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Psychiatry Newsletter - Stress: Can It Bring More Than Teen Angst?

Hopkins BrainWise-Spring 2013

Stress: Can It Bring More Than Teen Angst?

Date: April 15, 2013


Dr. Hanna Jaaro- Peled and Dr. Minae Niwa
For neuroscientists Hanna Jaaro-Peled and Minae Niwa, finely tailoring mouse models of psychiatric disease helps show how small shifts in brain chemistry change the very circuits that oversee thinking and behavior.

There’s a reason that Minae Niwa and Hanna Jaaro-Peled picked mice age 5 to 8 weeks old for their recent study: The rodents are teenagers. It’s a tender age for mice or humans and one increasingly eyed by researchers as key to pathology that schizophrenia, major depression and bipolar disorder likely have in common.

Recently, a mouse study by Niwa and Jaaro-Peled’s team, under mentor Akira Sawa, modeled current thought on triggers of those illnesses—mostly young adult-onset neuropsychiatric disorders. The results offer a way that stress, at a certain age and vulnerability, may trip major psychiatric disease. 

A body of science confirms that teenage mice and humans respond similarly to stress. The HPA axis, the brain’s key stress pathway, goes into overdrive, releasing cortisol. And at puberty, some studies say, that hormone’s effect in man and mouse appears more potent; brains stay longer in “red alert” mode after each stressor du jour has faded.

Still other research suggests some link between cortisol and brain levels of dopamine, a neurotransmitter active in cognition, learning, mood and reward. Dopamine goes awry in schizophrenia, bipolar disorder and depression.

But how, asked the Johns Hopkins group, to tie the threads together?

Niwa and Jaaro-Peled’s new study simulated the proposed human risks for illness: Test mice (and controls) were teenagers. The mice also had moderate gene-based chances for a troubled brain: They carried a mutation from a human family with depression tinged with psychosis. Finally, test mice in the study lived three weeks on their own, a situation exposing each animal to stress roughly as intense, say, as what teens face the first days of high school—a “suboptimal” stressor, says Sawa.

The results were telling. Carrying the abnormal gene had little effect on the mice unless they were also stressed. Then they became more readily hyperactive or displayed other behaviors that signal brain disorder.

On a biological level, there was more. The stress-plus mutation mice showed high cortisol levels and a significant drop in dopamine. Was cortisol at work in the drop? An added experimental step said yes. Injecting mice with an agent that blocks cortisol activity righted dopamine levels. It also corrected mouse behavior. 

The “take-home” from this, Sawa says, “seems to be that during adolescence, if there’s adequate genetic risk, stress can change biology and behavior in ways that we associate with neuropsychiatric disease.”

Perhaps more important in the long run were results that suggest therapy targets. The team found that cortisol affects key, dopamine-rich nerve paths between the midbrain and the prefrontal cortex. The “ventral tegmental area” is a vulnerable brain tract that rules concentration, for example, and other things cognitive that neuropsychiatric disease harms.

The second find suggests that cortisol’s effect at puberty may last. Mice returned to group life still behaved abnormally months later. The underlying biology suggests why: High cortisol clamps epigenetic “governors” on key dopamine genes.

“This study made me think prevention. It’s certainly not foolish to be more vigilant with our teenagers who are genetically vulnerable to psychiatric disorders,” says Sawa. “My gut feeling is that environmental stressors—social ones especially—are more important than the genetic in letting mental illness appear.”

 For information: 410-955-4726

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