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If there is one central tenet of the neurobiology of
learning and memory,it is that plasticity in the CNS is
essential for the representation of new information.
Experience-dependent plasticity in the brain might take
many forms,ranging from the synthesis and insertion of
synaptic proteins to whole-brain synchronization of
neuronal activity.An important challenge is to under-
stand how these various forms ofexperience-dependent
plasticity are reflected in the activity ofneuronal popu-
lations that support behaviour.Donald Hebb referred
to these populations as cell assemblies,and this concept
has had important heuristic value in empirical studies
ofthe neurobiology ofmemory1.With the advent of
modern electrophysiological recording techniques,
Hebb’s concept ofthe cell assembly is now amenable to
experimental study in awake,freely behaving animals.
Using parallel recording techniques,multiple extracellular
electrodes can be used to ‘listen’to the action-potential
dialogue between several neurons at once2,3(BOX 1).
In this article,we review recent single-unit recording
studies that have provided considerable insight into the
neuronal mechanisms oflearning and memory,focus-
ing particularly on Pavlovian fear conditioning.In this
form oflearning,a neutral stimulus,such as an acoustic
tone (the conditional stimulus,or CS) is paired with a
noxious unconditional stimulus (US),such as a foot-
shock.After only a few conditioning trials,the CS comes
to evoke a learned fear response (conditional response,
or CR). Pavlovian fear conditioning is particularly
amenable to electrophysiological analysis because it
is acquired rapidly and yields long-lasting memories.
Moreover,the behavioural principles and neural circuits
that underlie this form oflearning are well characterized,
allowing an unprecedented analysis ofthe relationship
between neuronal activity and learned behaviour.
Neuronal correlates of aversive memory
The search for the neurophysiological mechanisms of
aversive memory began in the early 1960s with the
observation that an auditory stimulus that was paired
with an electric shock modified auditory-evoked field
potentials in cats and rats4,5.Because cortical field poten-
tials are generated by large populations of neurons,
changes in early components of the field potentials
(reflecting processing in ascending auditory tracts) were
variable and poorly localized. Other investigators
observed changes in late components ofcortical poten-
tials that were attributed to a general state of‘fear’6,but
these changes were not associative (that is,they did not
reflect a specific CS–US association) because they
occurred in response to both the CS and a novel stim-
ulus. Therefore, it became clear that field-potential
recordings would not be sufficient to identify loci offear
NEURONAL SIGNALLING OF FEAR
Stephen Maren* and Gregory J.Quirk‡
Abstract | The learning and remembering of fearful events depends on the integrity of the
amygdala, but how are fear memories represented in the activity of amygdala neurons? Here, we
review recent electrophysiological studies indicating that neurons in the lateral amygdala encode
aversive memories during the acquisition and extinction of Pavlovian fear conditioning. Studies
that combine unit recording with brain lesions and pharmacological inactivation provide evidence
that the lateral amygdala is a crucial locus of fear memory. Extinction of fear memory reduces
associative plasticity in the lateral amygdala and involves the hippocampus and prefrontal cortex.
Understanding the signalling of aversive memory by amygdala neurons opens new avenues for
research into the neural systems that support fear behaviour.
and Neuroscience Program,
Ann Arbor,Michigan 48109,
Physiology,Ponce School of
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R E V I E W S
An extracellular electrode that
comprises four juxtaposed
recording channels,which can
be used to disambiguate the
signals emitted by individual
point sources.Because each
neuron occupies a unique
position in space,its spikes are
‘seen’ slightly differently by each
electrode,providing a unique
signature.This technique allows
the identification ofmany more
neurons than there are sampling
of plasticity, whereas those showing longer-latency
changes were probably downstream sites that were
involved in the expression oflearned responses.Short-
latency plastic responses (within 40 ms oftone onset)
were observed in the posterior thalamus,medial genic-
ulate nucleus and auditory cortex,indicating that these
areas might be primary sites ofplasticity.Although this
approach was criticized for not taking into account
descending modulation from the cortex13,subsequent
work by Disterhoft and colleagues showed that thalamic
neurons were able to learn in fewer trials than cortical
neurons14,15,confirming that thalamic plasticity preceded
cortical plasticity,in terms ofboth latency and trials.
