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Discovering Our Selves: The Science of Emotion
Executive Summary

Panel: The Science of Memory and Emotion

"From Transient Fear to Chronic Anxiety
on a Molecular Level"

Eric R. Kandel, M.D., is University Professor at Columbia University and Senior Investigator in its Howard Hughes Medical Institute.

"Emotion" refers to a broad range of affective responses that includes pleasure, elation, depression, fear, anxiety, anger, and calm. Here I focus only on fear and disorders of fear--the anxiety states.

Just as grief is a normal response to the loss of a loved one, so are transient fear and transient anxiety normal responses to threatening situations. In fact, normal levels of anxiety are adaptive: Anxiety signals potential danger and can contribute to the mastery of difficult situations. Excessive or chronic anxiety, however, is maladaptive and pathological, either because it is so intense or because it is provoked by events that no longer pose danger. Anxiety disorders, such as social phobias and post-traumatic stress disorder, are essentially malfunctions of the fear and anxiety system. Their universality makes the anxiety states of particular interest; they represent mental disorder that can be modeled in experimental animals.

To investigate the molecular underpinnings whereby a transient fear is converted to a chronic anxiety state, we work with the marine snail Aplysia, which has a very simple nervous system and shows distinctive responses to different levels of fear. We have trained Aplysia to produce two types of anxiety states: signal anxiety and generalized chronic anxiety. We produced "signal anxiety" or conditioned fear by teaching an Aplysia to associate a neutral stimulus (a light touch to the siphon, a fleshy protuberance) with a fearful stimulus (a shock to its tail). We produced chronic anxiety or sensitization by teaching an Aplysia simply to recognize and remember an unannounced (unsignaled) shock to the tail; no signal announces the shock or triggers the anxiety state.

Signal anxiety has one positive aspect: In the absence of the signal, animals and people feel quite safe; they have no cause to worry because they have learned to associate danger only with that signal. By contrast, with unsignaled anxiety, animals and people feel anxious in a variety of circumstances; there is no signal whose absence will make them feel comfortable.

How is a transient fear converted to a sustained anxiety state? If its siphon is touched, Aplysia will briskly and reflexively withdraw both its siphon and respiratory organ, the gill. Give the animal a noxious shock to the tail and it exhibits an even more powerful gill withdrawal and also withdraws its tail as it prepares to escape. If you give the animal a shock to the tail and a few minutes later a weak touch to the siphon, the animal will show a much more powerful gill withdrawal as well as a tail withdrawal, again preparatory to escape. In other words, it is overreacting to the mild stimulus, much as people with chronic anxiety overreact to only mildly threatening situations.

The duration of this generalized chronic anxiety is a function of the number of tail shocks. If you give one, the animal will remember that stimulus for a few minutes, a normal fear reaction; within those few minutes, it will overreact to a mild touch, but then it will revert to a less dramatic response. If you give the noxious stimulus repeatedly--say five times--however, you produce a chronic anxiety state that will last for days.

This chronic state has a completely different molecular basis; it requires the synthesis of new proteins. We know about this because when we introduce an inhibitor of protein synthesis, the long-term anxiety state is blocked but the short-term fear state is unaffected. Protein synthesis takes place within the animal's nerve cells and requires that certain genes be turned on, or "expressed."

We now have some insight into how these genes are activated. If you give a single stimulus to the tail, the cAMP signaling system within the animal's sensory nerve cells acts to enhance the release of a neurotransmitter, glutamate, which in turn strengthens the connections between sensory and motor nerve cells for a few minutes, but no genes are activated. With repeated stimuli, however, part of the cAMP signaling system, the catalytic subunit of the cAMP-dependent protein kinase, moves into the cell nucleus, which houses the animal's DNA. There it eventually triggers an activator gene that switches on a number of other genes and begins a cascade of activity ending in the production of a protein that promotes the growth of new synaptic connections (the connections between nerve cells), physically altering the brain's wiring. We now believe that a similar physical alteration occurs in the human brain not just when we are anxious but when we are learning and remembering, whether playing a musical instrument or memorizing the Gettysburg Address.

Modern molecular biology allows us to study emotion and memory by zeroing in on specific genes, discerning the ones, for example, that are expressed only in the amygdala, the brain structure so critical to fear and anxiety. Now that we are beginning to understand these processes, our goal is to be able to determine which are critical for anxiety states, and then to try to develop pharmacological agents to counteract them.

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