pavlovian fear conditioning is an extensively studied model for 
 stress and anxiety - like disorders . in this form of 
 learning , an animal is exposed to pairings of a neutral 
 conditioned stimulus ( cs ) such as a light or tone , with a 
 fear - inducing unconditioned stimulus ( us ) , such as a mild foot 
 shock , and comes to exhibit a conditioned fear response ( cr ) to 
 the cs . the cr includes freezing , increased startle reflexes , 
 autonomic changes , analgesia , and behavioral response suppression . experimental extinction is a behavioral technique leading to 
 suppression of the acquired fear , that is , a decrease in the 
 amplitude and frequency of a cr as a function of nonreinforced cs 
 presentations . experimental extinction is assumed to reflect an 
 active learning process that is distinct from acquisition of fear 
 and requires additional training to develop [ 25 ] . while clearly of importance to survival , the expression of 
 emotional associations may become disadvantageous when 
 the conditioned cue ceases to predict the appearance of danger . in 
 that respect , the ability to extinguish emotional responses in the 
 face of a no - longer relevant conditioned cue is an essential part 
 of a healthy emotional memory system , particularly with respect to 
 phobias , panic disorders , and posttraumatic stress disorder [ ptsd ; 
 [ 4 , 68 ] ] . thus , the suppression of the fear response ( i.e. , extinction ) receives increasing attention , since it could become 
 an effective intervention for the treatment of fear - related 
 disorders . for example , even the completely extinguished fear 
 can be recovered spontaneously after the passage of time 
 [ 9 , 10 ] , or be  reinstated  by presentations of the us alone 
 [ 11 , 12 ] , or be renewed by placing the animal in a context 
 different from the one in which it was extinguished . this is congruent with the notion that extinction is a form of 
 relearning ( of a cs - no us or  inhibitory  association ) rather 
 than unlearning ( of the cs - us association ) . accordingly , one suggestion put forward that extinction suppresses the expression of an 
 intact underlying fear response , and extinction memory is labile 
 and weak compared with the fear conditioning itself . hence , 
 understanding the factors that facilitate or impair extinction may 
 aid in accelerating behavior therapy for the treatment of anxiety 
 disorders . despite the efficacy of behavior therapy for human anxiety 
 disorders , extinction - like treatments require repeated cue 
 exposures and are vulnerable to reversal by a number of 
 environmental factors , particularly stress . the effects of stressful experiences on cognition are manifested 
 through the activation of multiple mechanisms and operating over 
 different time courses and have been linked to the onset of a 
 variety of affective disorders . stress can produce deleterious 
 effects on the brain and behavior , and it contributes towards 
 impaired health and an increased susceptibility to disease and 
 mental disorders [ 15 , 16 ] . investigations into the interaction 
 between stressful experiences and memory haves focused mainly on 
 the behavioral and neural mechanisms of memory acquisition ( i.e. , 
 fear conditioning ) , but not on memory extinction , even though 
 extinction is used for the treatment of psychiatric conditions 
 based on learned fear , such as phobias , panic , generalized 
 anxiety , as well as ptsd . extensive evidence indicates that the amygdala and the prefrontal 
 cortex are key structures in the response to stress and its 
 effects on learning and memory . importantly , it has been shown 
 that extinction of fear memory requires plasticity in both the 
 medial prefrontal cortex ( mpfc ) and the basolateral amygdala [ bla ; 
 [ 1719 ] ] . in this review , we will discuss the relevance of 
 the prefrontal cortex - amygdala circuit as a key mechanism for 
 understanding stress - induced alterations occurring during the 
 extinction of fear . there are intricate relationships between stress and cognitive 
 processes . on the one hand , cognitive processes are 
 necessary to cope adequately with a stressor , both actively and 
 passively , in that a subject has to be aware that there is a 
 stressor and at the same time it has to learn that the stressor 
 can be controlled by an appropriate response . adaptation to stress 
 occurs when the acquired response is successful in reducing the 
 impact of the stressor . if not there is strong evidence that stress and stress 
 hormones play an important role in the modulation of cognitive 
 processes . it should be noted that in the fear conditioning 
 paradigm , stress plays a role during conditioning and at least 
 during the first stages of extinction training . thus , we 
 differentiate here between the aversive situation in the learning 
 paradigm itself , for example , exposure to a foot shock , and the 
 effects of additional exposure to an out - of - context stressor on 
 fear extinction . when examining the effects of exposure to an out - of - context 
 stressor on fear extinction , we found that the stressor increased 
 resistance to extinction ( h. reizel , i. akirav , and m. 