Therefore,plasticity in subcortical structures could
occur independently ofthe cortex,and indeed,learning-
related plasticity might not even require the forebrain
under some circumstances. In the most systematic
neurobiological analysis ofPavlovian learning so far,
Thompson and colleagues found that although hippo-
campal neurons show considerable plasticity during
eyeblink conditioning,hippocampal plasticity is not
essential for this form of learning. In fact, neuronal
plasticity in the cerebellum is crucial for the acquisition
and expression ofeyeblink conditioning16,17.
Fear-related plasticity in the lateral amygdala
Notably absent from these early studies ofconditioning
was any mention ofthe amygdala.The thalamus and
cortex were thought to be the sites that most probably
encode emotional associations (but see REF.18),and the
amygdala was suspected to have a role in modulating
memory storage in these areas19.However,an influential
study by Kapp and co-workers showed that lesions of
the central nucleus ofthe amygdala prevented heart-rate
conditioning in rabbits20,consistent with central nucleus
modulation offear-expression centres in the midbrain
and hypothalamus21,22.Subsequent single-unit recording
studies ofthe central nucleus revealed associative plastic-
ity23,24,indicating that the amygdala might be a site of
plasticity in fear conditioning.
Converging on a similar conclusion,LeDoux and co-
workers discovered direct projections from the auditory
thalamus to the amygdala in rats,and determined this
projection to be vital for auditory fear conditioning25–27.
Specifically,the lateral nucleus of the amygdala (LA)
receives direct projections from the medial subdivision of
the medial geniculate nucleus and the adjacent thalamic
posterior intralaminar nucleus (MGm/PIN), and it
relays this information by way ofthe basal amygdaloid
nuclei to the central nucleus28–31(FIG.1).Small lesions of
the LA or the MGm/PIN prevent fear conditioning,
whereas large lesions ofthe auditory cortex or striatum
do not32,33,indicating that thalamo–amygdala inputs are
sufficient for conditioned fear responses.This finding
galvanized interest in the LA as a potential site ofplastic-
ity in fear conditioning,and set the stage for the next 15
years ofwork on the role ofthe amygdala in this form of
learning.Indeed,considerable research now indicates
that the amygdala is necessary for both the acquisition
and expression ofPavlovian fear memories34,but not for
all forms ofaversive memory35,36.
Subsequent single-unit recording studies in cats and
monkeys showed conditioning-induced changes in
evoked spike activity in several brain areas,including
the midbrain,thalamus and cortex7–9.These changes
seemed to be associative because they were not
observed during pseudo-conditioning,in which the CS
and US were unpaired.In addition,sensitizing effects of
the shock were ruled out with discriminative models,in
which responses to a CS that was paired with the US
(CS+) were compared with responses to a CS that was
never paired with the US (CS–)10,11. However, from
these studies it was not possible to determine whether
structures that showed increased neuronal responsive-
ness after conditioning were primary sites ofplasticity
or were downstream from other plastic sites.
To address this issue,Olds and colleagues12assessed
the latency of conditioned single-unit responses in
various brain areas in an appetitive auditory condition-
ingtask.They reasoned that structures showing the
earliest increases in auditory responses (in terms of
milliseconds after CS onset) were probably primary sites
Box 1 | Single-unit recording methods
Parallel advances in computing hardware (for example,data storage capacity and processor
speed),software (for example,neuronal data acquisition and spike sorting) and electrode
technology have coalesced to yield powerful multichannel single-unit recording systems for
behaving animals.In a typical system,recording electrodes consist ofbundles ofsingle
wires,multi-wire stereotrodes or TETRODES,or thin-film silicon arrays (a).Electrode
assemblies are either chronically implanted in brain tissue or affixed to moveable
microdrives,some ofwhich have been engineered to independently drive up to 16 tetrodes
(64 channels) (b).Voltages recorded on each electrode are typically passed through
integrated circuits in source-follower configurations that are mounted near the animal’s
head (a headstage) to convert neuronal signals into low-impedance signals that are less
sensitive to cable and line noise (c).Signals are then fed from the headstage through a
commutator to allow free movement ofthe animal and cable assembly (d).Neuronal signals
are amplified,band-pass filtered and digitized (e).Once digitized,spike waveforms on each
electrode channel are sorted into single units using sophisticated clustering algorithms (f).
The isolation ofsingle units using such methodology varies widely and depends on several
parameters.Most importantly,multichannel electrodes,such as tetrodes,seem to yield the
most reliable single-unit isolation.Several commercial packages are available to acquire
neuronal signals from high-density recording systems,although most electrophysiologists
use a combination ofhome-made technology and commercial products.
