Prefrontal cortical regulation of fearlearningMarieke R. Gilmartin1,2, Nicholas L. Balderston1, and Fred J. Helmstetter1

1 Department of Psychology, University of Wisconsin-Milwaukee, 2441 E. Hartford Ave., Milwaukee, WI 53211, USA2 Department of Biomedical Sciences, Marquette University, 561 N 15th Street, Milwaukee, WI 53233, USA

Review

The prefrontal cortex regulates the expression of fearbased on previously learned information. Recently, thisbrain area has emerged as being crucial in the initialformation of fear memories, providing new avenues tostudy the neurobiology underlying aberrant learning inanxiety disorders. Here we review the circumstancesunder which the prefrontal cortex is recruited in theformation of memory, highlighting relevant work inlaboratory animals and human subjects. We proposethat the prefrontal cortex facilitates fear memorythrough the integration of sensory and emotional sig-nals and through the coordination of memory storage inan amygdala-based network.

An expanded role for the prefrontal cortex in fearmemoryAdaptive responding to threat is crucial for survival. Learn-ing to avoid cues that predict danger and approach cues thatpredict safety depends on highly conserved neural circuitry.Anxiety disorders manifest when threat assessmentbecomes maladaptive, leading to exaggerated physiologicaland behavioral reactions to perceived or anticipated threatsor inappropriate fear in non-threatening situations. Be-cause approximately 18% of the US population may sufferfrom an anxiety disorder [1], understanding the neurobiolo-gy of fear and anxiety is an important goal. At its core, threatassessment requires the accurate prediction of an aversiveoutcome from available environmental signals. For thisreason, fear conditioning has proved to be a powerful toolfor investigating the neurobiology supporting emotionallearning and fear expression in both human and non-humansubjects. Fear conditioning studies have described criticalroles for the amygdala, hippocampus, and cerebral cortex inthe regulation of fear memory and behavioral expression.Standard fear conditioning requires subjects to associate aneutral conditional stimulus (CS), such as a tone, with anaversive unconditional stimulus (UCS), such as a shock.After repeated CS–UCS pairings, the CS elicits conditionalfear responses in the subject, including changes in autonom-ic activity, analgesia, and freezing behavior. The power ofthis procedure comes from its simplicity, rapid acquisition,translational application, and sensitivity to cellular/molec-ular-, genetic-, and systems-level manipulations. Early

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� 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2014.05.004

Corresponding author: Gilmartin, M.R. (marieke.gilmartin@marquette.edu).Keywords: fear conditioning; prelimbic; memory; learning; PFC; fMRI; awareness.

work characterizing the circuitry for fear conditioning iden-tified the amygdala as a critical site for memory formationand CS–UCS convergence during learning [2,3]. Over thepast 25 years, the use of fear conditioning has greatlyadvanced our understanding of memory formation, consoli-dation, and stability with a primary focus on the amygdala[2,4]. Likewise, more-complex variants of the procedure,such as contextual fear conditioning and trace fear condi-tioning, have been used to study hippocampal and corticalcontributions to emotional memory. The prefrontal cortex(PFC) has attracted substantial interest in recent years forits ability to bidirectionally modulate the expression ofpreviously learned fear [5,6]. The ventral PFC in the ratseems to be necessary for controlling fear to a CS that nolonger predicts danger, as in extinction learning [7,8]. Bycontrast, the dorsal PFC was found to promote the expres-sion of learned fear. Similar complementary patterns ofactivation have been observed in human dorsal and ventralPFC subregions, suggesting possible top-down regulation ofamygdala circuitry in adaptive responding to threat [9].

In addition to regulating the behavioral expression ofexisting fear memories, it is becoming clear that prefrontalneurons are engaged in various aspects of fear memoryformation. An appreciation of how the PFC might regulatethe initial formation of aversive memories is crucial todetermining how dysfunction in cortical–subcortical cir-cuits leads to maladaptive threat assessment in anxietydisorders. Here we review the circumstances under whichthe PFC seems to be necessary for fear memory based onevidence from work in laboratory animals and humans. Wediscuss the functional and anatomical heterogeneity of thePFC as it relates to fear-memory regulation and point toavenues of future study that ultimately will improve ourunderstanding of emotional memory formation.

