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Prefrontal Mechanisms in Extinction
of Conditioned Fear
Gregory J. Quirk, René Garcia, and Francisco González-Lima
Interest in the medial prefrontal cortex (mPFC) as a source of behavioral inhibition has increased with the mounting evidence for afunctional role of the mPFC in extinction of conditioned fear. In fear extinction, a tone-conditioned stimulus (CS) previously pairedwith a footshock is presented repeatedly in the absence of footshock, causing fear responses to diminish. Here, we review convergingevidence from different laboratories implicating the mPFC in memory circuits for fear extinction: (1) lesions of mPFC impair recallof extinction under various conditions, (2) extinction potentiates mPFC physiological responses to the CS, (3) mPFC potentiation iscorrelated with extinction behavior, and (4) stimulation of mPFC strengthens extinction memory. These findings support Pavlov’soriginal notion that extinction is new learning, rather than erasure of conditioning. In people suffering from posttraumatic stressdisorder (PTSD), homologous areas of ventral mPFC show morphological and functional abnormalities, suggesting that extinctioncircuits are compromised in PTSD. Strategies for augmenting prefrontal function for clinical benefit are discussed. Key Words: Amygdala, infralimbic, long-term potentiation, prelim-
in rodents supporting this hypothesis. We also suggest ways in which prefrontal mechanisms of extinction may be augmentedso as to enhance extinction, with potential clinical applications.
Thestudyoffearandanxietyinexperimentalanimalshas LesionStudies
advanced rapidly with the use of Pavlovian fear condition-ing, in which a tone-conditioned stimulus (CS) is associ- The idea that extinction circuits involved the prefrontal cortex ated with a footshock unconditioned stimulus (US). Conditioned originated with early primate studies of appetitive conditioning, fear reactions to the tone extinguish in the absence of the shock.
in which lesions of the ventral mPFC (vmPFC) and orbitofrontal The resurgence of interest in extinction is due in large part to its cortex resulted in increased responding during extinction potential applicability to the treatment of anxiety disorders, such for a complete history of prefrontal cortex in extinc- as posttraumatic stress disorder (PTSD), in which extinction is thought to be compromised. A thorough understanding of the neural circuits of extinction of fear could yield new treatments for observed that rats with vmPFC lesions could acquire fear nor- augmenting exposure-based therapies that are used to treat mally but had difficulty extinguishing across several days of In his classic investigation of appetitive conditioning in dogs, that rats with vmPFC lesions that were centered on the infralim- Pavlov observed that extinguished responses spontaneously bic cortex (IL) could extinguish normally within a session but recovered with the passage of time This suggested had difficulty recalling extinction 24 hours later, suggesting that that extinction did not erase the memory for conditioning but IL is not required for fear inhibition under all circumstances but represented new learning. More recent behavioral studies have is important for recalling extinction after a long delay. Other confirmed and extended this finding for conditioned fear studies have confirmed that vmPFC lesions impair recall of extinction does not erase the conditioning memory, it must form a new memory that inhibits the conditioned response. This suggests that some structure or structures are activated byextinction, so as to excite inhibitory circuits that are responsible Recording Studies
for reducing the expression of fear Despite early Lesion studies presuppose that regional contributions to brain theoretical formulations of extinction-related inhibition function may be inferred from a damaged brain. A more direct the search for inhibitory circuits largely approach is to record from neuronal activity in awake animals undergoing extinction training. Do mPFC neurons signal extinction? However, studies that build on recent advances in the Paralleling mPFC lesion findings, single neurons in IL did not signal acquisition of conditioned fear point to the medial prefrontal the tone CS during acquisition or extinction training cortex (mPFC) as an important part of the neural circuit for fear The next day, however, when rats were recalling extinction. In this review, we describe converging evidence from extinction, IL units showed potentiation of short-latency tone re- lesion, recording, metabolic, stimulation, and microinfusion studies sponses The larger the tone response, the lower thespontaneous recovery of freezing, consistent with IL-mediatedinhibition of fear after extinction. No such potentiation was ob- From the Department of Physiology (GJQ), Ponce School of Medicine, served in adjacent prelimbic cortex. Thus, extinction potentiated Ponce, Puerto Rico; Neurobiologie et Psychopathologie (RG), Universite auditory inputs to IL neurons, providing direct support for the de Nice-Sophia Antipolis, Nice, France; and the Institute for Neuro- Pavlov-Konorski hypothesis that extinction potentiates neuronal science and Department of Psychology (FGL), University of Texas at activity in structures that are involved in inhibition of the condi- Address reprint requests to Gregory J. Quirk, Ph.D., Department of Physiol- ogy, Ponce School of Medicine, P.O. Box 7004, Ponce, Puerto Rico 00732; What inputs to mPFC might become potentiated as a result of Received August 1, 2005; revised October 16, 2005; accepted March 3, 2006.
