. To help settle such questions, Meaney and his colleagues are now working to determine every step of the molecular pathway. “We know the signals that activate the process, but not the final step,” Meaney says.