Prefrontal cortical recruitment in fear memoryFear expression versus fear learning

The PFC was initially implicated in emotional regulationon the basis of reports of emotional and behavioral dysre-gulation after prefrontal damage [10]. This prompted acloser examination of the role of this structure in emotionallearning using a standard fear-conditioning paradigm, alsoknown as ‘delay’ fear conditioning (DFC), in which the UCSis delivered at the end of a discrete stimulus, such as a lightor tone. However, early lesion studies found that the PFCwas not required for learning the basic CS–UCS associa-tion, but instead might participate in the extinction of cuedfear [8]. This general pattern has been observed repeatedly

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using lesions and temporary inactivation [11–13], leadingto the generally accepted conclusion that the PFC con-tributes to the regulation of previously learned fear rath-er than to forming the initial CS–UCS association. Theinitial learning of the association may instead be sup-ported largely by the amygdala and plasticity in sensorysystems. Sensory information from the CS and UCS con-verges in the lateral nucleus of the amygdala via thethalamus [3], and subsequent processing through amyg-dala connections with the hypothalamus and brainstemnuclei produces conditional fear responses to the CS(reviewed in [2]). This subcortical fear circuit allows rapidautomatic responding to threatening stimuli without theneed for cortical processing.

The recruitment of the PFC to regulate fear expressionbased on previously learned information fits with knownroles of this region in cognitive control and flexibility: thatis, coordinating action through the integration of diversemnemonic inputs and top-down regulation of specific braincircuits [14]. Contextual control of extinction, for example,requires input from the hippocampus to the PFC for theappropriate expression of fear responses in a new context,but not in the extinction-related, or safe, context [15].These higher-order cognitive functions are not necessaryfor the basic association of the CS and UCS. However, workover the past decade has revealed that the PFC alsocontributes to the initial learning of fear in more cogni-tively demanding variants of fear conditioning. For exam-ple, the insertion of an empty temporal gap, or ‘traceinterval’, between the CS and UCS renders learning theassociation critically dependent on the PFC [11,16–19]. Insome cases, the association of complex contextual stimuliwith shock also requires the PFC [11,18,20]. It is possiblethat the added spatial and temporal complexity in thesetraining procedures may require cognitive functions attrib-uted to the PFC, particularly working memory, attention,and shock expectancy or contingency evaluation. Further-more, the examination of the PFC in memory formation isbeginning to reveal that even in standard delay condition-ing, the PFC may normally regulate the formation of theassociation [18,21,22]. This is not surprising given that inboth humans and laboratory animals, PFC subregionsexhibit changes in learning-related activity during delayconditioning [23–27]. In general, associative fear requiresplasticity in a distributed network of brain structures [4],and the PFC might contribute to memory formation in thisnetwork in addition to regulating the subsequent expres-sion of fear. In the next section we discuss findings fromtrace and contextual fear conditioning, which provide anavenue for studying the role of the PFC in fear memoryformation.

Trace and contextual fear conditioning

Dorsal regions of the PFC are necessary for associative fearlearning when temporal or contextual complexity is intro-duced. In trace fear conditioning, a cue predicts the occur-rence of an aversive shock that will occur many secondslater. The association of the cue and shock cannot besupported by simultaneous sensory stimulation converg-ing on amygdala neurons, as can be the case for delayconditioning. Thus, additional circuitry is recruited to

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process this temporal component, including the PFC,hippocampus, and entorhinal and perirhinal cortices[11,17,28–33]. The precise role of each structure is largelyunknown, but it is thought that activity in one or more ofthese structures may support trace conditioning by provid-ing a bridging signal between representations of the CSand UCS. Although some computational models suggestthat the hippocampus might provide a bridging signal[34,35], neither the CA1 nor dentate gyrus (DG) areasexhibit firing patterns that are consistent with providingthis signal [36]. More recently, the PFC has emerged as astrong candidate for this function. Cue-initiated persistentfiring lasting several seconds had been well documented instudies of working memory in primates. Recording studiesin trace fear conditioning showed that units in the PFCmaintain firing past CS offset and into the trace intervalfor both short (2 s [24]) and long (20 s [37]) intervals(Figure 1A). These ‘bridging’ cells are observed in thedorsal, prelimbic area (PL), but not the ventral, infralimbicarea (IL) [37]. Similar results have been obtained in rabbitsperforming trace eyeblink conditioning, with persistentfiring neurons located primarily in deep, output layers ofthe dorsal PL and anterior cingulate cortex (ACC) [38–40].This anatomical position is in line with a model in whichthe PL provides a bridging signal, allowing CS-activatednetworks to coincide with UCS delivery. Elegant work bythe Mauk laboratory has provided physiological supportfor such a model. Electrical stimulation of cortical input tocerebellum during the CS and trace interval was sufficientto support acquisition of eyeblink conditional fearresponses in the absence of a functioning PFC [41]. Addi-tional lines of evidence provide indirect support for abridging role for the PFC in associative fear learning.Molecular mechanisms that are associated with the per-sistent firing of cortical cells, such as the activation ofNR2B-containing NMDA receptors and muscarinic acet-ylcholinergic (mACh) receptors, are important for tracefear conditioning [18,42]. We recently directly tested therequirement of prefrontal trace interval bridging activityto learning using optogenetic silencing of PL neuronsduring the trace interval [19]. Silencing PL activity duringthe 20 s trace interval, but not during the CS or inter-trialinterval, prevented the development of fear to the CS(Figure 1). This finding showed for the first time thatprefrontal cortical activity is likely to link discrete eventsin memory. The next challenge is to determine the infor-mation content of this bridging activity. It is unlikely to besensory processing per se, a function that may be supportedby persistent firing in perirhinal cortex [30,43]. Instead, itmight reflect the maintenance of attentional resourcesduring the CS–UCS interval and/or the coordination ofassociative encoding downstream in the amygdala andrhinal cortices. Whether this activity contributes to localstorage of the association in the PFC is also a question ofcurrent interest (Box 1).