whether repeated presentations of a tone CS in the absence of doi:10.1016/j.biopsych.2006.03.010 2006 Society of Biological Psychiatry behavioral networks. Metabolic responses to a test tone were compared in groups of mice that received fear conditioning, a pseudorandom treatment (unpaired tones and shocks), or con- ditioning followed by extinction. Consistent with single-unit andevoked-potential recording, the largest increase in metabolic activityafter extinction occurred in the mPFC. The infralimbic (but not theprelimbic) area showed significantly more metabolic activity thancontrols. In addition to IL, significant metabolic increases were Conditioning Extinction
observed in dorsal, medial, and lateral frontal cortex, which areareas not yet studied with the unit-recording technique. Hence, Figure 1. Schematic relating conditioned behavior to memory for condi-
multiple prefrontal regions may play a role in extinction memory.
tioning and extinction. As first suggested by Pavlov, extinction training does There also were changes in the interaction between the prefron- not eliminate memory for conditioning but generates a new memory that tal cortex and other regions, particularly in auditory and limbic competes with conditioning for control of behavior. For conditioned fear,this schema suggests that there are structures in the brain that increase their networks. In support of an inhibitory role, FDG labeling in neuronal activity with extinction, so as to drive down fear via inhibition of dmPFC, in IL cortex, and in dorsal and lateral frontal cortex was correlated significantly with extinction behavior Finally, there was a strong negative correlation between the US induces long-term potentiation (LTP) in the mPFC. The prefrontal areas and regions thought to be involved in expression mPFC receives glutamatergic inputs from the hippocampus of conditioned fear, such as the ventral tegmental area, MD thalamus, and the entire auditory system (brainstem, thalamic, High-frequency stimulation of each of these input areas results in These mapping data suggest that extinction training engages a network of interactive brain regions, which may serve two functions: to inhibit the conditioned response after extinction pathways have confirmed development of LTP-like changes in and to preserve some of the original CS-US associative effects the mPFC with extinction training. MD-evoked responses inmPFC show little change during extinction training but areincreased 1–7 days after extinction Similarly, extinction-related LTP takes place in thehippocampal–mPFC pathway after extinction training Interestingly, failure to recall extinction wasassociated with inhibition of MD-evoked potentials, and depressingthe MD-mPFC pathway with low-frequency stimulation caused fullrecovery of conditioned fear after extinction Thus, extinction training results in LTP of thalamicinputs to mPFC even days after extinction, paralleling the single-unitrecording studies and indicating a role ofmPFC in long-term retention of extinction memory. Thus, inputs tothe mPFC from the thalamus, hippocampus, or the BLA maybecome potentiated after extinction.
Microinfusion data have strongly implicated the BLA in acqui- sition of extinction however, lesions of the basal nucleus have no effect on short- orlong-term memory for extinction This highlights the potentialimportance of the lateral amygdala in the acquisition of extinc-tion. Another potentially important input to mPFC is the auditoryassociation cortex in light of reports thatauditory-cortex lesions impair extinction of auditory fear condi-tioning Local inactivationof various inputs to mPFC is needed to determine which onesmay impair extinction learning and memory.
Figure 2. Converging lines of evidence showing that the infralimbic pre-
Metabolic Mapping
frontal cortex (IL) is functionally involved in recall of extinction. (A) Lesions of
IL do not prevent extinction but interfere with recall of extinction the follow-
In addition to single-unit and evoked potential recording, ing day (modified from Quirk et al 2000). (B) Unit recording shows that IL
extinction of auditory conditioning also has been investigated neurons respond to the tone only during recall of extinction, suggesting with metabolic-mapping techniques that assess the uptake of that IL tone responses are responsible for low fear after extinction (modified fluorodeoxyglucose (FDG), a radiolabeled glucose analog from Milad and Quirk, 2002). (C) Infusing the protein synthesis inhibitor
Brain activity can be mapped with FDG because anisomycin (Aniso) into the IL just before extinction (arrow) has no effect onextinction learning but blocked recall of extinction the following day (mod- brain cells use glucose and its analogs for energy metabolism ified from Santini et al 2004). These and other data suggest that extinction- An important advantage of metabolic mapping induced potentiation of prefrontal neuronal activity is necessary for sup- over electrophysiological recording methods is that the entire pression of fear after extinction. vmPFC, ventral medial prefrontal cortex; brain can be examined at once, permitting visualization of Habit., habituation; Cond., conditioning.
