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Biology 202
2001 First Web Report
On Serendip

The Neurobiology of Fear: Emotional Memory and Post-Traumatic Stress Disorder

Daniel J. Burdick

For survivors of traumatic events, the trauma itself is often only the beginning. While some are relatively unaffected, many others will develop post-traumatic stress disorder, or PTSD, an affliction that haunts its victims with terrifying memories, nightmares, and panic attacks. (For a comprehensive list of symptoms and diagnostic criteria, the reader may refer to the DSM-IV, relevant portions of which may be found online (7).) The National Institute of Mental Health estimates that 3.6 percent of Americans between the ages of 18 and 54 suffer from PTSD; 30 percent of those who have spent time in war zones - one million veterans of Vietnam alone - are affected (6). PTSD is treated with several forms of psychotherapy, including exposure therapy, centered around a controlled confrontation of frightening stimuli. While medication may treat co-occurring depression, anxiety, or insomnia (6), pharmacological agents targeting PTSD remain unavailable. In part, this is because researchers have only begun to describe the underlying neurobiology. Several recent studies have pointed to the brain structure known as the amygdala as a central player, but questions remain: How does this small structure "recognize" danger? How does it create emotional memories? What causes recurrence of these memories?

Answers to these questions are complex and incomplete. As an anxiety disorder, PTSD has its foundations in fear and "emotional memory." Like factual memory, emotional memory also involves the storage and recall of events and details; this has been termed the explicit or conscious memory (2). Emotional memory, though, has a second, distinct component. This facet, the implicit or unconscious memory, is the memory of the physiological response, such as increased blood pressure, a higher respiratory rate, and muscle tensing, and is responsible for the emotional impairment that PTSD causes.

The distinction between conscious and unconscious memory suggests - and it is generally accepted - that emotional memory involves two brain systems. While conscious memory is mediated by the hippocampus, the amygdala is implicated in emotional memory (1). A small collection of nuclei in the center of each temporal lobe, the amygdala controls the fear response, receiving and integrating sensory input to determine the level of threat. If the input is sufficiently intense to initiate an action potential, the amygdala triggers other areas of the brain that induce the physiological response that humans interpret as fear (3); the danger has been "recognized."

The amygdala, though, is involved not just in the fear response, but in the memory of fear, as well. In one test, researchers used functional MRI scans to measure amygdala activity while showing subjects a number of frightening and neutral images. They found that the degree of amygdala activity was a good predictor of both fear level (as reported by the subject) and of the ability several weeks later to recall having seen the image (1).

This evidence, along with other studies with similar findings, has made the amygdala the target of much anxiety-disorder research (5), but it continues to raise the question of mechanism. The answer, partial though it may be, appears to lie in classic fear-conditioning and in the neuronal property called long-term potentiation (LTP). In conditioning experiments performed by Joseph LeDoux at New York University (2), rats were administered a mild electric shock in conjunction with an auditory tone. The rats soon responded to the tone alone with a fearful response: increased blood pressure, faster breathing, and motionlessness. This may explain the recurrence of emotional responses in PTSD. Just as a non-threatening stimulus (the tone) that had been associated with a threatening one (the shock) could trigger the same emotional response in the conditioned rats, so can an innocuous sound or sight or person associated with a trauma trigger the intense emotions of PTSD.

But how does this association get created? How does the amygdala learn to recognize and remember danger, even if it does so erroneously sometimes? Long-term potentiation, it is believed, is the cellular mechanism of learning and memory. When a neuron receives frequent stimulation, a stronger neuronal connection is formed; either receptivity is increased so that a smaller stimulus is required to induce the same postsynaptic depolarization, or presynaptic release of neurotransmitter is enhanced (3). Central to LTP is the activation of so-called NMDA receptors. NMDA receptors are double-gated, requiring both the binding of the neurotransmitter glutamate and membrane depolarization for activation (8); this therefore provides a possible cellular mechanism for association and conditioning.

Since LTP has been shown to occur in the amygdala (8), it would seem that this explanation could be easily extended to PTSD. If an amygdala pathway is sufficiently stimulated, it will become potentiated, in effect remembering the frightening input and easily reproducing the cascade of fear-triggering neuronal activity that was necessary to respond to the original trauma. However, PTSD differs from normal memory in that it is the result of a single intense event, rather than the repeated stimulation that precipitates LTP. Granted, the nervous system communicates intensity by translating it into greater frequency, and this may well be the explanation, but it seems that more experimentation is needed to determine whether a single intense input can induce long-term potentiation.

Whether any of this research will translate into clinically useful solutions for those suffering from PTSD is a question that will certainly not be answered for several years. In addition to the research that directly attempts to address this issue, of some interest is the creation of genetically engineered "smart mice" by Princeton University researcher Joe Zsien (8). Although most of the attention generated by these discoveries focused on age-related memory disorders, some of the findings may be applicable to anxiety disorders. Zsien reported that these mice performed better at fear-extinction tests than their "normal" counterparts. After having been conditioned as described above, the engineered mice, when repeatedly exposed to a tone without a shock, learned to be unafraid faster. This appears to have obvious implications for exposure therapy in treating PTSD, though again, translating these research results into something useful for practitioners will require time. In the meantime, those who suffer can only wait and find hope in the rapid increases in our knowledge that this field of research is generating.

WWW Sources

1)The Journal of Neuroscience Online, Canli, Turhan, Zuo Zhao, James Brewer, John D.E. Gabrieli, and Larry Cahill. 2000. Event-related activation in the human amygdala associates with later memory for individual emotional experience. J Neurosci, 20:RC99(1-5).

2)Emotion, Memory and the Brain, from the Joseph LeDoux Laboratory of the Center for Neural Science at New York University.

3)Models of Fear Conditioning, from Stephen Maren's Emotion and Memory Systems Laboratory at the University of Michigan.

4)Summary of Research at Stephen Maren's Emotion and Memory Systems Laboratory at the University of Michigan.

5)Anxiety Disorders Treatment Target: Amygdala Circuitry, from the National Institute of Mental Health.

6)Facts About Post-Traumatic Stress Disorder, from the National Institute of Mental Health.

7)PTSD Diagnostic Criteria from the DSM-IV, from Bully Online, a service of the United Kingdom National Workplace Bullying Advice Line.

8)Building a Brainier Mouse. Zsien, Joe T. 2000. Scientific American.




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