A specific role for the PFC in contextual learning is lessclear. Contextual fear conditioning is largely supported bythe hippocampus and amygdala. Lesions or inactivation ofthe PFC typically leave contextual fear memory intact ifthe context is the sole predictor of the shock (i.e., ‘fore-ground’ contextual learning), as in shock-only training,

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Figure 1. Bridging activity in the prelimbic area (PL) of the prefrontal cortex (PFC) is necessary for trace fear conditioning. (A) Rats were trained with trace fear conditioning, and

unit activity in the PFC or hippocampus was recorded during training. PL, but not hippocampal, neurons exhibit sustained bridging activity during the trace interval separating

the conditional stimulus (CS) and unconditional stimulus (UCS). Each histogram shows the mean change in firing from baseline in 1 s bins for a population of neurons in the PL

or dentate gyrus, averaged across several trace conditioning trials. The arrowhead indicates shock delivery. (B) Rats were injected with the inhibitory opsin ArchT into the PL of

the PFC, and spontaneous activity was recorded in the presence or absence of laser light (532 nm). The example multiunit activity trace recorded from the PL of a rat previously

injected with ArchT in the PL shows that brief, 20 s periods of light (green bar) effectively silenced spontaneous activity. (C) Rats were injected with ArchT in the PL, and optic

fibers were implanted in the PL. Rats were then trained with trace fear conditioning. The diagram shows when light (green bar) was delivered during each trial for each group.

The graph shows the mean freezing during the training session. Each point shows the freezing during each trial (10 s CS and 20 s trace interval). (D) The following day, all rats

were tested for memory of the CS in a novel chamber in the absence of laser light. The graph shows the freezing response during the CS. Light delivered during the trace interval

or whole trial the previous day impaired learning relative to control rats, showing that trace interval activity in the PL links the CS and UCS in memory. *P < 0.05. Part (A) is

adapted, with permission, from [36,37]. Parts (B–D) are adapted, with permission, from [19]. Abbreviations: IL, infralimbic area. ITI, inter-trial interval.

Review Trends in Neurosciences August 2014, Vol. 37, No. 8

unpaired pseudoconditioning, or differential contextual con-ditioning [11,12,44–46]. However, the PFC seems to benecessary for contextual fear learning if the context itselfis not the only reliable predictor of shock (i.e., ‘background’

contextual learning). Inactivation of either the PL or ACCprior to auditory cued fear conditioning impairs memory forthe training context [11,20]. Lesions of more ventral PFCcan actually enhance contextual fear memory [47]. Thus, the

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Box 1. Role of the prefrontal cortex in memory storage

Activity in the prefrontal cortex (PFC) is critical for the acquisition of

trace and contextual fear memories, but whether the PFC also serves

as a storage site for these memories is a matter of some debate. In

trace fear conditioning, the initial association of the conditional

stimulus (CS) and unconditional stimulus (UCS) across a temporal

gap requires prelimbic area (PL) bridging activity during the

acquisition session [19]. Once acquired, does the expression of fear

to the CS require the PFC? Do long-term plastic changes occur at

prefrontal synapses as a result of learning? Post-training or pre-

testing manipulations of the PFC have attempted to address these

questions. Excitotoxic lesions of the PFC administered 1 day after

trace fear conditioning do not prevent the successful recall of CS

memory several days later [98], consistent with systems consolida-

tion of hippocampus-dependent memory. However, consolidation

of trace fear conditioning does depend on plastic changes within the

PFC shortly after training. Training activates phosphorylated extra-

cellular-regulated kinase (pERK) in the PFC, and blocking prefrontal

pERK activation prior to training impairs memory formation [81].

