One of the biggest fears Joseph E. LeDoux had when he was growing up was of getting stuck in Eunice, La. His small hometown sits among creeks and rice fields, and its Cajun country roots give it a certain charm. It is hard to swing a possum without hitting a good gumbo restaurant. An old theater downtown hosts the weekly Rendezvous des Cajun radio show, a yipping version of Prairie Home Companion, only with dancing, and anyone can join the live studio audience for a mere $5.
But when LeDoux was coming of age in the 1960s, he found Eunice too sedate. He did some radio disc jockeying in high school, and the era's music, along with his own inquisitiveness, drew his attention to the wider world. His parents, however, told him they would pay for college only if he studied business and only if he did not venture farther than Baton Rouge, 80 miles east. His father, a butcher, envisioned his son as a leading local businessman. The main interest Joseph had in butchering was that it allowed him to do his first neural explorations: digging through cow brains to extract the bullets that had killed the cattle, so his father could sell the brains as a delicacy.
Nevertheless, LeDoux dutifully enrolled at Louisiana State University. Now 55 and a leading neuroscientist specializing in the study of fear, LeDoux recently told me in his office at New York University that he did not care much for his business studies, yet they ultimately led him to brain research. "I studied marketing," he explained in an amiable voice that carries the slightest hint of Cajun. It was a bright day, and the Empire State Building gleamed in the distance outside his office window. "As I went along, the thing that interested me most was why people bought stuff they didnt really need."
LeDoux's interest in such manufactured desire led him to a course on learning and motivation with L.S.U. psychologist Robert Thompson. Professor and student hit it off, and Thompson urged LeDoux to go on to graduate school in neuroscience. LeDoux applied to 30 programs, but just one, the State University of New York at Stony Brook, accepted him and only, LeDoux says, because Thompson convinced his friend Michael S. Gazzaniga, then head of the school's neuroscience program, to take a chance.
Gazzaniga and LeDoux would both go on to stellar careers. Gazzaniga has become a prime leader in cognitive neuroscience, and this winter left Dartmouth College after a decade to direct the new Sage Center for the Study of the Mind at the University of California, Santa Barbara. His protg, meanwhile, has turned an area of research that most neuroscientists were loathe to plumb--the biology of emotion, particularly of fear--into one of neuroscience's most revealing disciplines.
With remarkable tenacity and creativity over two decades, LeDoux has used simple fear conditioning in the rat to identify the neural pathways and processes through which the rodents acquire, act on and sometimes extinguish their fears. Because most of these neural networks operate similarly in humans, his findings have vastly expanded our understanding of how emotions affect our thoughts, moods, motivations, memory and behavior. His work is also aiding the development of drugs and other treatments for the millions of people who suffer mental disorders caused or aggravated by anxiety. "Joe has been the driving force," Gazzaniga says. "When he started, he was a long-hair ponytail, and maybe some wouldnt have thought him impressive. But there are people who walk in and you see right away that they have it. Joe was one of them."
Assess the Threat
Behind many a long, productive inquiry stands a simple method. For LeDoux, that has been the conditioned response. Like many of his colleagues, LeDoux has used rats, and his basic tool has been the pairing of a tone with a mild electric shock. He puts a rat in a cage, sounds a tone, then sends a mild shock through the metal cage floor. After a few repetitions, the mere sound of the tone, without the shock, makes the rat "freeze" in fear. Such conditioning has been a staple of mind research since Russian physiologist Ivan Pavlov published his dog studies in 1903. LeDoux's genius--first as a graduate student with Gazzaniga, then as a postdoc and professor at Cornell University from 1977 to 1989, and since then at N.Y.U.--has been to use this simple conditioned response to analyze ever more closely how the rat's brain creates the association of tone and shock and incorporates that learning into future behavior. Of particular interest is the amygdala, the almond-shaped structure near the center of the brain, long considered the seat of emotions.