Table 1. Converging Lines of Evidence from Recent Rodent Studies Showing that Extinction can be Facilitated by Activation of Medial Prefrontal
Cortex (mPFC)
Electrical stimulation paired with CSa,e Field potentials evoked by thalamic stimulationb Field potentials evoked by thalamic stimulationd Long-term potentiation of thalamic inputsd Metabolic enhancement with methylene bluef from acquisition. Thus, there is remarkable convergence be- memory, although transcription inhibitors and transgenic ap- tween the three different techniques (single-unit, evoked poten- proaches will be needed to determine whether gene expression tial, metabolic mapping) in two species (rat and mouse), show- ing that extinction potentiates vmPFC responses to the tone CS These results clearly support Pavlov’s cortical inhibi- Expression of Extinction
tion hypothesis and contradict the simpler notions of extinction Once potentiated, how does mPFC inhibit fear after extinc- as unlearning or reversal of acquisition.
tion? The infralimbic subregion of mPFC has extensive projec-tions to the amygdala, as well as the amygdala’s targets in the Molecular Studies
Formation of long-term memory has been linked to a molec- If these projections are inhibitory, the IL could ular cascade involving N-methyl-D-aspartate (NMDA)-mediated override amygdala-generated fear responses. The physiological calcium entry, activation of protein kinases, gene expression, effect of many of these projections is not known, but anatomical and protein synthesis Involvement of this cascade support exists for IL-mediated inhibition of the amygdala. IL in extinction would provide support for the idea that extinction projects robustly to the region between the central and basolat- constitutes new learning. It has been known for some time that eral nuclei, containing intercalated (ITC) cells formation of long-term memory for extinction. Protein kinases responsible for feed-forward inhibition of central nucleus output and protein synthesis in the amygdala also have been implicated neurons In support of this model, electrical stimulation of the IL area decreased the excitability of brainstem- Recent evidence suggests that a similar molecular cascade oper- projecting neurons of the amygdala central nucleus ates in the mPFC during extinction. Antagonists of NMDA receptors and decreased the expression of conditioned fear According to this model extinction-induced potentiation of tone responses in IL neurons would cause prevent the formation of long-term (but not short-term) extinction feed-forward inhibition of the central nucleus, thereby prevent- when microinfused into the mPFC. In each case, delaying the ing fear signals in BLA from exiting the amygdala. Consistent infusion 2 or 4 hours after extinction eliminated the effect, consistent with this, it recently was shown that chemical stimulation of IL with a time-limited role of molecular processes in consolidation ofextinction. Western blot analysis of prefrontal tissue shows that A. Before Extinction
B. After Extinction
infusion of MAPk inhibitor PD098059 into the mPFC immediatelyafter extinction decreased levels of phosphorylated ERK2 without affecting total ERKs Future experiments will determine whether inhibition of extracellular signal-regulated ki- nase-2 (ERK2) phosphorylation is related to LTP in the MD-mPFC or hippocampal–mPFC pathways or to other inputs to the mPFC (for Does activation of the ERK-MAPk system in the mPFC trigger gene expression necessary for extinction memory? Although little Figure 3. Schema for mPFC inhibition of fear via the amygdala. (A) Before
is known about extinction-induced gene expression, it recently extinction, the tone CS activates the basolateral amygdala (BLA), which was shown that extinction training stimulates the immediate activates the central nucleus (Ce) output neurons, triggering fear responses.
(B) After extinction, prefrontal (PFC) responses to the tone are potentiated,
Controls indicated that this up-regulation was not a result which activates GABAergic intercalated cells (ITC) within the amygdala. ITCinhibition of the Ce competes with BLA excitation of Ce, effectively cancel- of tone stimulation or acquisition of fear conditioning. c-Fos is a ing fear responses. Potentiation of PFC responses to the CS and inhibition of marker of cellular activity but also can act as a transcription factor conditioned fear responses also may involve reciprocal PFC interactions with hippocampal, thalamic, and neocortical pathways. Modified with per- are consistent with a role of gene expression in extinction increased c-Fos expression in amygdala ITC cells the spontaneous recovery of conditioned freezing that normally ITC cells also exhibit NMDA-mediated plasticity is observed with the passage of time.
