McLean Researchers Uncover Missing Link

Discovery helps resolve debate, could lead to new anti-anxiety medications

April 10, 2002

Public Affairs

Belmont, MA - McLean Hospital researchers report in the April 11 Neuron a discovery that could help resolve one of the liveliest controversies in contemporary neuroscience-how the brain changes during learning and memory.

In addition, the discovery could lead to a better understanding of a class of psychiatric disorders that affects millions of Americans-namely, anxiety disorders.

Researchers have argued that for memory and learning to occur, neurons must become more responsive to one another-so responsive that they will communicate at a high level even when they are no longer being stimulated by an external source, such as input from the senses or other neurons. But so far no one has been able to show that this enduring responsiveness, or long-term potentiation, actually occurs during learning and memory, leading some to doubt a causal link between learning and this physiological change in the brain.

McLean Hospital researchers Vadim Bolshakov, PhD, and William Carlezon, PhD, working with Nobel Prize winner Eric Kandel, PhD, and other McLean Hospital colleagues, report that they have found clear evidence of a causal link between long-term potentiation and learning-in this case, learned fear-in the brains of rats.

"There have been a series of progressive attempts but there has been no demonstration of a causal interaction between the two," said Kandel, a scientist at the Columbia University College of Physicians and Surgeons, and the recipient of the 2000 Nobel Prize in Medicine. "I think that this is the first really important causal link."

Some of the most common forms of mental illness-panic, phobias, posttraumatic stress disorders, obsessive-compulsive disorders and generalized anxiety-are thought to involve the fear system of the brain.

"It has been shown that an individual can have very poor conscious memory of a certain traumatic event but, at the same time, very strong unconscious emotional memories can be formed through a fear conditioning mechanism," said Bolshakov, the study’s lead author. "These fears, which are very resistant to extinction, can become a source of intense anxiety."

Understanding how cellular mechanisms, including long-term potentiation, work to generate such unconscious fears could lead to novel therapeutic treatments for anxiety disorders.

"The study of learned fear in laboratory animals is likely to provide a new generation of anti-anxiety agents that will be very useful," said Kandel.

The focus on fear conditioning proved key in uncovering the link between long-term potentiation and learning. Previous attempts had focused on spatial learning in the hippocampus, a complex curlicue of tissue buried in the brain that is thought to be involved in many kinds of learning. Bolshakov and his colleagues directed their attention instead to the amygdala-a well-studied but simpler pyramid-shaped structure that is involved in producing a wide variety of learned emotional responses, most notably fear.

To see if learned fear involved long-term potentiation in the neurons of the amygdala, Bolshakov and his colleagues trained rats to fear a sound. In the animal's amygdala, they stimulated individual neurons at a very high frequency-a technically difficult feat. Normally during high frequency stimulation, presynaptic neurons release glutamate in a continuous manner, which causes their postsynaptic partners to produce an enduring increase in electrical current. This prolonged heightened response is precisely what occurs during long-term potentiation. But in the postsynaptic neurons of the fear-conditioned animals, output of current barely increased above their baseline levels, suggesting that their presynaptic partners had already been stimulating them as a result of fear-conditioning.

"The presynaptic connections have already been potentiated," said Bolshakov. "You basically cannot put anything on top of them because they are potentiated already." Upon closer examination, the researchers found that high levels of glutamate were released at the presynaptic terminals, suggesting that long-term potentiation had occurred.

McLean Hospital maintains the largest research program of any private, U.S. psychiatric hospital. It is the largest psychiatric teaching facility of Harvard Medical School.

Email this page