In one of LeDoux's first papers, written in 1985, he found that the primary neural pathway for emotional auditory memories--for example, tones or other sounds that instill fear--runs directly from the thalamus (the brain's receiving room for most sensory information) to the amygdala. This is a very quick path--the impulse completes the run in five milliseconds--that bypasses conscious awareness so it can instantly put the body on alert. LeDoux then isolated a second circuit, slower but more information-rich, that heads from the thalamus to the auditory cortex in the brain's "thinking" area (which helps to further define and interpret the sound) before continuing on to the amygdala. To the general alarm created by the first pathway, this longer path adds context from memories, other elements of cognitive awareness, and more complex learned responses.
Tinkering with those paths revealed some interesting phenomena. LeDoux found that if he cut the first pathway, a rat could not develop a new conditioned response; if a tone was paired with a shock, the animal would not learn to fear the tone. But if he destroyed the second, "smart" route in a conditioned rat, it would be unresponsive to virtually all sound, yet it would still freeze when the tone rang. Although the rat was not consciously aware of any noise, its ear passed the tone to its amygdala, which sounded the alarm. If this procedure were done to a human, the person would be functionally deaf but would still jump if a door slammed behind him. The amygdala's most basic reactions take place independent of awareness.
The second, slower loop adds all the information that allows us to identify and react appropriately to the alarming stimulus. This cortical pathway is crucial to what LeDoux calls emotional actions (rather than reactions) that are designed to help a creature avoid, escape or discount a threat. The simpler pathway makes your muscles tense and heart race so that they are ready for action when the smoke alarm in your kitchen goes off. The longer, cortical pathway gives you the assessment that sends you out the door in the case of a fire--or just across the room to turn off the alarm if bread is being singed in the toaster.
Along with defining these pathways, LeDoux has found functional regions in the amygdala that play different roles in communicating with other brain areas. The most vital of these other structures are the hippocampus (a kind of directory for memory storage), the prefrontal cortex (which incorporates sensory information into the "thinking" brain), and the hypothalamus (which in tense situations recruits the adrenal and pituitary glands to mobilize the body for response). By knocking out or isolating the various pathways among these regions, LeDoux has found that the amygdala plays a crucial part not just in acquiring emotionally laden memories but also in consolidating them. Startle someone a few seconds after she has seen a picture of a threatening face--while she is consolidating that memory--and her memory of the face will be strengthened. The memory will also be strengthened if she is startled when she is recalling that threatening face later.
Decide What Matters
LeDoux's earliest studies, then, helped to establish the surprisingly complex dynamics behind our seemingly simplest fear reactions. His subsequent work, and that of others who have built on his platform since the early 1990s, has shown that the amygdala figures heavily in the more complex human spheres of perception, attention and even social relations. As Ralph Adolphs of the California Institute of Technology, an expert on emotion, memory and social cognition, has put it, the amygdala "pervades the organization of thought and behavior at all levels."
Socially, for instance, patients with amygdala damage often overlook emotionally laden stimuli. They may not recognize an expression of fear on someone's face, and they find all faces more trustworthy and approachable than the rest of us do. They are slightly, happily naive. Similarly, monkeys with amygdala lesions approach other monkeys more quickly and openly than unaffected monkeys do.
The amygdala's recruitment of memory, knowledge and association is also vital to deciding, amid the sensory din coming at us all the time, what matters. In addition to LeDoux's rat studies, high-resolution images of healthy and damaged human brains by N.Y.U. colleague Elizabeth A. Phelps and others, as well as behavioral studies, support this idea. Growing evidence indicates that the amygdala enhances and directs our perception and attention regarding emotions other than fear, such as pleasure or disgust. It makes key parts of our brains more responsive, as well as "stickier" in forming memories and associations.
By attuning the brain to all manner of threats and pleasures--not just the snake on the path but also the smile on your child's face--the amygdala helps to confer emotional significance on a wide range of experiences. The amygdala helps to give life meaning.
One implication is that the amygdala may play a leading role in establishing what consciousness researchers call "salience"--choosing which stimuli we prioritize and therefore of what we are conscious. This Oz-behind-the-curtain power has LeDoux convinced that the amygdala and its subcortical allies, rather than our consciousness, define who we are. "Consciousness may get all the focus," LeDoux notes, "but consciousness is a small part of what the brain does, and it's a slave to everything that works beneath it. I dont think that's what produces our selves." Rather, he says, our identities arise from the unique arrays of learned fears, desires, associations and expectations that are ingrained most fundamentally and broadly in our unconscious.
