Sometimes the best approach to problem solving is no strategy at all—an exploratory, “try anything” gambit. Such wild guessing can be a smart way to face a challenging competitor or explore unfamiliar terrain. Yet occasionally we get stuck in this random-guessing mode—we essentially keep pressing buttons with no thought to strategy. That is a phenomenon called learned helplessness, observable in people and animals who believe nothing they do can produce a desired outcome. Now scientists at the Howard Hughes Medical Institute's Janelia Research Campus in Ashburn, Va., have discovered the molecular switch that allows rats to flip between strategic and random behavior, a finding that could reveal how individual neural circuits contribute to decision making and provide clues for dealing with learned helplessness in humans.

To uncover the brain switch, biologist Alla Karpova and her colleagues challenged rats to compete against one of three computerized competitors. The competitors attempted to predict which of two holes the rats would poke their head through to earn a treat. The treat only appeared, however, if the computer failed to predict the rats' behavior. Against the first two competitors, the rats took a strategic approach and satisfied their sweet tooth. But the third competitor was devilishly capable, and the rats resorted to guessing. Then Karpova's team surreptitiously replaced the third competitor with one that rewarded a specific behavior pattern—something rats can usually figure out. Yet these rats floundered. They were stuck in random mode, insensitive to the cues that would have led to a reward. They never discovered the pattern after even thousands of attempts.

By manipulating levels of the stress hormone epinephrine, the researchers demonstrated that a part of the brain called the anterior cingulate cortex (ACC)—a crescent of brain tissue behind the frontal lobes in humans—was key. When norepinephrine levels were high in the ACC, as they would be during stress, the rats abandoned strategic behavior. By suppressing norepinephrine in the ACC, Karpova's team was able to rescue rats stuck in random mode and restore their ability to learn from their mistakes.

The results jibe with earlier studies of learned helplessness in rats, which found that both exercise and antidepressants effectively eliminated the helpless behavior that often accompanies depression. These remedies are also known to relieve stress. “Because norepinephrine is regulated in stress, anything that lowers stress could help us behave strategically,” Karpova says.