Investigators Pinpointing Fear's Activity in the Brain

Organisms cannot live without fear. "Fearfulness is one of the most basic physiological and behavioral responses we have. It probably supersedes everything because of its survival value," says Ned Kalin, Hedberg professor of psychiatry and psychology at the University of Wisconsin-Madison. He also is chair of the department of psychiatry and director of the university's HealthEmotions Research Institute. But fear gone awry can debilitate animals and humans. Excessive fear can lead to psychopathology and extremely uncomfortable lives. Kalin and other investigators are probing the behavioral, hormonal, and neural components of this vital emotion to understand its "normal" basis, but also to learn what causes an individual to have an enduring fearful temperament--one marked by inhibition, withdrawal, and other indicators of a high level of stress. In general, when an organism perceives a situation recognized as fearful, neurons running from the eye or other sense organs stimulate the amygdala, a structure (about the size of a walnut in humans) deep in the brain. Nerves, which extend from the amygdala to another small brain structure, the hypothalamus, are then triggered, activating the HPA (hypothalamic-pituitary-adrenal) axis, which brings hormones into action. The hypothalamus releases corticotropin releasing factor or hormone (CRF or CRH), which stimulates the pituitary to release ACTH (adrenocorticotropic hormone), which in turn signals the adrenal glands to produce cortisol, a hormonal sign of stress. With cortisol in the bloodstream, an individual's resources are mobilized. Fuel in the form of glucose goes to the brain and the muscles. While it is difficult to point to one critical player in such a complex and interrelated system, some researchers do single out CRF as being of major importance. In an as-yet-unpublished study, Kalin has found that dispositionally fearful rhesus monkeys have higher levels of CRF in their cerebral spinal fluid than those who aren't so fearful. The differences were stable when animals were tested at eight months, one year, and three years of age. He found higher levels of CRF in the cerebral spinal fluid of monkeys with "fearful dispositions" at eight months, 12 months, and three years of age, compared with animals of less fearful disposition. "CRF we think has a lot to do in the brain in integrating and regulating all the aspects of the stress response, including the hormonal and the autonomic response," explains Kalin. "We think this particular neurotransmitter is the master integrator in the brain of the fear response," he adds, pointing out its role as initiating the cascade of central and peripheral fear responses. Photo: Annmarie Poyo EVER PRESENT: Paul Plotsky, of Emory University, says that CRF seems to be present wherever there is an integrated or coordinated output to a major stressor. "It seems to be involved in every single circuit that would give you an integrated or coordinated output to a major kind of stressor," says Paul Plotsky, SmithKline Beecham professor of psychiatry at Emory University. CRF acts on a brain stem structure called the locus coeroleus. This structure controls the level of attention to environmental events. "It sets the animal's vigilance level. "It seems to be fired off when the animal is in a circumstance where there may be danger," maintains Plotsky. ALL AROUND: Michael Davis, of Yale University School of Medicine, says that many CRF cell bodies and receptors are present in various parts of the brain. The brain stem isn't alone in having CRF receptors. "There are lots of CRF cell bodies and receptors in different parts of the brain. The fascinating thing is if you locally infuse CRF into the brain of animals, you produce a whole pattern of behaviors that look like the fear reaction," says Michael Davis, a professor of psychiatry and psychology at Yale University School of Medicine. These animals don't eat, they don't copulate, their heart rate and blood pressures rise. "And if you give a compound that blocks the ability of CRF to bind to its receptors in the brain, you can block the effects of a variety of natural stress situations," he notes. A CRF antagonist, such as alpha helical CRH, blocks the fear-induced rise of heart rate or blood pressure. Exactly what the CRF in the amygdala does, however, is unclear, states Davis. However, he adds, unlike other neurotransmitters, when it is injected into the brains of lab animals, the fear reaction lasts hours. An animal's early experience can influence its adult response to CRF, Plotsky has found. He and his colleagues report (C. Caldji et al., Proceedings of the National Academy of Sciences, 95:5335-40, 1998) that rats whose mothers engaged in little grooming or licking of them as pups showed increased numbers of receptors at the sites where CRF has its action, compared to animals whose mothers groomed and licked them more. Furthermore, adult animals with more CRF receptors showed more fear of a new situation as measured by their reluctance to explore and eat in a novel environment than those with fewer CRF receptors. The environment was an area measuring approximately six feet square in an experimental room. Plotsky argues these findings don't represent a simple genetic effect. He says similar CRF effects are seen when the effect of handling of rat pups is studied. Regardless of their genetic background, mothers whose pups are handled by experimenters lick and groom their pups more than mothers whose pups are not handled. And these handled pups show less fearful behavior than those not handled. Moreover, mice born to a normally fearful strain, when raised by a strain that grooms and licks their pups more frequently, show less fear as adults, Plotsky reports. Plotsky and his colleagues also found ( Journal of Neuroscience, in press) that maternal separation for prolonged periods, such as three hours, also produced increased levels of CRF. The table can be set for fearful behavior even before birth. Adult rat offspring who