The Emotional Brain: Lessons from Fear Conditioning
By Mary Lynn Hendrix
You are walking through the woods, and you see a coiled shape lying across your path. Instantly -- before you even think "A snake!" -- your brain begins to respond fearfully to the danger. Fear is an ancient emotion involved in a number of mental disorders, says neuroscientist and NIMH grantee Dr. Joseph LeDoux of New York University. His research and that of fellow scientists, reported at the 24th annual Mathilde Solowey Award Lecture in the Neurosciences at NIH on May 8, has shown that the fear response has been tightly conserved in evolution, and probably follows much the same pattern in humans and other vertebrates.
Dr. Joseph LeDoux
According to LeDoux, he and others are making progress in tracing the brain circuitry underlying the fear response. Research attention is now focused on the amygdala, a small almond-shaped structure deep inside the brain. A portion of the amygdala known as the lateral nucleus appears to play a key role in fear conditioning, an experimental procedure in which an animal (rats were used in most of these experiments) is taught to fear a harmless stimulus such as a sound tone. The conditioning is accomplished by pairing the tone with a mild electrical shock to the animal's foot. After a few times, the animal comes to exhibit defensive responses whenever it hears the tone. These responses include freezing (remaining motionless) and elevation of blood pressure.
Use of cell-staining procedures to trace the connections between the neurons of the amygdala and other brain structures shows that frightening stimuli trigger neuronal responses along a dual pathway. One path, dubbed the "high road," carries nerve impulses from the ear to the thalamus (a brain structure near the amygdala that serves as a waystation for incoming sensory signals). From the thalamus, the nerve impulses are sent to the auditory portion of the sensory cortex, a region of the brain that conducts sophisticated analysis of inputs and sends appropriate signals to the amygdala. Alternatively, nerve impulses may be sent much faster from the thalamus directly to the amygdala. This "low road" signal system does not convey detailed information about the stimulus, but it has the advantage of speed. And speed is of great importance to an organism facing a threat to its survival.
When the amygdala receives nerve signals indicating a threat, it sends out signals that trigger defensive behavior, autonomic arousal (usually including rapid heartbeat and raised blood pressure), hypoalgesia (a diminished capacity to feel pain), somatic reflex potentiation (such as an exaggerated startle reflex), and pituitary-adrenal axis stimulation (production of stress hormones). In animals that have consciousness, these physical changes are accompanied by the emotion of fear.
LeDoux pointed out that having a very rapid, if imprecise, method of detecting danger is of high survival value. "You're better off mistaking a stick for a snake than a snake for a stick," he said.
Cell-tracing and physiological studies show that the lateral nucleus of the amygdala has all the ingredients necessary for fear conditioning to take place: a rich supply of nerve cell extensions connecting it to the thalamus, other portions of the amygdala, and various parts of the cortex; rapid response to stimuli; high threshold for stimulation (so that unimportant stimuli are filtered out); and high frequency preference (which corresponds to the pitch of rat distress calls).
Another part of the amygdala, the central nucleus, is the portion responsible for sending out the signals to trigger the "fight or flight" response.
The various portions of the amygdala communicate with each other by way of internal nerve cell connections. Once fear conditioning has taken place, these interior circuits tend to perpetuate the response to the frightening stimulus. So a person with a phobia, such as a morbid fear of snakes or heights, may undergo behavioral treatment and seem to be cured, only to have the phobia return during an episode of high stress. What happened, LeDoux suggests, is that the signal pathways from the thalamus to the amygdala and sensory cortex have been normalized, but the internal circuits in the amygdala have not.
There are far more cell circuits leading from the amygdala to the prefrontal cortex (the area of the brain most responsible for planning and reasoning) than there are going the other direction. This may be one reason why it is so difficult to exert conscious control over fear, LeDoux said.
These findings have important implications for treating people who suffer from anxiety disorders, according to LeDoux. Recent functional magnetic resonance imaging scans of brains in living human subjects are beginning to show that the amygdala is the central site of fear conditioning, just as in rats. And fear conditioning is believed to play a role in such anxiety disorders as phobias, post-traumatic stress disorder and panic disorder. If, as research suggests, the memories stored in the amygdala are relatively indelible, the aim of therapy for anxiety disorders must be to increase cortical control over the amygdala and its outputs, LeDoux said.
LeDoux sees the need for more behavioral and neuroscientific research to increase understanding of how multiple memory systems work together in fear conditioning and other emotional responses. The brain is closer to yielding secrets of emotion now than ever before, he said, because more scientists are focusing on emotion. Soon we will have a very clear picture of fear and other ancient aids to survival that are products of the emotional brain.
Observed NIMH director Dr. Steven Hyman, "Joseph LeDoux's investigations of how the brain processes fear and forms emotional memories are pathbreaking science in their own right; they also provide the most important current leads for research on anxiety disorders."
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