Vadim Bolshakov
Vadim Bolshakov contemplates the results of his successful experiments to measure changes in the brains of rats caused by emotional learning. He and his colleagues believe such changes can be used to treat anxiety disorders in humans. (Staff photo by Stephanie Mitchell)

After decades of speculation and experiments, researchers have discovered brain changes that may underlie learning and memory.

According to a long-standing theory, learning takes place and memories form when the same message travels repeatedly between specific cells in the brain. Communication between these cells grows stronger with repetition. Eventually, the cells no longer need to be stimulated by an outside source such as a teacher or input from the senses.

It sounds logical enough, but for 25 years, no one was able to measure changes in the brain and correlate them with changes in behavior associated with learning. Some neuroscientists began to doubt whether such a link really exists. Finally, researchers at Harvard Medical School and McLean Hospital in Belmont have proved that it does.

Vadim Bolshakov, assistant professor of psychiatry, and his colleagues taught rats that a certain sound they heard would be accompanied by an electric shock. After learning that unpleasant fact, the animals became startled every time they heard the tone whether a shock followed or not. Bolshakov and his team then examined their brains, and found conclusive changes not seen in rats that heard the sound or felt the shocks separately.

“This is the first really important causal link” between changes in the brain and changes in behavior, says Eric Kandel, a neuroscientist at Columbia University and winner of the 2000 Nobel Prize in Medicine. Kandel participated in the research.

Rats aren’t us. But Bolshakov points out that “complexity aside, there is no reason to believe that fundamental differences exist between their brains and ours. The major features of nerve-impulse transmission in the brain have been conserved in mammals throughout evolution.” The recently sequenced genome of mice, first cousins of rats, reveals that their complement of genes is very similar to our own.

Because of that similarity, the Bolshakov team’s discovery could lead to a better understanding of and new treatments for some of the most common forms of mental illness. Panic, phobias, post-traumatic stress disorders, obsessive-compulsive behavior, and generalized anxiety affect millions of people and are believed to involve the fear system in the brain.


Shocking sounds

Bolshakov worked on the brain roots of learning and memory for six years at Columbia University before coming to McLean, Harvard’s largest psychiatric teaching hospital, in 1999. Like others, Bolshakov probed changes in cell communications in the hippocampus, an s-shaped bit of tissue deep in the brain of all mammals that is suspected of being a seat of learning. But this approach turned out to be frustratingly unproductive.

Searching for a more tractable way to go, Bolshakov settled on the amygdala, an almond-shaped cluster of cells near the hippocampus. Fear and other learned emotional responses come from the amygdala. If a rat learned to fear something, would that produce measurable changes in its brain, specifically in the amygdala?

Bolshakov, Evgeny Tsvetkov, and other experimenters on the team introduced rats to a sound accompanied near the end by a low-intensity foot shock. The shock wasn’t painful, Bolshakov says, but it got the rats’ attention. They were visibly startled.

The day after being trained this way, the animals heard the sound but didn’t receive any shocks. Nevertheless, the sound frightened them. In fact, they appeared more alarmed than during their training. And this was no temporary effect. It lasted for the rest of their lives. (Lab rats live for two to three years.)

Other experimenters did not investigate the amygdala because of the tremendous technical difficulty involved in probing single nerve cells in this minute organ. Bolshakov and his colleagues managed to overcome this obstacle. When they stimulated an amygdala cell in untrained rats with high-frequency electrical pulses, they recorded the equivalent of a flood of nerve impulses. These subjects included animals that had heard the training sound and felt the shocks, but never in combination with each other.

When the trained rats were stimulated in this way, however, communications between cells, as measured by electric currents, hardly increased. That signaled the researchers that the lesson had been learned. “You couldn’t put anything on top of what had already been learned,” Bolshakov comments. “We had changed the brains of the animals forever.”


Soothing an anxious brain

The emotional learning these experiments demonstrate “could be the mechanism behind human anxiety disorders,” Bolshakov and Kandel believe. “A person can have no conscious memory of a traumatic event, but very strong unconscious memories can be formed through fear-conditioning,” Bolshakov adds. “It is believed that these fears, which are very resistant to extinction, can become a source of intense anxiety.”

He cites the example of post-traumatic stress disorders. A person traumatized by war, terrorism, or sexual attack may feel that he or she has left the worst behind. Later, however, an unrelated sound, sight, or smell can bring back unwanted memories and fears.

Of course, such events in humans are more complicated than the Pavlovian response of a rat to an electric shock. But Bolshakov and Kandel think enough of a similarity exists for the research to eventually have an effect on the treatment of anxiety disorders.

It is possible to erase learned fear in animals. Expose them to the same fearsome tone for days or weeks without adding a shock, and the sound no longer startles them. “We don’t know if this erases the fear or if the animals learn something new,” Bolshakov admits.

He doubts this research could be done in humans, at least with currently available technology. You simply can’t shock them repeatedly then go probing around inside their brains. However, animal experiments might yield enough information about how the brain changes during learning and memory for scientists to design new drugs.

Animal studies of learned fear are “likely to provide a new generation of anti-anxiety drugs that will be very useful,” Kandel asserts. “Discovering more about the biochemical and molecular processes involved could produce specific targets for drugs that act in the amygdala.”

Before that happens, however, neuroscientists must learn a lot more about what goes on in the brain when this kind of emotional learning occurs. To obtain such information, Bolshakov and his colleagues are doing several different types of experiments. They want to see if animals can be trained to distinguish between different sound frequencies such as a shrill, high-pitched tone and a growl-like, low-pitched one. They also want to determine if fear conditioning can be done with other sensory stimuli such as light, color, or smell.

In addition, the researchers are investigating what goes on inside a brain cell during fear conditioning. According to Kandel, they have found a gene that causes fear to become intensified when it is knocked out or blocked experimentally. The next step will be to determine whether increasing the activity of such genes can inhibit corrosive fear and anxiety.

“As we learn more about the mechanisms of fear conditioning,” Bolshakov says, “I have no doubt it could eventually be applied to help humans.”

The only thing we have to fear is fear itself.Franklin D. Roosevelt