were stressed prenatally have higher CRF levels in the amygdala than controls (M.S. Cratty et al., Brain Research, 675:297-302, 1995). Prenatal stress also boosts the level of corticosterone, the rat analog of cortisol. And this increase is manifested in behavior. For instance, Lorey Takahashi, an assistant professor of psychiatry at the University of Wisconsin School of Medicine, and his colleagues have found that adult rats who were prenatally stressed froze when shocked and avoided open fields in laboratory tests to a greater degree than unstressed rats (E.G. Takahashi et al., Physiology and Behavior, 51:319-22, 1992). DISPOSITION COUNTS: Ned Kalin, of the University of Wisconsin-Madison, has found that dispositionally fearful rhesus monkeys have elevated levels of CRF. Explorations of fear have also included the higher centers of the brain in both humans and nonhuman primates, specifically the rhesus monkey. Kalin and his colleagues (N.H. Kalin et al, Behavioral Neuroscience, 112[2]:1-7, 1998) found a stable constellation of fear measures in rhesus monkeys involving brain activity, behavior, CRF levels, and cortisol levels. Monkeys who froze for longer periods when an intruder entered a room in which they were caged had more electrical activity in the right frontal cortex and higher cortisol levels and CRF levels than monkeys who froze for shorter periods. The latter group showed more left frontal activity. Kalin says this stability was found during the first three years of these animals' lives. The study is the "first to link individual differences in asymmetric frontal activity with circulating levels of cortisol. This is important because both parameters have been independently associated with fear-related temperamental styles," the authors write. High activity in the right frontal cortex is a marker of individuals who are shy and inhibited, says Richard Davidson, professor of psychology and psychiatry and director of the Wisconsin Center for Affective Science. High left frontal activity is found in individuals who are less inhibited and who seek social contact and activity. He has found this difference, or asymmetry, in adults and children. HealthEmotions Research Institute 6001 Research Park Blvd. Madison, WI 53711 Telephone: 608 263-6161 FAX: 608 263 9340 http://www.healthemotions.org Journal of Behavioral Neuroscience Michela Gallagher, Editor-in-Chief Dept. of Psychology Johns Hopkins University 3400 N. Charles St., 138 Ames Hall Baltimore, MD 21218-2686 Telephone: 410 516 0167 http://www.apa.org/journals Developmental Neuroendocrinology Lab Douglas Hospital Research Center 6875 Boul. LaSalle Montreal, Quebec H4H 1R3 CANADA Telephone: 514 762 3048 FAX: 514 762 3034 http://www.mcgill.ca/douglas/ Society For Neuroscience 11 Dupont Circle N.W. Washington DC 20036 Telephone: 202 462 6688 FAX: 202 234 9770 27,000 members http://www.sfn.org Although the findings in monkeys appear stable, early in life they may not be as stable in human children. Studying different populations of children, Nathan Fox, professor of human development and psychology at the University of Maryland, and Maureen Rickman, a postdoctoral clinical psychology intern at Mendota Mental Health Institute in Madison, Wis., have found that while children show behavior and accompanying physiological signs at one age, that constellation is not necessarily found in later years. Fox reported at the 1998 International Conference of Infant Studies in Atlanta that children who eschewed contact in social situations at two years of age were not necessarily fearful of such contact at four. "Forty percent do remain fearful, but the other 60 percent change. Not only do they change behaviorally, but their biology changes. No longer are they right frontal, they no longer have high cortisol. They look [like], and their physiology appears to be that of, a noninhibited child," notes Fox. Similarly, Rickman, in her doctoral dissertation, found no relation between brain activity and behavior in children who were tested at three years of age and again at nine. In other words, a child who was fearful of social contact at three was just as likely to be significantly less fearful at nine. She found that brain activity was similarly labile. Davidson, who supervised Rickman's research, says he is now beginning to examine the family and school experiences these children had. "What we hope to do is identify some of the environmental determinants that might be responsible for some of these changes," he says. He emphasizes the findings clearly demonstrate the plasticity of the brain during childhood. In explaining the changes he observed, Fox hypothesizes that his uninhibited children may have modeled or learned behaviors from others or may have become less fearful of situations as they became used to them. But a complete understanding of the reasons for these changes remains to be uncovered. Understanding such changes sets the stage for further exploration of fear: turning it off. "We've learned a fair amount of the circuitry that's involved in generating the initial fear response. We really know relatively little about the circuitry that's involved in turning it off," observes Davidson. Already, however, it appears that the neural connections between the left prefrontal cortex and the amygdala play a role. Davidson points to imaging studies of his showing that individuals who have more activity in their left frontal cortex are able to inhibit the amygdala to a greater degree than people with more right frontal activation. As researchers continue to amass basic knowledge of fear and its control, it is likely to be translated into a better understanding of the environmental and genetic factors that influence its development and possibly into environmental and pharmacological interventions that can control its abnormal expression. Harvey Black, a freelance science writer in Madison, Wis., can be reached online at 73773.2227@compuserve.com.

Investigators Pinpointing Fear's Activity in the Brain

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