Also see the archival
list of Science's Compass: Enhanced
F. T. Arnsten[HN1]
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],
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],
and turn off the prefrontal cortex [HN6],
(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
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).
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,
Conversely, stress-induced cognitive deficits can be mimicked by
infusion of a dopamine D1 receptor agonist in the prefrontal cortex
Similarly, in electrophysiological studies, large concentrations of
D1 agonist abolish the calcium currents that convey signals along
effectively "strangling" information transfer from dendrite to soma
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
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],
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
(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.
- J. P. Aggleton, The
Amygdala (Wiley-Liss, New York, 1992).[HN13]
- 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
- Reviewed in L. Cahill and J. L.
McGaugh, Trends Neurosci., in press.
- Reviewed in M. Davis, Annu.
Rev. Neurosci. 15, 353 (1992) [Medline];
J. E. LeDoux, Annu. Rev. Psychol. 46,
209 (1995) [Medline].
- E. W. Lamont and L.
Kokkinidis, Brain Res., in press.
- D. S. Charney et al.,
Arch. Gen. Psychiatry 50, 295 (1993) [Medline];
L. Cahill, Ann. N.Y. Acad. Sci. 821, 238
- M. G. Packard, L. Cahill, J. L.
McGaugh, Proc. Natl. Acad. Sci. U.S.A.
91, 8477 (1994) [Medline].
- M. Davis et al.,
Brain Res. 664, 207 (1994) [Medline];
L. E. Goldstein et al., J. Neurosci.
16, 4787 (1996) [Medline].
- Reviewed in A. F. T. Arnsten and
P. S. Goldman-Rakic, Arch. Gen. Psychiatry
55, 362 (1998) [Medline].
- B. L. Murphy et al.,
Proc. Natl. Acad. Sci. U.S.A. 93, 1325
- Reviewed in J. Zahrt, J. R.
Taylor, R. G. Mathew, A. F. T. Arnsten, J. Neurosci.
17, 8528 (1997) [Medline].
- C. R. Yang and J. K. Seamans,
J. Neurosci. 16, 1922 (1996) [Medline].
- G. V. Williams and P. S.
Goldman-Rakic, Nature 376, 572 (1995) [Medline].
- A. F. T. Arnsten and J. D.
Jentsch, Pharmacol. Biochem. Behav. 58,
55 (1997) [Medline].
- C. M. Mazure, Does Stress
Cause Psychiatric Illness? (American Psychiatric Press,
Washington, DC, 1995).
The author is with the Section of Neurobiology, Yale University
School of Medicine, New Haven, CT 06520-8001, USA. E-mail: email@example.com
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is described by Newton's
Apple, a national science program produced by KTCA-TV in
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