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Because the LAd projects to ventral parts ofthe LA,which
in turn project to basolateral and central nuclei,plasticity
downstream from the LAd could be passively fed forward
from the LAd.To address this issue,Quirk and colleagues
recorded LAd neurons in behaving rats,and observed
robust increases in tone responses during fear condition-
ing compared with a sensitization control phase39(FIG.2;
BOX 1).Most ofthe conditioned increases in spike firing
occurred within 15 ms oftone onset,corresponding to
the latency ofthalamic (12 ms) rather than cortical (>20
ms) activation of LA neurons40.Maren subsequently
confirmed this extremely short-latency plasticity in LAd,
and showed that it persisted at these latencies through
extensive overtraining41. Parallel work has revealed
that LA neurons show synaptic LONG-TERM POTENTIATION
(LTP)42–44,and that fear conditioning is associated with
LTP-like changes in thalamo–amygdala synaptic trans-
mission45–47.Together with evidence ofconverging audi-
tory and somatosensory inputs onto LA neurons from
the thalamus48,49,this indicated that the LAd might be a
site oflong-term memory in fear conditioning (BOX 2).
Although these findings are consistent with a primary
locus ofconditioning-related plasticity in the LAd,it is
necessary to show that LAd plasticity is not passively fed
forward from either the auditory thalamus or the audi-
tory cortex.Indeed,short-latency plastic responses in fear
conditioning have been observed in both the MGm/PIN50
and the auditory cortex51.To determine the contribution
ofthe cortical pathway,Quirk and colleagues compared
conditioned unit responses ofLAd neurons with those in
An important question is whether neurons in the LA
show associative plasticity during fear conditioning.
Although previous work implied that this was the
case37,38,nobody had recorded from the dorsal subdivi-
sion of the LA (LAd), which is the primary target of
MGm/PIN inputs and a site ofCS and US convergence.
(LTP) An enduring increase in
the amplitude ofexcitatory
postsynaptic potentials as a
(tetanic) stimulation ofafferent
pathways.It is measured both as
the amplitude ofexcitatory
postsynaptic potentials and as
the magnitude ofthe
spike.LTP is most frequently
studied in the hippocampus and
is often considered to be the
cellular basis oflearning and
memory in vertebrates.
Figure 1 |Neural circuits that are necessary for auditory
fear conditioning. Tone and shock inputs from the medial
subdivision of the medial geniculate nucleus (MGm) converge in
the lateral amygdala (LA), resulting in potentiation of auditory
responses of LA neurons. The LA projects to the central
nucleus of the amygdala (Ce), both directly and indirectly by way
of the basal amygdala (BA). Descending outputs of the Ce to
brainstem and hypothalamic structures trigger fear responses.
01 2 sec
01 2 sec
Before fear conditioning After fear conditioning
Conditioned response latency (ms)
20 3040 5060 708090
Figure 2 |Effects of fear conditioning on lateral amygdala neurons. Fear conditioning induces increases in conditional stimulus
(CS)-evoked spike firing in lateral amygdala (LA) neurons. a | Electrode placements in the dorsal (LAd) and ventral (LAv) divisions of the
lateral amygdala. AB, accessory basal nucleus; AST, amygdalo-striatal transition zone; B, basolateral nucleus; Ce, central nucleus of
the amygdala; EN, endopiriform nucleus. b | Peri-event time histograms from eight simultaneously recorded single units in the LA.
Each histogram represents the sum of ten CS presentations (black bar) before or after fear conditioning. Representative spike
waveforms for each unit are shown as pink lines in the insets. c | Neurons in the LAd show conditioned increases in spike firing at
shorter latencies (from CS onset) than do auditory cortical neurons. Adapted, with permission, from REF.52© (1997) Cell Press.
