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NEUROSCIENCE:
Enhanced: The Biology of Being Frazzled

Consider this: You are driving to work, planning an important morning meeting with a colleague and intermittently reminding yourself that you must remember to turn left at the traffic light, not right as usual, in order to bring your suit to the cleaners. Suddenly, you find yourself passing an accident--a crowd is gathered around a gruesome scene. The ambulance screams up behind you, and you hurry to get out of the way. You feel your heart quicken and notice that your foot is faster than usual as you step on the brake at the red light. You try to resume planning the morning's meeting, but your thoughts are disorganized now and you lose concentration, distracted by a disk jockey's prattle from the radio. You get to work, the memory of that gruesome scene all too vivid, and berate yourself because you forgot to go to the cleaners.

This scenario captures many of the cognitive changes that occur in response to acute, uncontrollable stress: We become distracted and disorganized, and our working memory abilities worsen, leaving prepotent or habitual responses to control our behavior. Yet our memories of the stressful event are actually better than usual. Neurobiological research can now begin to explain many of these cognitive changes in response to stress. A family of neuromodulators called catecholamines (dopamine, norepinephrine, and epinephrine)[HN2], [HN3] are released in the peripheral and central nervous systems during stress. And just as catecholamines "turn on" our heart and muscles and "turn off" the stomach to prepare for fight-or-flight responses during stress, similar opposing actions in the brain may turn on a structure called the amygdala [HN4], [HN5] and turn off the prefrontal cortex [HN6], [HN7] (a higher cognitive center), allowing posterior cortical and subcortical structures to control our behavior. The amygdala is a phylogenetically older structure in the medial temporal lobe, long known to be essential for the expression of emotion and the formation of associations between stimuli and emotions (1). In contrast, the prefrontal cortex expands greatly in primates and permits working memory to guide our behavior, inhibiting inappropriate responses or distractions and allowing us to plan and organize effectively (2). High levels of catecholamines exert opposite actions on these brain regions.

Catecholamine stimulation during stress can activate the amygdala and improve memory consolidation (3). The pioneering studies of McGaugh, Gold, Tanaka, and others demonstrated that mild to moderate stressors increase norepinephrine release within the amygdala and enhance memory consolidation in rodents. More recently, this work has been translated to humans, in whom the memory of emotionally stressful scenes is associated with activation of the amygdala (3) and is mediated via norepinephrine actions at b-adrenergic receptors (3). The amygdala is also activated in conditioned fear paradigms, in which a previously neutral stimulus becomes aversive through its association with a stressful stimulus such as an electric shock (4). The expression of conditioned fear requires dopamine D1 receptor stimulation in the amygdala in rodents (5). Thus, increased release of dopamine and norepinephrine in the amygdala during mild to moderate stress enhances amygdala function. These mechanisms likely contribute to post-traumatic stress disorder in humans (6). [HN8], [HN9] Catecholamine-induced activation of the amygdala in turn leads to facilitation of declarative memory mediated by hippocampal structures (enhancing memory of the accident scene) and to facilitation of the habit memory functions of the striatum (stepping on the brake faster at the light) (7). During stress, the amygdala also induces increased catecholamine release in the prefrontal cortex (8). However, in contrast to the facilitative actions in subcortical structures, high levels of catecholamine release in prefrontal cortex result in cognitive dysfunction.

Exposure to mild to moderate uncontrollable stress impairs prefrontal cortical function in humans, monkeys, and rats (9). For example, humans exposed to loud noise stress are less able to sustain attention or to inhibit inappropriate responses. As in animal studies, these changes are most evident when the subject feels no control over the stress. In contrast, performance of simple, well-rehearsed tasks can actually be better than usual after stress exposure. Similar results have been seen in studies of rats and monkeys, where stress impairs the spatial working memory functions of the prefrontal cortex but has little effect on the visual discrimination abilities of more posterior cortices. Stress-induced working memory deficits result from increased catecholamine receptor stimulation in the prefrontal cortex and can be ameliorated by agents that prevent catecholamine release or block dopamine receptors (9, 10). Conversely, stress-induced cognitive deficits can be mimicked by infusion of a dopamine D1 receptor agonist in the prefrontal cortex (11). Similarly, in electrophysiological studies, large concentrations of D1 agonist abolish the calcium currents that convey signals along dendrites (12), effectively "strangling" information transfer from dendrite to soma (11). In contrast, the iontophoresis of low levels of D1 receptor antagonists can enhance memory-related neuronal responses in monkeys performing working memory tasks (13). These studies emphasize the importance of dopamine D1 receptor actions in taking the prefrontal cortex "off line" during stress. Other neuromodulators may contribute as well [for example, norepinephrine via a1-adrenoceptors (14)], ensuring rapid yet reversible loss of prefrontal cortical control over behavior.

This bimodal reaction to stress likely had survival value in evolution: Under stress, the faster, habitual, or instinctual mechanisms regulated by the amygdala, hippocampus, striatum, and posterior cortices would control behavior, and long-lasting memories of aversive stimuli would be enhanced in order to avoid such stimuli in the future. However, in modern human society these brain actions may often be maladaptive; now we need prefrontal cortex regulation to act appropriately. These neurochemical changes may explain why the stress of an initial error can cause an athlete to lose concentration and thus lose a competition, or why children in stressful home environments (for example, undergoing divorce) can exhibit behaviors resembling attention deficit hyperactivity disorder, a disorder of prefrontal cortex function. [HN10], [HN11], [HN12], Further research on these important neurochemical mechanisms may help us to elucidate why prefrontal cortical deficits are so prominent in many mental illnesses that are exacerbated by stress (15) (affective disorder, schizophrenia) and to develop better treatments for these devastating disorders. And finally, this understanding may allow us to be more compassionate with our own failings in response to life's stressors.