Even if the amygdala is not the fount of human experience, its function is certainly fundamental to a pleasant life. As LeDoux notes, fear and its more persistent cousin, anxiety, "are the root of almost all our emotional disorders." More than half of mental health visits in the U.S. every year are for anxiety or related conditions, including post-traumatic stress disorder (PTSD), generalized anxiety disorder, obsessive-compulsive disorder, schizophrenia and depression. Most often anxiety either drives these conditions or makes them unbearable.
Unlike fear, anxiety does not spring from an immediate stimulus; rather it is from our worries or memories, real or imagined. From a LeDouxian perspective, one can view anxiety as a mismatch in traffic capacity between pathways from the ancient amygdala (which appeared in animals that evolved earlier) and the centers of thought, imagination and planning (which humans have so recently developed). LeDoux and others have found many more neural routes running from the amygdala to the cortex than from the cortex to the amygdala. This imbalance may be why our anxieties often control our thoughts, whereas our thoughts have trouble quelling our anxieties. Our imagination easily amplifies and feeds the fears coming from the amygdala and hippocampus, but we cannot send enough controls back to dampen the anxiety. That is why we can seldom calm ourselves by telling ourselves to be calm.
LeDoux hopes that we will soon learn enough about anxiety's neural circuits to be able to correct with drugs or other therapies the truly debilitating conditions that result from this flaw. One neural dynamic that could be exploited is known as extinction--the apparent erasure of a learned fear. Researchers have known for decades that fears are extinguished not because they fade but because new, less threatening associations take their place [see "Can We Cure Fear?" by Marc Siegel; Scientific American Mind, Vol. 16, No. 4, 2005]. If a rat conditioned to fear a tone subsequently hears the noise repeatedly without receiving any shock, a neutral association slowly replaces the fearful one; at some point the tone will sound and the rat will not react at all.
Researchers have recently found that this process relies on the medial prefrontal cortex calming the amygdala. If they can identify the particular neural, molecular or genetic switches for this process, they might be able to design drugs or other treatments that ease the pain of traumatic memories or even erase them. "Some people are uncomfortable with that idea," LeDoux notes, referring to concerns that such treatments could be used in Big Brother fashion to control people's minds or by criminals, say, to erase a victim's memory of a crime. "But they never seem to be people with PTSD. Few object to the idea of improving our memories," he says, nodding at the coffee I am drinking to enhance my own attention and cognition. I dont see a big difference between improving your aunt's memory and removing a memory that she doesnt want."
As the study of emotions, memory and their implications expands, LeDoux seems certain to remain at the forefront of investigation and understanding. He possesses enormous energy and creativity. And as the director of the Center for the Neuroscience of Fear and Anxiety, which forms collaborative links among leading researchers at N.Y.U., the Rockefeller University, the Mount Sinai School of Medicine and Cornell Medical School, he is part of a network offering stunning resources and intellect.
Lately he has been investigating reconsolidation--the controversial but exciting notion that memories are vulnerable to change, or even erasure, when we recall them. Strengthening the synapses--the junctions between neurons--that hold long-term memories requires protein synthesis, and LeDoux and other researchers have recently found that if this process is disrupted while a long-standing memory is being recalled, the memory can actually be made fleeting [see "Erasing Memories," by R. Douglas Fields; Scientific American Mind, Vol. 16, No. 4, 2005].
Some fears, of course, are universal. Even a rat born from 40 generations of ancestors that were lab animals and had never seen a cat will freeze at the scent of a tabby. People fear the dark, a rattlesnake's rattle, snarling dogs, their own deaths and the deaths of people they love. These seemingly elemental fears rise partly from imagination and partly from foresight. But LeDoux, who has suffered his share of shocks and grief, feels these fears also affirm the things we live for.
"The backside of every positive emotion," he says, "is the fear that you'll lose what makes you happy. Not only do you love your wife, but youre also afraid of what life would be like without her. How much should you trust your positive emotions? How do you focus on and enjoy them and not give in to the fear? These are things we all wrestle with. I'm afraid fear is terribly basic."