suggesting that they may participate in long-term An additional approach to enhancing mPFC function is the use of metabolic enhancers such as methylene blue (MB), whichimprove activity-dependent brain energy production by targeting Conflicting Lesion Evidence on the Role of the mPFC
in Extinction
memory-improving action of MB in rats first was demonstratedfor inhibitory avoidance learning Although there is much physiological evidence in favor of a functional role of mPFC in learning and expression of extinction, administration of MB could enhance retention of an extinguished there also are conflicting lesion reports. Two groups did not find conditioned response. Postextinction freezing was 50% lower in any effect of pretraining mPFC lesions on extinction of condi- rats that were receiving 4 mg/kg of MB, a dose that chronically is used in human beings without negative side effects another study found that lesions made after conditioning did not Control rats injected with MB showed no changes in motor impair subsequent extinction Interpretation activity or general fearfulness, suggesting that postextinction MB of permanent lesion effects often is hampered by potential administration specifically enhanced memory for extinction. Rats recovery of function or compensation by other structures. There with improved retention of extinction also showed a greater is a pressing need, therefore, for studies that use temporary relative increase in cytochrome oxidase activity in the same inactivation of mPFC via microinfusion of local anesthetics or the prefrontal cortical regions that are activated during extinction GABA antagonist muscimol. Preliminary reports using these techniques are conflicting, showing increased fear augmenting extinction-induced potentiation of mPFC. Note the parallel with electrical stimulation and unit-recording findings Conversely, decreases in cytochrome oxidase activity challenge for future studies will be to identify the factors that in the prefrontal cortex produced by genetic selection of rats that could account for variability between laboratories. These might are predisposed to helplessness results in include contextual variables (e.g., AAA vs. ABB designs), the rats with deficits in fear extinction that simulate the PTSD presence of a competing appetitive instrumental response (such as bar-pressing for food), or the number of extinction trials (e.g.,overtraining-induced masking of effects). Another possible rea-son for negative lesion effects is that the mPFC likely is part of a Relevance to Treatment of Psychiatric Disorders
network of structures that collectively consolidate and expressextinction memory Disconnection of a There is great interest in finding more effective treatments for sufficient number of structures within the network may be a anxiety disorders, which are among the most common mental prerequisite for observing lesion deficits. Finally, recent studies health problems. Extinction deficits have been implicated as a show that mPFC neurons can signal acquisition of fear condi- possible risk factor for the development of PTSD show reduced extinction of aversively conditioned responses separate modules within mPFC for exciting versus inhibiting fear.
and show impairments in afunctional network involving the amygdala and anterior cingu- Enhancing Prefrontal Function Strengthens Extinction
late Brain-imaging studies ofPTSD patients show reduced activity If prefrontal activation is essential for extinction learning, then stimulating prefrontal cortex should strengthen extinction. Support prefrontal cortex, an area that is homologous with extinction- for this idea comes from experiments using electrical stimulation related regions of rodent mPFC These studies and metabolic enhancers. Electrical stimulation was used to mimic also show increased amygdala activity in PTSD patients who are short-latency tone-evoked responses of infralimbic neurons (100 – suggesting a lack of top-down control of the amygdala by Pairing this brief IL stimulation with conditioned tones reduced the structures involved in extinction of fear.
expression of freezing, consistent with feed-forward inhibition of Several recent functional imaging and volumetric studies dem- amygdala output neurons mPFC stimulation also onstrate that extinction activates perigenual and associated regions strengthened extinction learning as evidenced by persistent de- creased fear responses the day after the stimulation, suggesting LTP of extinction-related synapses in mPFC.
coworkers demonstrated that retention of fear extinction was cor- The role of LTP was tested directly by enhancing mPFC related with the thickness of the vmPFC suggest- responsiveness to MD thalamic inputs by applying high-fre- ing that the likelihood of developing PTSD depends on the integrity quency stimulation before extinction training of the prefrontal extinction system. For a complete review of the MD stimulation had no effect on the rate of extinction learning within the training session, supporting lesion and Behavioral therapy for PTSD (exposure therapy) is based unit-recording findings that mPFC is not responsible for short- term extinction memory. One week later, however, retention of Therefore, methods of facilitating extinction and preventing the extinction was markedly improved in potentiated rats, as evi- return of fear may lead to more effective therapeutic interven- denced by low rates of spontaneous recovery of freezing.
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