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The region ofthe amygdala that
encompasses the lateral,
basolateral and basomedial
It remains possible that LA plasticity is passively fed
forward from the MGm/PIN. However, this seems
unlikely,because inactivation ofthe BASOLATERAL AMYGDALA
(BLA) with the GABAA(γ-aminobutyric acid,type A)
receptor agonist muscimol prevents the acquisition of
fear conditioning,as well as the expression offear mem-
ory,24 hours after training when rats are tested drug-
free55–57.Therefore,the primary site ofplasticity in fear
conditioning is unlikely to be the MGm/PIN,although
an effect ofmuscimol on brainstem projections that reg-
ulate ascending modulation ofthe thalamus cannot be
An alternative explanation is that plasticity in thalamic
or cortical neurons depends on the amygdala. To
address this issue,Maren and colleagues used muscimol
to inactivate the BLA while recording single-unit activity
in the MGm/PIN58.In addition to preventing the devel-
opment ofconditioned fear,muscimol in the amygdala
prevented the development of unit plasticity in the
MGm/PIN.A similar observation was made for INSTRU-
MENTAL AVOIDANCE LEARNINGin rabbits59.In a related experi-
ment,Armony and co-workers recorded single-unit
activity from cortical area Te3 in rats that had first
received BLA lesions60.Although short-latency plastic
responses were still observed in amygdala-lesioned rats,
long-latency responses anticipating the onset offoot-
shock were lost.Because muscimol inactivation ofthe
BLA prevents the development of conditioned fear
responses57,58, amygdala-independent short-latency
plasticity in Te3 does not seem to be sufficient to drive
fear behaviour,and might represent associative learning
at a more cognitive level61.By contrast,the loss ofshock-
anticipatory responses in Te3 neurons indicates that
ascending projections from the amygdala might ‘inter-
rupt’cortical processing when danger is imminent62.
Rather than mirroring thalamic or cortical plasticity,
it seems that conditioning-related spike firing in the
amygdala is independent of— and in some cases essen-
tial for — plasticity in the MGm/PIN and Te3.In fact,
the LAd seems to be the first site in the auditory pathway
to show associative plasticity that is not fed forward
passively from upstream sites, is not dependent on
downstream sites and is crucial for conditioned fear
behaviour. Furthermore, LA neurons seem to drive
plasticity at both thalamic and cortical levels,indicating
that the amygdala facilitates memory storage in wide-
spread areas,as shown by McGaugh and co-workers for
inhibitory avoidance63–65.However,several important
issues need to be resolved before we can conclude that
the LA is a primary site ofplasticity in fear conditioning,
such as how LA spike firing relates to behaviour and the
frequency specificity ofLA plasticity in auditory fear
conditioning (BOX 3).
Associative coding in the amygdala
For any conditioning-induced change in neuronal activ-
ity,it is essential to determine whether the change is
related to the associative learning that encodes the
CS–US contingency or whether it represents a non-
associative process (a form of learning that does not
depend on a CS–US association) that is consequent to
cortical area Te3 during auditory fear conditioning in
rats52.Te3 is the auditory association area that projects to
the LAd53,54.They observed that conditioned plasticity in
Te3 neurons occurred later than in the LAd (30–50 ms
versus 10–20 ms;FIG.2c).Also,LAd neurons developed
conditioned responses within the first three trials offear
conditioning,whereas Te3 neurons required between six
and nine conditioning trials to show conditioned
responses.Therefore,plasticity in the LAd is not likely to
be fed forward passively from Te3,because it precedes Te3
both within and across trials.
Box 2 | NMDA receptors and associative plasticity in the amygdala
There is considerable evidence that long-term synaptic plasticity in the lateral amygdala
(LA) mediates the acquisition offear memory (see REFS 98–100for reviews).There is strong
evidence that the NMDA (N-methyl-D-aspartate) subclass ofglutamate receptors is
involved in both the acquisition offear memory and the induction oflong-term
potentiation (LTP) in the amygdala44,101,and although there is debate concerning the role of
NMDA receptors in the expression oflearned fear responses102,103,recent work indicates
that NMDA receptors might be selectively involved in fear-memory acquisition under some
conditions104.A recent experiment by Maren and colleagues (see figure) examined whether
NMDA receptors are also involved in the acquisition ofassociative neuronal activity in the
LA during fear conditioning105.In this experiment,CPP (3-(2-carboxypiperazin-4-yl)
propyl-1-phosphonic acid),a competitive NMDA-receptor antagonist,was administered
either before training (pre-train) or before retention testing (pre-test) to examine the
influence ofNMDA-receptor blockade on the acquisition and expression,respectively,of
conditional freezing and LA unit activity.Systemic administration ofCPP impaired both
the acquisition ofauditory fear conditioning (as indexed by conditional freezing;
arrowheads indicate conditional stimulus (CS) presentations) and conditioning-related
increases in CS-elicited spike firing (pre-train panels;first 100 ms ofthe 2-second CS is
indicated by the black bar and arrow).Although CPP completely eliminated the acquisition
ofconditional fear and associative spike firing in the LA,it had only a mild effect on the
expression ofthese responses (pre-test panels).That is,CPP administered before a retention
test in previously conditioned animals moderately attenuated conditional freezing,but did
not reduce the magnitude ofconditional spike firing in the LA.These data are consistent
with models offear conditioning that posit a role for NMDA-receptor-dependent synaptic
plasticity in the formation offear memory,and reveal that similar neurochemical
mechanisms underlie the induction ofamygdaloid LTP,conditioning-related increases in
spike firing and conditional fear behaviour.Modified,with permission,from REF.105
(2004) Blackwell Publishing.