References

1. J. P. Aggleton, The Amygdala (Wiley-Liss, New York, 1992).[HN13]
2. P. S. Goldman-Rakic, in Handbook of Physiology, F. Plum, Ed. (American Physiological Society, Bethesda, MD, 1987), pp. 373-417; D. T. Stuss and D. F. Benson, The Frontal Lobes (Raven, New York, 1986).
3. Reviewed in L. Cahill and J. L. McGaugh, Trends Neurosci., in press.
4. Reviewed in M. Davis, Annu. Rev. Neurosci. 15, 353 (1992) [Medline]; J. E. LeDoux, Annu. Rev. Psychol. 46, 209 (1995) [Medline].
5. E. W. Lamont and L. Kokkinidis, Brain Res., in press.
6. D. S. Charney et al., Arch. Gen. Psychiatry 50, 295 (1993) [Medline]; L. Cahill, Ann. N.Y. Acad. Sci. 821, 238 (1997) [Medline].
7. M. G. Packard, L. Cahill, J. L. McGaugh, Proc. Natl. Acad. Sci. U.S.A. 91, 8477 (1994) [Medline].
8. M. Davis et al., Brain Res. 664, 207 (1994) [Medline]; L. E. Goldstein et al., J. Neurosci. 16, 4787 (1996) [Medline].
9. Reviewed in A. F. T. Arnsten and P. S. Goldman-Rakic, Arch. Gen. Psychiatry 55, 362 (1998) [Medline].
10. B. L. Murphy et al., Proc. Natl. Acad. Sci. U.S.A. 93, 1325 (1996) [Medline].
11. Reviewed in J. Zahrt, J. R. Taylor, R. G. Mathew, A. F. T. Arnsten, J. Neurosci. 17, 8528 (1997) [Medline].
12. C. R. Yang and J. K. Seamans, J. Neurosci. 16, 1922 (1996) [Medline].
13. G. V. Williams and P. S. Goldman-Rakic, Nature 376, 572 (1995) [Medline].
14. A. F. T. Arnsten and J. D. Jentsch, Pharmacol. Biochem. Behav. 58, 55 (1997) [Medline].
15. C. M. Mazure, Does Stress Cause Psychiatric Illness? (American Psychiatric Press, Washington, DC, 1995).

HyperNotes
Related Resources on the World Wide Web

General Hypernotes

Neurosciences on the Internet contains a searchable and browsable index of neuroscience resources available on the World Wide Web. Neurobiology, neurology, neurosurgery, psychiatry, psychology, cognitive science sites and information on human neurological diseases are covered.

Neuroscience for Kids provides activities and experiments for students and teachers who would like to learn more about the brain.

NeuroRing is a collection of Web sites and pages that are devoted primarily to providing information related to the Neurosciences. Sites in NeuroRing cover basic science research, clinical research, neurology, behavioral neurosciences and neurocomputing.

Cognitive and Psychological Sciences on the Internet is a list of Web resources for psychology.

Introduction to the Brain is a tutorial that covers blood supply to the brain, functional localization of the cerebral cortex, an introduction to the brainstem, and an introduction to cranial nerves.

The Mining Company Guide to Neurosciences is a guide to Internet resources for neurology.

Shaping up an Intelligent Act from Humble Origins is a chapter of How Brains Think by William H. Calvin. This chapter outlines the anatomy and physiology of the neuron.

A Brief Tour of the Brain, developed at Syracuse University, describes the structure of the brain and the anatomy of neurons.

The Biological Neuron provides schematic illustrations of the neuron, dendrites, and the synapse. The Biological Neuron is a component of Neil's Neural Nets, a site maintained at Carleton College that describes the basic elements of neural networks.

The World Wide Web Virtual Library Neuroscience (Biosciences), one component of the World Wide Web Virtual Library, provides an extensive list of links to journals, books, software, laboratory Web pages, and other resources in the neurosciences.

Cognitive and Psychological Sciences on the Internet is an index to Internet resources relevant to research in cognitive science and psychology.

Memory is described by Newton's Apple, a national science program produced by KTCA-TV in Minneapolis-St. Paul.

Numbered Hypernotes

1. Amy Arnsten's Web pageat Yale University School of Medicine describes her research and lists selected publications.

2. Catecholamines and synaptic transmission are outlined in the Medical Biochemistry Online Textbook.

3. Neurotransmitters, including dopamine and norepinephrine, are described on a page authored by Heshani Abeysekera.

4. The Basal Ganglia Atlas provides diagrams that illustrate the location of the amygdala.

5. The Amygdala Home Page by Norman Bradley Keele describes the amygdala and provides links to other resources.

6. The Human Brain: Dissections of the Real Brain is an electronic atlas of brain structures.

7. The Whole Brain Atlas locates structures in the human brain.

8. The National Center for PTSD maintains a list of Web resources related to post-traumatic stress disorder. A link to PILOTS, an electronic index to the worldwide literature of traumatic stress, is also available.

9. The International Society for Traumatic Stress Studies provides a list of Internet resources for traumatic stress.

10. The National Attention Deficit Disorder Association (ADDA) provides information about attention deficit disorder and includes links to other Internet resources.

11. The Mining Company Guide to Attention Deficit Disorder is a guide to Internet resources for ADD.

12. ADDNet UK presents news summaries and other current information about attention deficit disorder.

13. The Amygdala is available from John Wiley & Sons .

14. Section of Neurobiology, Yale University School of Medicine