Post-training inhibition of protein synthesis or protein degradation

in the PL of the PFC impairs the formation of trace, but not delay,

fear memory [99,100]. Moreover, memory is enhanced by post-

training injection of a b2-adrenoceptor agonist [101]. Although

seemingly contradictory, these findings can be reconciled if

memory storage is distributed within a network of cortical and

subcortical sites. The PFC does serve as a memory storage site for

trace fear conditioning, but subsequent recall of memory may be

supported by the hippocampus or amygdala [98,102–104]. This

raises the question of what information about trace fear condition-

ing is being stored in the PFC. Protein synthesis-dependent synaptic

changes in PFC have been shown to be required for the consolida-

tion of spatial working memory [105], suggesting that learning

strategies or temporal relationships may be stored in prefrontal

circuits. Such information is likely to contribute to behavioral

flexibility in novel situations. Behavioral testing procedures that

are sensitive to these more complex aspects of the memory will be

needed to test these possibilities in fear memory storage.

Review Trends in Neurosciences August 2014, Vol. 37, No. 8

PFC may regulate memory formation based on the relativepredictive value of the available stimuli. Consistent withthis idea, the lateral amygdala might also participatedifferentially in foreground and background contextualconditioning because one study [48] showed that lesions ofthe lateral amygdala impair foreground learning but en-hance background context learning. The authors sug-gested that in the presence of a discrete predictor of theUCS, the lateral amygdala might help to suppress learn-ing to the background context. The PFC may assess thepredictive value of multiple excitatory cues and regulateactivity in the amygdala during learning. These findingsfrom trace and contextual fear conditioning point to aworking model of prefrontal regulation of fear learningin which the PFC integrates information about the tem-poral, contextual, and predictive relationship of the cueand shock in order to influence memory storage in amyg-dala circuitry (Box 2).

Neurobiological mechanisms of prefrontal function inemotional learningThe circumstances under which the PFC regulates fearlearning reflect features of higher-order cognitive function,such as working memory, attention, and top-down regula-tion of subcortical neural systems. In this way, trace andcontextual fear conditioning studies in laboratory animalsbring animal work further in line with findings in humansubjects. For example, acquisition of trace, but not delay,

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conditioning in humans requires conscious awareness [49–51]. This requirement is correlated with selective activa-tion of hippocampus and frontal cortical regions in traceconditioning [27,52,53] (Figure 2). Activation of dorsal PFCregions in general during emotional situations is associat-ed with conscious appraisal of threat [54,55], and dorsolat-eral PFC activation and dorsal ACC activation are thoughtto represent working memory and attentional processes,respectively [52,56,57]. Trace and contextual fear-condi-tioning studies in animals may therefore provide someinsight into the underlying neurobiology of these complexcognitive concepts.

Working memory

Working memory-like processes during fear learning, asmentioned above, require persistent activity during theCS–UCS interval [19,37], which may depend in part onglutamatergic signaling mediated by NR2B-containingNMDA receptors [18,58]. NMDA receptor-mediated signal-ing is critical for trace fear conditioning as well as forcontextual fear learning [11,18]. Importantly, prefrontalNMDA receptors containing the NR2B subunit have aselective role in the trace fear association compared withthe contextual association [18]. NR2B-containing subunitsconfer a longer deactivation window to NMDA-mediatedcurrent, a feature that is amenable to persistent firing inrecurrent networks [59,60]. NR2B has recently been shownto be necessary for working memory [58,61]. Thus, theselective involvement of NR2B-containing NMDA recep-tors in trace but not contextual fear lends support for aworking memory function of prefrontal persistent firing intrace conditioning. Interestingly, a similar specificity ofNR2B-mediated signaling for trace but not contextual fearconditioning has been observed in the hippocampus [62].Although hippocampal neurons do not exhibit persistentfiring during trace fear conditioning, NR2B-mediated sig-naling nonetheless supports temporal processing in thehippocampus. Selective knockout of NR2B-containingNMDA receptors in CA1 impairs spatial working memorybut leaves Morris water maze performance intact [63].Moreover, the hippocampus and PFC are co-activatedduring trace fear conditioning in humans and rodents,and communication between these two structures is im-portant for spatial working memory [27,36,37,64,65]. Fur-ther examination of the cellular signaling downstream ofthese receptors is likely to provide insight into how thehippocampus and PFC contribute to contextual versustemporal/episodic regulation of emotional memory.