Time (s) Time (s) Time (s)
Normalized spike firing
Normalized spike firing
Normalized spike firing
–0.1 0.00.1–0.1 0.00.1–0.10.00.1
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associative learning,and changes in behaviour to the CS–
relative to the pre-conditioning baseline are taken as an
index ofnon-associative sensitization.Ofcourse,the CSs
must be chosen carefully to avoid generalization between
the cues, which would mask the different associative
strengths ofthe CSs.
Collins and Paré66found that discriminative fear
conditioning produced CS-specific changes in fear
behaviour,single units and local field potentials in the LA;
that is,after fear conditioning,the CS+(a 5- or 10-kHz
pure tone) evoked a larger LA field potential and more
spike firing than it did before conditioning.Conversely,
fear conditioning decreased the field potentials and
spike firing that were elicited by the CS–.These changes
in CS-elicited neural activity also showed EXTINCTION,
returning to baseline levels after several presentations
of each CS without the US.Therefore,the increased
spike firing in the LA after fear conditioning is CS-spe-
cific and cannot be explained by a nonspecific sensiti-
zation ofspike firing to auditory stimuli or to pseudo-
conditioning. It should be noted, however, that a
complete frequency RECEPTIVE FIELD analysis61has not yet
been carried out in the LA.
Conditioning-related changes in LA activity are
closely correlated with the expression offear responses.
Presentations ofCSs that have been paired with a foot-
shock evoke behavioural responses,such as freezing or
an increased state ofarousal associated with fear67–69.In
many cases,these fear responses outlast the stimuli that
produce them,and might therefore affect the processing
ofsubsequent CSs.For example,LA neurons in cats that
have undergone auditory fear conditioning show
increased responsiveness not only to the auditory CS,
but also to electrical activation of cortical inputs70.
Because the cortical stimulation was never explicitly
paired with the shock US in these animals,the potentia-
tion of these responses might reflect nonspecific
increases in LA excitability.A similar change in the
intrinsic excitability ofLA neurons has been observed
after olfactory conditioning in rats71.
Therefore, it is necessary to determine whether
associative plasticity ofCS-elicited LA spike firing is a
cause oflearned fear responses or a consequence ofthe
behavioural changes that are engendered by the fear
state.One approach to this question is to examine the
development ofneuronal plasticity over the course of
conditioning12.IfLA firing codes for fear associations,
learning-related activity in the LA should occur before
(or coincident with) the emergence offear CRs.Repa
and colleagues addressed this question by examining
spike firing in the LA during the gradual acquisition of
CONDITIONED LEVER-PRESS SUPPRESSION72.Interestingly,most
of the neurons that were recorded in the LA showed
increases in CS-elicited spike firing on or before the
trial in which the first significant behavioural CR
appeared.There were also neurons that increased their
firing to the CS after this point.Moreover,some LA
neurons maintained their conditioning-related increase
in spike firing after extinction of the fear response,
indicating that the expression offear behaviouris not
driving LA responsiveness.
either CS or US exposure.It is possible,for example,
that increases in the responsiveness ofLA neurons to
auditory CSs are due to non-associative learning
processes such as sensitization or pseudo-conditioning.
Moreover, changes in behaviour and arousal that
accompany learned fear might alter sensory processing
in the brain in a way that mirrors associative learning
but is not itselfthe substance ofmemory6.
Quirk and colleagues39showed that CS-elicited firing
in the LA was greater after CS–US pairings than with an
earlier phase ofunpaired CS and US presentations.This
implies that LA firing is regulated by the associative con-
tingency between the CS and the US.However,it is also
possible that shock exposure during conditioning pro-
moted further non-associative sensitization ofspike firing
to the CS.Ifso,changes in CS-evoked spike firing after
conditioning might have resulted from nonspecific
changes in the responsivity ofamygdala neurons to any
auditory stimulus,rather than an associative change to
the specific CS paired with the US.
