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Annu. Rev. Neurosci. 1992. 15:353-75
Copyright © 1992 by Annual Reviews Inc. All rights reserved
Michael Davis
by Duke University on 08/01/12. For personal use only.
INTRODUCTION
Converging evidence now indicates that the amygdala plays a crucial role
in the development and expression of conditioned fear. Conditioned fear
is a hypothetical construct used to explain the cluster of behavioral effects
produced when an initially neutral stimulus is consistently paired with
an aversive stimulus. For example, when a light, which initially has no
behavioral effect, is paired with an aversive stimulus such as a footshock,
the light alone can elicit a constellation of behaviors that are typically used
to define a state of fear in animals. To explain these findings, it is generally
assumed (cf. McAllister & McAllister 1971 ) that during light-shock pair
ings (training session ), the shock elicits a variety of behaviors that can be
used to infer a central state of fear (unconditioned responses-Figure 1 ).
After pairing , the light can produce the same central fear state and thus
the same set of bchaviors formerly produced by thc shock. Moreover, the
behavioral effects that are produced in animals by this formerly neutral
stimulus (now called a conditioned stimulus-CS ) are similar in many
respects to the constellation of behaviors that are used to diagnose gener
alized anxiety in humans (Table 1 ). This chapter summarizes data sup
porting the idea that the amygdala, and its many efferent projections,
may represent a central fear system involved in both the expression and
acquisition of conditioned fear.
353
o1 4 7-006Xj92j0301 -0353$02.00
3 54 DAVIS
Grooming
Freezing
Figure 1 General scheme believed to occur during classical conditioning with an aversive
conditioned stimulus. During training, the aversive stimulus (e.g. shock) activates a central
fear system that produces a constellation of behaviors generally associated with aversive
stimuli (unconditioned responses). After consistent pairings of some neutral stimulus such
as a light or tone or puff of air with shock during the training phase, the neutral stimulus is
capable of producing a similar fear state and hence the same set of behaviors (conditioned
responses), formerly only produced by the shock.
Tablle 1 Comparison of measures in animals typically used to index fear and those in the
DSM-III manual to index generalized anxiety in people
A variety of animal models have been used to infer a central state of fear
or anxiety. In some models fear is inferred when an animal freezes , thus
interrupting some ongoing behavior such as pressing a bar or interacting
socially with other animals. In other models, fear is measured by changes
in autonomic activity , such as heart rate, blood pressure , or respiration.
Fear can also be measured by a change in simple reflexes or a change in
facial expressions and mouth movements. Thus fear appears to produce a
complex pattern of behaviors that are highly correlated with each other.
Annu. Rev. Neurosci. 1992.15:353-375. Downloaded from www.annualreviews.org
196 0, Kapp et a1 1984 , 199 0, Kapp & Pascoe 1986, Sarter & Markowitsch
1985) and supported by work in many laboratories that the central nucleus
of the amygdala has direct projections to hypothalamic and brainstem
areas that may be involved in many of the symptoms of fear or anxiety
(summarized in Figure 2 ). Direct projections from the central nucleus of
the amygdala to the lateral hypothalamus (Krettek & Price 1978a , Price
& Amaral 1981, Shiosaka et al 198 0) appear to be involved in activation
of the sympathetic autonomic nervous system during fear and anxiety (cf.
LeDoux et al 1988 ). Direct projections to the dorsal motor nucleus of the
vagus nerve (Hopkins & Holstege 1978, Schwaber et a1 1982, Takeuchi et
a11983, Veening et a11984) may be involved in several autonomic measures
of fear or anxiety, sincc the vagus nerve controls many different autonomic
functions.
Projections of the central nucleus of the amygdala to the parabrachial
nucleus (Hopkins & Holstege 1978, Krettek & Price 1978a, Price & Amaral
w
VI
�
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�
Effect of Amygdala Behavioral Test or Sign of
Anatomical Target Stimulation Fear or Anxiety
--.. Tachycardia, Galvanic skin response,
Lateral Hypothalamus ---..,�� Sympathetic Activation
Paleness, pupil dilation, blood pressure elevation
Cenlral Grey � Cessalion of behavior • Freezing, Conflict lesl, CER, Social lnleraction
Trigeminal, Facial Molar N. --. Moulh open, jaw movemenls -.. Facial Expressions of Fear
Figure 2 Schematic diagram showing direct connections between the central nucleus of the amygdala and a variety of hypothalamic and brainstem
target areas that may be involved in different animal tests of fear and anxiety.
AMYGDALA, FEAR, AND ANXIETY 357
fear stimuli (Rasmussen & Jacobs 1986), as well as being involved in other
actions of the locus coeruleus linked to fear and anxiety (cf. Redmond
197 7). Direct projections of the amygdala to the lateral dorsal tegmental
nucleus (e.g. Hopkins & Holstege 1978) and parabrachial nuclei (see
above), which have cholinergic neurons that project to the thalamus (cf.
Pare et aI1990), may mediate increases in synaptic transmission in thalamic
sensory relay neurons (Pare et al 1990, Steriade et al 1990) during states
of fear. This cholinergic activation, along with increases in thalamic trans
mission accompanying activation of the locus coeruleus (Rogawski &
Aghajanian 1980), may thus lead to increased vigilance and superior signal
Annu. Rev. Neurosci. 1992.15:353-375. Downloaded from www.annualreviews.org
Reis & Oliphant 196 4, Schlor et al 1 984, Stock et al 1978, 1981, Timms
1981). These effects are often critically dependent on the state of the animal
and level of anesthesia (e.g. Frysinger et al 1 984, Galeno & Brody 1983,
Harper et a11984 , Iwata et a11987, Stock et a11978, Timms 1981) and in
some instances may result from stimulation of fibers of passage rather
than cell bodies (cf. Lewis et al 198 9). Amygdala stimulation can also
produce gastric ulceration (Henke 198 0b, 1 98 2, Innes & Tansy 1 98 0, Sen
& Anand 1957 ), which may result from chronic fear or anxiety.