Cholinergic signaling mediated by mACh receptors mayalso contribute to successful encoding of fear memory in thePFC. Systemic delivery of the mACh-receptor-antagonistscopolamine impairs performance in both trace fear condi-tioning and working memory [42,66], and disrupts persis-tent firing in the dorsolateral PFC of primates [66].Facilitating cholinergic signaling with physostigmineenhances trace fear conditioning [67]. Cholinergic activa-tion via mACh receptors has been shown to be necessaryfor persistent firing and trace conditioning in several othercortical regions [31,43,68], suggesting a common corticalmechanism in working memory or transient bridging ac-tivity supporting emotional memory formation.

Box 2. Working model of prefrontal regulation of memory formation

The prefrontal cortex (PFC) is required for associative fear learning

involving temporal or contextual complexity. Recent evidence

suggests that the PFC is likely to be recruited for learning based on

its known roles in temporal bridging, attention, and assessment of

cue salience or predictive value. What is not clear is how the PFC

integrates relevant cue and contextual information within local

circuitry, and how the PFC then facilitates associative plasticity and

memory storage in the amygdala and other regions. The hippocam-

pus and amygdala are strong candidates for providing the PFC with

processed information about cues and context. Communication

between the ventral hippocampus and PFC is necessary for the

contextual modulation of fear extinction [15,106] and for successful

performance in spatial working memory tasks [64,65]. Projections

from the amygdala to the PFC can modulate cortical activity during

discrete fear cues [22,79,87], and a brainstem–thalamic–prefrontal

pathway might relay unconditional stimulus (UCS) expectancy [25].

How might the PFC integrate these diverse inputs? One possibility

is the modulation of prefrontal firing by separate inputs converging

onto the same prefrontal circuits. Projections from the hippocampus

and amygdala converge in the PFC, and the relative timing of these

inputs can either enhance or attenuate the influence of each input on

prefrontal firing [107]. Ventral hippocampal activation of inhibitory

circuits in the PFC can gate prefrontal responses to amygdala input

during the presentation of an extinguished fear conditional stimulus

(CS) [108]. Similar modulation of prefrontal activity by converging

inputs from the hippocampus, amygdala, sensory cortices, or

thalamus may contribute to the recruitment of the PFC during more

complex forms of fear learning. Another possible mechanism of

prefrontal integration of diverse input is the entrainment of prefrontal

firing to hippocampal theta rhythm. Synchronization of unit firing to

an ongoing rhythm can organize a distributed network of distal cells

[109], and this may serve to coordinate the activity of separate sets of

cells, perhaps with distinct projection targets, within a larger

functionally and anatomically heterogeneous population. Prefrontal

units tend to fire at specific phases of the ongoing hippocampal theta

rhythm during spatial working memory tasks [110,111], with more

consistent phase-locking observed on correct performance trials than

on error trials [110]. Prefrontal units also exhibit phase-locking to local

or hippocampal theta rhythm during appetitive or eyeblink trace

conditioning [40,112]. In fact, acquisition of trace eyeblink condition-

ing is enhanced when trials are delivered contingent upon hippo-

campal theta rhythm, and sustained unit activity in the PFC during the

trace interval is only observed in trials delivered during hippocampal

theta [40]. The PFC also exhibits increased synchronization in the local

theta rhythm during a cue that predicts shock (CS+), but not during a

cue that predicts no shock (CS–), and this synchrony is dependent on

transient disinhibition of principal neurons by parvalbumin-contain-

ing interneurons [90]. The origin of this synchronizing signal is

unknown, but projections from the amygdala to the prelimbic area

(PL) exhibit increased burst firing to predictive cues during fear

learning [87] and may help to synchronize firing at cue onset. These

findings support a model in which the PFC might integrate cue

salience from the amygdala with temporal and contextual information

from the hippocampus to facilitate attention or working memory to

appropriate stimuli (Figure I).

