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Treating Adolescent Stress: Timing Matters

Treating Adolescent Stress: Timing Matters

It’s no surprise that adolescence, a critical period of neural development, coupled with exposure to chronic stress, can leave a lasting impact on mental health. Finding optimal ways to intervene to prevent long-term depression or other disorders has been the goal of psychiatry researcher Minae Niwa, a junior faculty member in the Johns Hopkins Schizophrenia Center.

In a paper in Science, published in 2013, Niwa and colleagues demonstrated that adolescent stress in mice bred with a genetic risk for psychiatric disorders led to biochemical, behavioral and epigenetic changes that lasted well into adulthood. These changes turned genes on and off by adding chemicals—methyl groups—to the DNA for the gene tyrosine hydroxylase (Th), which is the rate-limiting enzyme in the synthesis of dopamine, a neurotransmitter implicated in cognition and mood that goes awry in depression and other psychiatric disorders.

The epigenetic changes also resulted in excess production of glucocorticoids, hormones that are released in response to stress exposure. Treating the animals with the nonselective glucocorticoid receptor antagonist RU486 during stress, the researchers found, could ameliorate these pathological changes.

While exciting, the research left two crucial unanswered questions: Is Th the only target of epigenetic modifications mediated by the glucocorticoids? And what is the precise time period during which medication could have the most impact?

To address these questions, Niwa, psychiatry researcher Richard Lee and colleagues conducted a follow-up study in the genetically susceptible mice, which were placed in separate cages during the three-week stress regimen. The results were published in the journal Human Molecular Genetics.

The investigators examined several genes along the animals’ hypothalamic-pituitary-adrenal axis, the brain’s key stress pathway. Findings showed significant epigenetic changes—not only in Th, but also in brain-derived neurotrophic factor (BDNF), which helps regulate connections important for learning and memory, and in FK506 binding protein 5 (Fkbp5), which plays a role in stress response and immune function. Treatment with RU486 during the three-week stress period (5 to 8 weeks of age in the adolescent mice) prevented epigenetic changes in the Th, BDNF and Fkbp5 genes.

To identify the precise period when RU486 could offer the most benefit, the researchers divided the treatment periods into three windows: the first week of the stress regimen, the first two weeks of the stress regimen and the two weeks after the stress regimen.

“What we found was that treatment during the first week seems to have the most effect in terms of blocking the epigenetic, behavioral and biochemical deficits initially observed,” Lee says. This suggests, he explains, that early adolescence may be a specific period of maturation and function of dopaminergic neurons and their sensitivity to glucocorticoids. Treatment during the first two weeks was also helpful; however, “treating these adolescent mice after the stressor doesn’t reverse any of the effect, because the stress hormone has already done its damage.”

Niwa and Lee are now looking to study the impact of adolescent stress in typical mice that do not carry the genetic risk and to examine epigenetic changes genomewide using a platform Lee developed. They also plan to test a newer, more selective compound that blocks only the glucocorticoid receptor.

The work has relevance for neural development in adolescence, says Lee. In particular, he notes, this past January, President Obama announced a ban on solitary confinement for jailed juveniles. “I think [people are realizing] what social isolation does to your mental health, especially around the time when your brain is still developing in terms of maturation and reorganization.”

Therapeutic strategies that can amend the debilitating consequences of stress are highly desirable, adds Niwa. “We need to develop a new compound that can reverse these changes, even after their establishment,” she says, as well as identify a biomarker for the maturation of dopaminergic neurons. “If we can find such a biomarker, we could intervene with drug treatment or cognitive training in adolescents.”

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