Electrical stimulation of the amygdala also alters respiration (Anand &
Dna 195 6, Applegate et al 1983, Bonvallet & Gary Bobo 197 2, Harper et
al 1984 ), a prominent symptom of fear, especially in panic disorders.
Electrical stimulation of the central nucleus of the amygdala produces a
cessation of ongoing behavior (Applegate et a11983, Gloor 196 0, Kaada
1972, Ursin & Kaada 196 0). Cessation of ongoing behavior is the critical
measure of fear or anxiety in several animal models, such as freezing
(Blanchard & Blanchard 196 9, Bolles & Collier 197 6, Fanselow & Bolles
1979), the operant conflict tcst (Gcllcr & Scifter 196 0), the conditioned
emotional response (Estes & Skinner 194 1 ) that correlates with freezing
(e.g. Bouton & Bolles 198 0, Mast et al 198 2 ), and the social interaction
test (File 198 0). Electrical stimulation of the amygdala also elicits jaw
movements (Applegate et al 1983, Gloor 196 0, Kaku 1984, Ohta 1984 )
and activation of facial motoneurons (Fanardjian & Manvelyan 1987 ),
both of which may be included in the facial expressions seen during the
fear reaction. These motor effects may be indicative of a more general
effi�ct of amygdala stimulation, namely that of modulating brainstem
reflexes such as the massenteric (Gary Bobo & Bonvallet 197 5, Bonvallet
& Gary Bobo 197 5 ) , baroreceptor (Lewis et al 1 98 9, Schlor et al 1984,
Pascoe et al 1 98 9), nictitating membrane (Whalen & Kapp 1 991), and
AMYGDALA, FEAR, AND ANXIETY 3 59
startle reflex (Rosen & Davis 1988a,b). In most cases, stimulation of the
amygdala facilitates these reflexes, although whether it does or not may
depend on the exact amygdala sites being stimulated (see Whalen & Kapp
1991 for a discussion of this point). In humans, electrical stimulation of
the amygdala elicits feelings of fear or anxiety, as well as autonomic
reactions indicative of fear (Chapman et al 195 4, Gloor et al 1981 ). Some
of the emotional content of dreams may result from activation of the
amygdala, stimulation of which increases ponto-geniculo-occipital activity
that occurs during paradoxical (dream) sleep (ef. Calvo et al 1987).
Finally, electrical stimulation of the amygdala has been shown to
Annu. Rev. Neurosci. 1992.15:353-375. Downloaded from www.annualreviews.org
prior to or in the amygdala, rather than from a change in its efferent target
areas. The ability to produce long-term potentiation (Clugnet & LeDoux
1 990, Chapman et al 1 990 ) in the amygdala and the finding that local
infusion of NMDA antagonists into the amygdala blocks the acquisition
(Miserendino et al 1 990) and extinction (Falls et a1 1 992) of fear con
ditioning is consistent with this hypothesis.
Other measures that have been used to index innate fear have produced
less consistent data concerning amygdala lesions, however. Large elec
trolytic lesions of the amygdaloid complex (Bresnahan et all976, Corman
et al1967, Eclancher & Karli 1979, Greidanus et a1 1979, Jonason & Enloe
1971, Schwartzbaum & Gay 1966), or electrolytic or ibotenic acid lesions
of the central nucleus of the amygdala (e.g. Grijalva et al 1990, Jellestad
et a� 198 6, Werka et al 1978) or of the lateral and basal nuclei (JeUestad
& Cabrera 1986) produce an increase in exploratory behavior in the open
field test. This does not seem to occur, however, when (a) open field testing
is preceded by other tests on the same animals (Grossman et aI197 5), (b)
test conditions are especially familiar (e.g. McIntyre & Stein 1973), (c)
Annu. Rev. Neurosci. 1992.15:353-375. Downloaded from www.annualreviews.org
testing occurs after considerable handling and a long time after surgery
(Kemble et al 1979), or (d) the lesions are very small (Riolobos et al 198 7),
and may depend on the age of the animal when the lesions are performed
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Everitt 1988). In these studies , ibotenic acid lesions of the amygdala fail to
block taste aversion learning, whereas ibotenic acid lesions of the gustatory
insular cortex do. Once again, the amygdala does not seem critical for all
types of aversive conditioning but only conditioning that involves an
obvious fear component such as that produced by aversive shocks.
Finally, the amygdala may also be importantly involved in stimulus
response associations that do not obviously involve aversive conditioning
(e.g. Aggleton & Mishkin 1986, Cador et al 1989, Everitt et al 1989,
Gallagher et a1 1990, Kesner et a1 1989, Murray 1990, Murray & Mishkin
1985, Peinado-Manzano 1990; but see Zola-Morgan et al 1989). Hence,
Annu. Rev. Neurosci. 1992.15:353-375. Downloaded from www.annualreviews.org
CONCLUSIONS
ACKNOWLEDGMENTS
extended to Bruce Kapp for helpful discussions about the brainstem pro
jections of the amygdala and to Leslie Fields for help in typing the paper.
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