How might the PFC then subsequently regulate plasticity and

memory storage elsewhere? The PFC might facilitate transfer of

information between other structures through neuronal synchroniza-

tion, as has been observed in rhinal cortices following hippocampus-

dependent learning [113]. Prefrontal–amygdala synchrony in

non-human primates is associated with stronger memory and

resistance to extinction in animals fear conditioned with a partial

reinforcement schedule: a procedure that introduces uncertainty into

the CS–UCS association [114]. Alternatively, learning-related plasticity

in amygdala circuits may be achieved through phasic or tonic firing in

PFC projections to the amygdala [91,115–117]. The prefrontal cells that

exhibited increased theta synchrony during the CS+ in the Courtin et al.

study described above were identified as amygdala-projecting cells.

Theta synchrony in these cells correlated with fear expression after

learning [90]. Thus, a subset of prefrontal cells projecting to the

amygdala may convey information about the predictive value of the

relevant CS during learning. The PFC is likely to regulate other inputs to

the amygdala in order to modulate memory formation based on

working memory or attention. Converging input from the ventral

hippocampus and PFC is thought to mediate the contextual control of

extinction [15], and prefrontal input to the amygdala interacts with

neurotransmitter systems to modulate amygdala plasticity to fear cues

[118]. A recent optogenetic study of prefrontal and hippocampal inputs

to the amygdala highlights the diversity of cell-type targets, demon-

strating the potential for very fine control of plasticity in amygdala

circuitry by the PFC and ventral hippocampus [119].

More work is needed to identify the mechanisms by which the PFC

integrates diverse emotional and associative inputs and regulates

memory formation in a distributed network. The combination of fear

conditioning paradigms that engage this network during learning and

sophisticated optogenetic approaches are providing an avenue for

testing the hypotheses of this working model.

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Dorsal mPFC

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Figure I. Proposed working model of prefrontal cortical regulation of fear

memory formation. The dorsal prefrontal cortex (PFC) integrates processed

information about associative stimuli and context in order to perform subregion-

specific regulation of attention or working memory necessary for complex fear

associations. The PFC probably facilitates learning-related plasticity and memory

storage in the amygdala and rhinal cortices. Coordination of memory storage in

this distributed network may be achieved through synchronous neuronal firing.

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Attention

Prefrontal activity during trace conditioning may alsoreflect the regulation of attentional resources duringcue–shock pairings. Trace conditioning, to a much greaterextent than delay conditioning, is impaired if human sub-jects are given a distracting task during the period of CS–UCS pairings [69]. Similarly, in mice, distracting visualstimuli impair trace but not delay fear conditioning [45].

Han and colleagues provide indirect support for the ACCmediating this effect. Trace conditioning led to greater c-fos expression in ACC compared with delay and foregroundcontextual conditioning [45], and pre-training lesions ofthe ACC with NMDA selectively impaired trace condition-ing [45]. Pre-training intra-ACC injection of NMDA-recep-tor NR2B antagonists also impairs trace fear conditioning[70]. Whether these receptors in the ACC serve a role in

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Figure 2. Distinct activation patterns in trace and delay conditioning in frontal cortical regions. (A) Subjects were trained in a differential fear conditioning procedure in

which a delay conditional stimulus (CS) was paired with shock (CS+), a trace CS was paired with a shock delivered after a 10 s trace interval (CS10), and a third CS was never

paired with shock (CS–). Activation related to forming the CS–UCS association (i.e., trace and delay, but not CS–) was observed in the anterior cingulate. The histograms

depict the baseline-adjusted area under the impulse response curve (AUC) measured for each stimulus within each region of interest. The response magnitude within these

regions was significantly larger during the CS+ and trace interval than during CS– presentations. (B) Activation specific to the trace interval was observed in the middle

frontal gyrus (a dorsolateral prefrontal cortex area). The response magnitude within this region was larger during the trace interval than during the CS+, CS10, and CS–.

Additional areas activated during the trace interval may reflect other cortical processes specific to a delay period, such as motor preparation in anticipation of unconditional

stimulus (UCS) delivery [the supplementary motor area (SMA)] or timing of the sensory UCS (frontal operculum) (discussed in [27]). Reproduced, with permission, from

[27]. (C) Summary figure highlighting the functional uniqueness of various cortical areas in fear conditioning, observed across several studies of trace fear conditioning

[27,53,69].