To assess this possibility,Paré and colleagues used a
discriminative fear-conditioning procedure in conscious
cats to determine the specificity ofLA plasticity for the
auditory CS paired with the US66.In this procedure,there
were two distinct auditory cues:a CS+that was paired
with a US,and a CS–that was not.In such a design,differ-
ential behaviour to the two CSs is taken as an index of
Instrumental learning is a form
oflearning that takes place
through reinforcement (or
punishment) that is contingent
on the performance (or
withholding) ofa particular
response is instrumental in
producing an outcome.
Compare with Pavlovian
The reduction in the
conditioned response after non-
reinforced presentations ofthe
That limited domain ofthe
sensory environment to which a
given sensory neuron is
responsive,such as a limited
frequency band in audition or a
limited area ofspace in vision.
Normalized spike firing
Normalized spike firing
Normalized spike firing
Normalized spike firing
CS– in scary place
CS+ with drug
Figure 3 |Lateral amygdala neurons encode fear memory independently of fear
behaviour. Each panel shows population averages for single units recorded in the lateral
amygdala (LA) during presentations of an auditory cue paired with a footshock (CS+) or an auditory
cue that has never been paired with a shock (CS–). Onset and offset of the auditory CSs are
indicated by arrowheads. Fear conditioning increases both CS-evoked spike firing and freezing
behaviour to the CS+(bottom right), but not to the CS–(top left). This typical correlation between
the associative history of the CS and freezing behaviour can be broken by testing a CS–in a
context that has been paired with unsignalled shock (CS–in scary place; bottom left) or by testing
a CS+after inactivating the central nucleus of the amygdala (CS+after drug; top right). In these
cases, the CS–is presented against a background of high fear behaviour, or the CS+is presented
to animals that are not capable of showing conditioned fear responses. Nonetheless, LA neurons
continue to show activity patterns that are consistent with the associative history of the CS–and
CS+; that is, LA neurons represent fear memory, and are not biased by the performance of fear
responses. Adapted, with permission, from REF.73© (2003) Cell Press.
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fear conditioning70,74.It has been suggested that increased
synchrony after fear conditioning could increase the
impact ofthe LA on neocortical targets that consolidate
and store emotional memories75.
Fear not: amygdala inhibition after extinction
Fear memories enable us to anticipate and respond to
dangers in our environments.However,when signals for
aversive events no longer predict those events,fear to
those signals subsides.This inhibitory learning process,
known as extinction,has important clinical relevance
as a treatment for anxiety disorders, such as panic
disorder76and post-traumatic stress77. Importantly,
the inhibitory memories that are learned during extinc-
tion compete with the excitatory memories that are
formed during conditioning,thereby suppressing fear
responses78.Although fear subsides after extinction,the
fear memory is not erased.In fact,the inhibitory mem-
oriesofextinction are relatively short-lived and context-
dependent.This means that extinction is expressed only
in the context in which extinction was given,and even in
that context,fear responses will spontaneously recover
over time79.This transience and context dependence of
extinction implies that biology has deemed it better to
fear than not to fear.
There is considerable interest in understanding the
neurobiological mechanisms offear extinction,and sub-
stantial progress has been made in recent years80,81.As for
fear conditioning,the amygdala seems to have a vital role
in the extinction of learned fear. Pharmacological
manipulations that inhibit neuronal activity or disrupt
the cellular processes that underlie synaptic plasticity in
the amygdala impair extinction82,83.The mediation of
extinction by the amygdala is also manifested in the
firing ofLA neurons.Presenting the CS in the absence of
the US reduces the expression ofboth behavioural CRs
and CS-evoked spike firing in most LA neurons39,72.
However,not all LA neurons reduce their firing after
extinction72,and even neurons that do reduce their firing
continue to show the synchrony that is fostered by condi-
tioning39.This implies that even after extinction,residual
traces ofconditioning persist in the activity patterns of
The reduction in CS-evoked spike firing in the LA
that accompanies extinction correlates with the attenu-
ation of fear CRs to the extinguished CS.However,as
described earlier,fear extinction is context-dependent
and is primarily expressed only in the extinction context.
This raises the question ofwhether the suppression in
LA spike firing after extinction is also context-dependent.
To address this question,Hobin and colleagues used an
elegant within-subjects behavioural design to observe
the activity that is elicited in LA neurons by extin-
guished CSs that are presented either within or outside
their extinction context84.Rats were conditioned to
fear two distinct auditory CSs, then they received
extinction training to each CS in a different context.
