The amygdala controls autonomic responses associated with fear, arousal, and emotional stimulation and has been linked to anxiety disorder and social phobias.

You must make an oral presentation in front of your peers. As you take your place before the group, your heart pounds in your chest, your palms become sweaty, and your knees shake uncontrollably. In short, you are stricken with fear, a strong emotion caused by the threat of danger or something unwelcome happening. The body’s alarm circuit for fear lies in an almond-shaped mass of nuclei deep in the brain’s temporal lobe. The amygdala, from the Greek word for almond, controls autonomic responses associated with fear, arousal, and emotional stimulation and has been linked to neuropsychiatric disorders, such as anxiety disorder and social phobias. Scientists have recently discovered keys to the neural mechanisms behind the brain’s response to fear, including its extinction, which may help improve treatments for anxiety disorders and other neuropsychiatric conditions. The amygdala is essential for decoding emotions, particularly threatening stimuli. External stimuli reach the amygdala via two different pathways, which complement each other. A short, imprecise route comes from the thalamus, which receives sensory stimuli and allows us to prepare for potential danger before knowing exactly what the danger is. A longer, more precise route comes from the medial prefrontal cortex, the area of the brain that is involved in the final phase of fear, in which the brain reacts to danger and chooses a course of action. Fear and Anxiety Despite the common perception that anxiety and fear are linked, they are distinctly different emotions. “Fear is a physical response to danger,” says Daniel R. Weinberger of the National Institute of Mental Health’s Clinical Brain Disorders Branch. “Anxiety is a psychological response to perceived danger.” Fear is generated by a specific stimulus. Seeing a snake in the grass, for example, can trigger a fear response. Anxiety, which is not necessarily tied to a specific stimulus, is a feeling of being at risk, but from no imminent danger. Many people felt anxious following the September 11 terrorist attacks because they were uncertain if or when another attack might occur. In addition, fear and anxiety emanate from different regions of the amygdala. The fear response, says Emory University behavioral neuroscientist Michael Davis, comes from the central nucleus of the amygdala, the region responsible for commands for bodily responses associated with fear. Anxiety originates in an area responsible for emotions that mediates slower-onset, longer-lasting behavioral responses that may persist after a perceived threat terminates. Fear Response In the late 1930s, researchers discovered that monkeys with damage to the amygdala and surrounding areas of the brain showed a dramatic decrease in fearfulness. Later, scientists found that rats with targeted amygdala damage would snuggle with cats, their natural enemy. Much of the knowledge about the neural circuitry involved in fear processing comes from research conducted by neuroscientist Joseph E. LeDoux and his colleagues at New York University. Focusing on fear conditioning, in which an animal learns to fear a specific stimulus in its environment, LeDoux’s team found that the amygdala processes sensory signals and generates a fear response by stimulating autonomic responses such as increased heart rate and blood pressure and involuntary muscle control. In his lab at Emory, Davis has studied another fear process called extinction, in which fear is reduced after repeated exposure to a fearful event without adverse consequences (see “Have No Fear,” January-February 2004 BrainWork). He found that a receptor for a particular protein called N-methyl-D-aspartate (NMDA) in the amygdala is critical for the extinction of a conditioned fear. Davis also discovered that a compound called D-cycloserine (DCS) injected into rats’ amygdalas enhanced the function of the NMDA receptor and accelerated fear extinction. “DCS helps speed up the extinction process by promoting a new form of learning to cope with memories of an aversive event,” Davis says. DCS, which the Food and Drug Administration has approved for the treatment of tuberculosis, is now being studied in humans, in pill form, as a complement to psychotherapy to treat a variety of neuropsychiatric conditions, Davis says. These conditions include panic disorders, social phobias, and post-traumatic stress disorder. Anxiety and Genetics Emotional memories are thought to be stored in a central part of the amygdala and may play a role in anxiety disorders and phobias. Although the pathophysiological mechanisms of anxiety disorders have yet to be determined, scientists believe that dysregulation of neurotransmitters such as serotonin, dopamine, and gammaaminobutyric acid, or GABA, have been implicated. Weinberger has looked at anxiety disorders and the amygdala from a genetic perspective. He has studied the genes involved in depression, specifically a variant of the serotonin transporter gene called 5-HTTLPR. “The data on fear and anxiety show dense serotonin input to the amygdala,” he says. “We looked at a variant of the serotonin transporter gene and found that this variant helps determine whether someone will develop an anxiety disorder.” In his studies, Weinberger and his colleagues showed research subjects the faces of frightened humans (he says humans are “exquisitely sensitive” to a strong emotion on the face of another human). Under a classical functional imaging paradigm, the subjects’ brains showed outflow from the amygdala to the hypothalamus, resulting in sweaty palms and increased heart rate, autonomic responses related to fear and anxiety. A follow-up study was conducted with individuals who had no history of taking selective serotonin reuptake inhibitors, battling alcohol or drug problems, or living with psychiatric disorders. The results were similar to those in the first study. Basically, says Weinberger, “the behavioral level of the person’s anxiety was related to the biological level of his amygdala activity.” He adds, however, that this gene variant alone is not responsible for the development of anxiety disorders. Other factors, including early-life stress, in conjunction with genetics can predispose people to anxiety disorders. “Anxiety disorders are genetic,” Weinberger says. “That’s no surprise. The surprise is what genes are actually involved, what they do to a person to increase the risk of these disorders, and how they affect the architecture of the brain.” Both Weinberger and Davis are examining the role of other genes in fear and anxiety. Weinberger is studying the serotonin and dopamine transporter genes and how they interact with other critical genes in the development of the amygdala’s circuitry. Davis is looking at genes that are turned on and off during fear conditioning and extinction, particularly gephyrin, a protein involved in GABA transmission that increases in the amygdala following extinction of fear. Although scientists have made great strides in understanding the brain’s neural response to fear and anxiety, Weinberger says there are no good answers yet regarding treatment of fear-and anxiety-related disorders. “Based on the knowledge we have, we’re not quite there yet in terms of treatment,” he says. “We have to create target characteristics [of the disorders] to develop treatments that can benefit patients.”

amygdala, fear, anxiety, , brain, neuropsychiatry, thalamus, prefrontal, cortex