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attention distinct from that in persistent firing and work-ing memory remains to be determined. The dorsal PL/ACCof the rodent shares functional and anatomical homologywith the primate ACC in attention regulation [57,71–73].Attention regulation may underlie a common function ofthe PFC in emotional learning in general. Recent work has

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implicated the PL and ACC, but not the IL, in detection ofprediction error and regulation of attention based on UCSexpectancy [25,74,75]. The element of surprise from anunexpected outcome is a fundamental requirement forlearning in several learning models [76], and expressionof c-fos in the PL increases specifically when the UCS is

Review Trends in Neurosciences August 2014, Vol. 37, No. 8

unexpected early in training [25]. After sufficient training,the CS is a reliable predictor of the UCS, and if a novel cueis presented in compound with this well-learned CS, asso-ciating the new cue with the shock is impaired, a phenom-enon called blocking. Interestingly, inactivating the PLduring this compound training unblocks fear learning tothe new CS [25]. This suggests that the PL is regulatingattentional resources to this new cue based on associativeinformation from other available cues. In support, Bucheland colleagues [77] used eye tracking to show that humansubjects tracked the more predictive stimulus for shock ofthe compound stimulus during a blocking paradigm. Fur-thermore, gaze fixation time correlated with blood-oxygen-level dependent (BOLD) responses in both the ACC andamygdala, suggesting a possible functional interactionbetween these two regions in attending to predictive cues.

Reconsidering a role for the prefrontal cortex in delayfear conditioningWhereas more complex variants of basic fear conditioning,such as trace and contextual fear learning, critically dependon prefrontal cortical function, expression of fear in delayconditioning can clearly occur in the absence of the PFC. Inhumans, conscious awareness is not required for the associ-ation of the CS and UCS when they co-terminate [49,50].Nonetheless, some prefrontal cortical regions, such as themiddle frontal gyrus and ACC, do exhibit changes in activityin delay fear conditioning and might reflect explicit proces-sing of fear cues or their predictive value [23,26,27,78].Similarly, in rodents, neurons in the PFC are active duringdelay fear conditioning [24,25,79], and these responses canbe modulated by amygdala input [22,79,80]. These activa-tion patterns might reflect a role for the PFC in mediatingthe expression of fear during learning, or they might reflectthe appraisal of the predictive value or the salience of fearcues [12,25,54]. Dissecting these possibilities in delay con-ditioning has been difficult because lesions or temporaryinactivation do not normally prevent learning [8,11,12], butmore selective manipulations of specific molecular path-ways or monoamine signaling are beginning to reveal thatthe PFC normally contributes to delay fear learning. Dis-ruption of dopamine signaling in thePFC impairs olfactorydelay conditioning in addition to auditory trace conditioningand fear extinction [22,81,82]. Dopamine in prefrontal net-works may regulate input from other regions [83,84], anddisrupting dopaminergic tone could thus affect cue salienceor the integration of subcortical input during memory for-mation. In addition to dopaminergic signaling, cannabinoidsignaling is important for normal delay fear conditioning.Signaling via the CB1 receptor in the PFC is necessary forolfactory conditioning, and activation of the CB1 receptorpotentiates unit responses in the PFC to fear cues andfacilitates memory retention [85]. Importantly, the role ofthe PFC in delay fear conditioning involves bidirectionalcommunication with the amygdala [22,80,85–87].

Fear learning and prefrontal network balance

A possible explanation for these discrepant findings inprefrontal regulation of delay conditioning comes from re-cent work by Yizhar and colleagues using optogeneticsto probe network dynamics in the PFC. Elevation of the

