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The brain uses the prefrontal cortex to make judgments, control impulses, and find chocolate chips in lab tests.

Diagrams: Data from "Protein Kinase C Overactivity..." (see bibliography).

I'm freaking out. My boss is bellowing, my kids are klamoring, I'm stuck in a maze, and I can't find my chocolate chips. I think I'm losing my mind. What's a poor rat like me to do?

Dear Stressed:
You're not alone. I get this kind of letter every week. Whether it's final exams, impatient pups or writing applications for research grants, many of us feel stressed these days. I suggest you take time off work, visit a rodent retreat, and check your protein kinase C levels.
- Amy Arnsten
Department of Neurobiology
Yale Medical School

Blaming the messenger
Everybody laughs about stress, but stress can change your brain. In a psychology lab, it's easy to show that stress interferes with your working memory, making you temporarily dumb. But stress can also trigger serious mental illnesses like bipolar disorder (manic depression) and schizophrenia.

Stress affects the prefrontal cortex, the executive section of the brain that regulates thought, behavior and emotion. But how? Perhaps through a messenger compound called protein kinase C (PKC).

When Amy Arnsten of Yale Medical School and her colleagues increased PKC levels in rats and monkeys, the animals got stupid. Before the test, they had an easy time finding a chocolate chip they had seen before. But after getting a chemical that increased their PKC levels, they had trouble finding this critical food.

Then, when the researchers blocked PKC, the rats could again find the chips.

In a second experiment, the researchers created the same picture by administering a chemical that simulates stress. As before, the decline was reversed by a PKC-blocking chemical.

Major maladies
If you konstantly kvetch about stress, you might greet these results as interesting, but not terribly significant. But stress and PKC also factor into the most severe mental disabilities among young adults:

Bipolar disorder causes profound mood swings in 1 percent of adult Americans.

Schizophrenia causes hallucinations, delusions, disordered thinking, bizarre speech or behavior, and social withdrawal in 1.1 percent of American adults.

Curiously, both these brain diseases, according to Arnsten, "involve profound dysfunction of the prefrontal cortex, the most highly evolved part of the brain, which lets us concentrate, organize, plan for the future." The prefrontal cortex is the home of working memory, a short-term storage that helps you recall where you left your keys.

Photo: OSHA

But there's more: The prefrontal cortex also "inhibits inappropriate thoughts and lets you act appropriately socially," Arnsten adds. So a problem with the prefrontal cortex can prevent you from finding chocolate chips in a lab -- or impair impulse control, distraction, insight and judgment.

The present study grew from the observations of scientists like Husseini Manji of the National Institute of Mental Health, who found excess PKC in brains of people with bipolar disorder. But there are other reasons to wonder about the role of PKC in brain diseases. For example, some drugs for bipolar disorder and schizophrenia "reduce PKC very markedly" in rodent brains, Arnsten says, even though they "are very disparate molecules... and seemingly have nothing in common."

Messing with the messenger
If stress raises PKC levels, and PKC changes how the prefrontal cortex works, Arnsten says PKC could explain the role of stress in bipolar disorder and schizophrenia. "Often the first psychotic break happens when a teenager goes to college or to the military for the first time. Stress is often what puts them over the edge."

The research is starting to flesh out a more complete understanding of two grave brain diseases, she adds. "Genetic changes in the regulation of protein kinase C may cause some of the symptoms of bipolar disorder and schizophrenia. In other words, we are coming to a rational understanding of irrational behavior."

Photo: Insurance Commission of Western Australia

Having identified how the messenger molecule PKC affects the prefrontal cortex, Arnsten hopes that blocking PKC might help bipolar disorder and schizophrenia. Marinus Pharmaceuticals, of New Haven Conn., and the Stanley Medical Research Institute are now funding some of her research to see if PKC inhibitors can be used safely in humans. "We hope this might be a new direction for treating bipolar disorder and schizophrenia, because it would be acting inside the cell, and it might act more quickly," Arnsten says. "We hope that if it's more selective, there will be fewer side effects."
-- David Tenenbaum

Bibliography
Protein Kinase C Overactivity Impairs Prefrontal Cortical Regulation of Working Memory, S.G Birnbaum et al, Science, 29 October, 2004.