Neurophysiological recordings were taken in a series of
four test sessions,in which each CS was tested in each
context.This design eliminated the possibility that any
particular CS, context or CS/context combination
In a more direct examination ofthis issue,Goosens
and colleagues recently asked whether increases in LA
spike firing are caused by the expression ofconditional
freezing behaviour73(FIG.3).In one experiment, rats
received discriminative fear conditioning using distinct
auditory CSs.Separate groups of animals were then
tested to each CS in either a neutral context (control
group) or in a context that they had come to fear
through contextual fear conditioning (experimental
group).In this way,it could be determined whether fear
per sewas sufficient to alter LA spike firing to a cue (CS–)
that was not paired with a footshock.In fact,the expres-
sion offear behaviour did not alter LA spike firing,and
the degree of neuronal discrimination between the
control and experimental rats was nearly identical.In a
follow-up experiment,the influence ofinhibiting the
expression ofconditional freezing on LA plasticity was
explored72.Reversible inhibition ofthe central nucleus
ofthe amygdala eliminated conditional freezing behav-
iour but not associative increases in CS-elicited spike
firing in the LA.
Together,these experiments show that the expres-
sion of fear is neither sufficient nor necessary for the
expression ofassociative plasticity in the LA,support-
ing the view that LA neurons encode fear memories.
The essence of this mnemonic code seems to be
contained in the rate at which LA neurons fire action
potentials in response to auditory CSs.In addition to
this rate code,however,the LA might also signal fear
associations by the timing ofspikes within a CS-evoked
spike train:a rhythm code.Fear conditioning has been
shown to increase synchrony in LA neurons39,70,and
THETA OSCILLATIONSbecome more frequent in the LA after
The reduction in pressing for
food reward in the presence ofa
Rhythmic neural activity with a
frequency of4–8 Hz.
Box 3 | Localizing fear memory
Fear conditioning increases the responses ofsingle lateral amygdala (LA) neurons to the
conditional stimulus (CS).However,this observation alone is not sufficient to imply that
LA neurons signal fear memory.Additional criteria (all ofwhich are met by the LA) are
Is plasticity in the LA associative?
Yes.LA neurons increase their tone responses during conditioning in contrast to pseudo-
conditioning (unpaired tones and shocks).Increases are specific to stimuli that are paired
with a shock (CS+),and are not seen with unpaired stimuli (CS–).
Does plasticity in the LA depend on plasticity in the auditory cortex?
No.Plasticity in the LA precedes plasticity in the auditory cortex,both within and across
Does plasticity in the LA depend on plasticity in the auditory thalamus?
Probably not.Inactivation ofthe LA with the GABAA(γ-aminobutyric acid,type A)
agonist muscimol prevents the development ofplasticity in medial geniculate inputs to
the LA.Therefore,plasticity in the medial geniculate nucleus seems to depend on
plasticity in the LA.
Do LA neurons learn as fast as the rat learns?
Yes.Across trials,plasticity in the LA develops as fast as — or faster than — conditioned
Is plasticity in the LA caused by fear behaviour?
No.Plasticity in LA neurons can be dissociated from freezing behaviour,implying that
LA neurons signal the strength ofthe conditional–unconditional stimulus association
rather than fear per se.
8 5 0 |NOVEMBER 2004 |VOLUME 5
R E V I E W S
population average mirrored the behavioural expression
of fear, indicating that the context dependence of
extinguished fear is modulated at the level of the LA
It is ofconsiderable interest to understand how LA
activity and fear expression are modulated after ext-
inction.Recent data indicate an important role for the
medial PREFRONTAL CORTEX (mPFC). Rats with mPFC
lesionscan learn to extinguish fear CRs,but have diffi-
culty recalling the extinction memory 24 hours after
training85–87. This is precisely the time when mPFC
neurons show robust increases in CS-elicited firing88,89,
consistent with a role in inhibition offear after extinc-
tion (FIG.4).mPFC neurons show an inhibitory influence
on both the LA90and the central nucleus91,the main out-
put regions ofthe amygdala.Furthermore,pairing CSs
with electrical stimulation ofthe mPFC mimics extinc-
tion behaviour88,92.Electrical stimulation ofthe mPFC
inhibits both lateral and central amygdaloid neurons,
presumably through a rich network of inhibitory
interneurons embedded in the amygdala93,94(FIG.5).