excitatory/inhibitory (E/I) balance in prefrontal networks byselectively increasing excitatory tone impaired delay fearconditioning to an auditory cue [21]. Decreasing E/I balanceby increasing inhibitory tone or inactivating excitatory cellswith halorhodopsin did not affect learning. These resultssuggest that manipulations that selectively reduce inhibi-tory tone may be the important factor in prefrontal regula-tion of memory formation in delay fear conditioning.Disruption in E/I balance within prefrontal networks viaaberrant activity of parvalbumin (PV)-containing inhibitorycells has been hypothesized to underlie cognitive dysfunc-tion in schizophrenia and autism [88,89], as well as dysre-gulated emotional memory in these disorders. A recentstudy by Herry and colleagues showed that PV-containinginterneurons are necessary for the expression of learned fearthrough regulation of principal neuron firing [90]. Previouswork has demonstrated a correlation between prefrontalfiring and the expression of fear behavior [91], and disinhi-bition of principal cell firing by PV-containing interneuronspromotes fear expression [90]. Although these studies seemto suggest that PV-regulation of cell firing may have oppos-ing effects on fear learning and fear expression, they clearlyhighlight the importance of network balance in emotionalmemory. The previously described manipulations of dopa-minergic, glutamatergic, and cannabinoid signaling thatimpair delay fear conditioning may primarily affect inhibi-tory tone in the PFC. Dopaminergic input from the ventraltegmental area acting on D2 and D4 receptors has beenshown to regulate the balance of excitatory and inhibitorytransmission in the amygdala-PFC circuit [92]. CB1 recep-tors in the PFC are located on inhibitory terminals and maymodulate local inhibition [93,94]. Recently, we showed thatan NR2A-preferring antagonist impaired the acquisition oftrace, contextual, and delay fear conditioning [18]. PV-con-taining interneurons express proportionally more NR2A-containing NMDA receptors compared with principal cells,[95], and NR2A antagonists may disrupt glutamatergicactivation of inhibitory networks in the PFC. Another recentstudy found that the perineuronal net in the PL of the PFC isnecessary for cued fear including both trace and delayconditioning [96]. The perineuronal net is the extracellularmatrix surrounding neurons, which is thought to regulatesynaptic stabilization during learning. In the PFC, this netis more intense around PV-positive inhibitory neurons [96].Interestingly, the amygdala, which is required for thereported effects of cannabinoid and dopamine signalingon fear learning [22,80], typically suppresses prefrontalfiring, possibly via glutamatergic action on PV interneurons[79,92,97]. Taken together, these findings contribute to anemerging picture that amygdala regulation of prefrontalnetwork activity is necessary for the adaptive encoding ofcued fear. This opens up the possibility that genetic disrup-tion in these prefrontal circuits contributes to aberrantthreat assessment in the development of anxiety disorders.

Concluding remarksThis review has highlighted an expanded role for the PFCin the regulation of fear memory. The PFC is important notonly for regulating the behavioral expression of fear andextinction of previously acquired fear memories but also forthe initial formation of emotional memories involving

461

Box 3. Future directions

� Further work is needed to determine the specific role of the

prefrontal cortex (PFC) in contextual fear memory. Current evidence

suggests that its involvement relates to appraising the predictive

relationship of contextual stimuli relative to discrete stimuli [11].

The contextual or spatial component may be essential, because

differential fear conditioning with two discrete cues does not

require the PFC [46]. Given the importance of the PFC in contextual

modulation of fear extinction [15], the PFC may have a selective role

in contextual associations. Furthermore, it remains to be deter-

mined whether the anterior cingulate cortex, prelimbic area, and

infralimbic area of the PFC differentially regulate contextual fear.

� An open question is how bridging activity in the PFC during trace

fear conditioning is communicated with the amygdala, hippo-

campus, and rhinal cortices for coordination of conditional fear

responses and facilitation of memory formation. The PFC may

provide a sustained input to amygdala neurons during each trial,

similar to the proposed top-down cortical input pattern hypothe-

sized to support trace eyeblink conditioning in cerebellar circuits

[38,41]. The PFC may also coordinate persistent firing to the

auditory conditional stimulus in the entorhinal and perirhinal

cortex, both of which exhibit persistent firing properties and are

necessary for trace fear conditioning [31,43,68,120]. Current work

in our laboratories is testing these possibilities.

� The PFC exhibits protein synthesis- and protein degradation-

dependent consolidation of trace fear conditioning, similar to the

hippocampus and amygdala [99,100,102,103], suggesting a dis-

tributed network of memory storage for these complex variants of

fear conditioning. Does this distributed plasticity change the

circuitry of fear extinction? Recent work from our laboratory

suggests that this may be the case. Whereas extinction of delay

fear requires NMDA receptor-mediated transmission in the

amygdala, trace fear extinction is intact after intra-amygdala

injection of NMDA receptor antagonists [121]. Instead, extinction

of trace fear depends on both the PFC and retrosplenial cortex

[121]. Determining how the extinction of trace and contextual fear

memories differs from delay extinction may shed light on

individual differences in clinical efficacy of extinction-based

therapies for fear and anxiety disorders.

Review Trends in Neurosciences August 2014, Vol. 37, No. 8

sufficient temporal or contextual complexity. This broad-ened understanding of cortical regulation of emotionalmemory is likely to lead to new insights into how thesesystems might confer susceptibility or resilience to anxietydisorders. The next decade promises rapid advances alongseveral exciting new lines of research (Box 3).

AcknowledgmentsThis work was supported by funding from the US National Institutes ofHealth grants R01 MH069558 to F.J.H. and F32 MH083422 to M.R.G., aswell as by MH060668 and MH090246.

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