Ifthe inhibitory signal for extinction originates in the
mPFC,then it is probably modulated by context.One
possible modulator ofthe mPFC is the hippocampus.A
recent study indicates that the hippocampus modulates
the expression of extinction memories95.Temporary
inactivation ofthe dorsal hippocampus with muscimol
eliminated renewal of fear to an extinguished CS;
extinction performance prevailed under conditions in
which it would normally be weak.This implies that
although the hippocampus is not the repository for
extinction memories,it is involved in regulating when
and where extinction memories are expressed. The
mechanism by which the hippocampus interacts with
the amygdala to regulate CS-evoked spike firing is not
clear,and could involve either a direct projection from
the hippocampal formation to the LA44,96or an indirect
projection through the prefrontal cortex97(FIG.5).
Numerous studies have revealed electrophysiological
correlates ofmemory in neuronal activity patterns of
behaving animals,but few ofthese studies have estab-
lished causality between learning-induced changes in
neuronal activity and behaviour.Recent work in fear
conditioning renews the promise oflocalizing memory
in neuronal activity patterns in the mammalian brain.
LA neurons seem to be the origin ofassociative plasticity
that is relevant for both learned behavioural responses
and physiological plasticity in other brain regions after
aversive conditioning.Moreover,modulation ofthe fear-
memory code in the LA is involved in the suppression
and renewal offear responses after extinction.
This research opens up new avenues to investigate
how the hippocampus,prefrontal cortex and amygdala
interact during the acquisition,storage and retrieval of
fear memories,and how cellular and synaptic mecha-
nisms encode inhibitory extinction memories together
with excitatory fear memories. The central role for
amygdala neurons in both processes reveals a common
target for clinical interventions for anxiety disorders.
might itselfaffect LA spike firing independently ofthe
extinction history ofthe CS and context.Interestingly,
most single units in the LA modulated their firing rates
to extinguished CSs according to the context in which
the CS was presented.When a CS was presented in the
extinction context,spike firing to that CS was typically
lower than when the CS was presented outside its
extinction context;a small number ofneurons showed
the opposite pattern of modulation. However, the
(PFC) The non-motor sectors of
the frontal lobe that receive input
from the dorsomedial thalamic
nucleus and subserve working
processes and executive
functions such as planning,
and social cognition.
a Prefrontal cortex (safety memory)
Conditioning context Extinction context
b Lateral amygdala (fear memory)
Figure 4 |Neuronal signalling of extinction in the prefrontal cortex and lateral amygdala.
Panels show a representative single unit recorded from the infralimbic region of the medial
prefrontal cortex (PFC; a) and the lateral amygdala (LA; b). a | Unlike neurons in the LA, PFC
neurons are initially silent during conditional stimulus (CS) presentations after fear conditioning
(conditioning), but greatly increase their CS-elicited firing after extinction training (extinction).
b | Although spike firing is inhibited in the LA by extinction training (extinction context), it can be
renewed by a change in context (conditioning context). These data reveal that neurons in both the
PFC and LA respond to extinction contingencies, although they respond in opposite directions
under these conditions. Adapted, with permission, from REF.84© (2003) Society for
Neuroscience, and from REF.88© (2002) Macmillan Magazines Ltd.
b Modulation of extinction
a Expression of extinction
Figure 5 |Cortical modulation of amygdala fear memories in extinction. a | Following
extinction, neurons in the infralimbic region of the medial prefrontal cortex (IL) increase their
responses to tones. The IL exerts feed-forward inhibition of neurons in the lateral amygdala (LA) and
the central nucleus of the amygdala (Ce), thereby decreasing the expression of fear memories.
b | Extinction is expressed only in the context in which it occurred. Contextual modulation of
extinction requires the involvement of the hippocampus (Hip), which could modulate fear responses
either at the level of the LA or the IL. BA, basal amygdala; MGm, medial subdivision of the medial
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The authors thank K. Goosens and two anonymous reviewers for
helpful comments on the manuscript. This work was supported by
grants from the National Institute of Mental Health.
Competing interests statement
The authors declare no competing financial interests.
Encyclopedia of Life Sciences: http://www.els.net/
GABAAreceptors | Long-term potentiation | Neural informaton
processing | NMDA receptors
Maren’s laboratory: http://marenlab.org
Quirk’s laboratory: http://www.psm.edu/Quirk%20Lab/index.htm
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