 maroun , unpublished observation ; figure 1 ) . 
 specifically , after contextual fear conditioning 
 ( using a us of 3 foot shocks of 0.5 ma each ) , control rats 
 gradually extinguished their freezing ( cr ) when placed in the 
 extinction box ( cs ) for 3 consecutive days , for 5 minutes each 
 time . by contrast , the experimental rats were exposed to the 
 out - of - context stressor on being placed on an elevated 
 platform for 30 minutes immediately after the first extinction 
 session . animals placed on the platform exhibited behavioral 
  freezing ,  that is , immobility for up to 10 minutes , 
 defecation , and urination [ 21 , 22 ] . this stressor was found to 
 increase plasma corticosterone levels by 38% as compared with 
 nave rats   and we have recently found that it impairs long - term potentiation in the ca1 area of the hippocampus 
 and in the bla - medial prefrontal pathway . in the contextual fear extinction experiment , the stressed rats showed 
 increased levels of freezing in the extinction box even 48 hours 
 after a single exposure to the elevated platform . this suggests 
 that exposure to the stressor had the long - term effect of 
 impairing the extinction of fear . we found that exposure to stress had a similar effect on 
 consolidation of the extinction of auditory fear conditioning ( see 
 later , see below , or ahead ) . the impairing effects of the elevated 
 platform on auditory fear extinction also persisted for 48 hours 
 following exposure to the stressor . reported that exposure to three episodes of stress ending 24 hours before fear conditioning significantly 
 attenuated the rate of cued fear extinction relative to 
 nonstressed controls . shumake et al .   showed 
 that rats that were selectively bred for increased susceptibility 
 to learned helplessness show resistance to extinction of 
 conditioned fear . furthermore , kellett and kokkinidis 
  showed that amygdala kindling , which enhances 
 emotionality , impaired the extinction of fear - potentiated startle , 
 and rats showed increased levels of fear . they also found that 
 electrical stimulation of the amygdala restored extinguished fear 
 responses and that the fear reinstatement was specific to the 
 extinction context . in a study with rainbow trout , moreira 
 et al .   compared two lines of fish that exhibit divergent 
 endocrine responsiveness to stressors : the high - responders ( hr ) 
 and low - responders ( lr ; the  stressed  ) . postconditioning , the 
 fish were tested by presentation of the cs at weekly intervals for 
 4 weeks , with no further reinforcement , and the extinction of the 
 cr in the two lines was compared . the number of individuals within 
 each line whose plasma cortisol levels indicated a stress response 
 when exposed to the cs was significantly greater among the lr than 
 hr fish at 14 and 21 days , with no hr fish falling into the 
 stress - response category at 21 days . thus , the stressed fish did 
 not extinguish as well as the hr fish . it is important to understand why exposure to stress impairs 
 extinction learning , and here we put forward four possible 
 explanations . one possibility is that extinction memory is labile 
 and weak compared with fear conditioning itself , and thus exposure 
 to a stressful experience interferes with the process of 
 extinction learning or with the retrieval of information . second , 
 it has been shown that a stressful experience following or 
 preceding a threatening or fear - related learning event enhances 
 retention . however , in extinction , the animals need to 
 learn to suppress their fear response that is associated 
 with the cs . thus , the aversiveness of the stressful experience 
 may counteract the extinguished emotional response . further , it is 
 possible that preexposure to the stressful experience increases 
 resistance to extinction through sensitization , leading to the 
 occurrence of a conditioned fear response even to a less intense 
  reminder  of the original us . thus , retrieval of the cs - us 
 association ( i.e. , acquisition ) overcomes the cs - no us association 
 ( i.e. , extinction ) following the sensitization effect , making 
 extinction more difficult to learn . however , this can hardly 
 explain why exposure to an unrelated stressful experience , such as 
 an elevated platform , should sensitize the animals to respond as 
 if to the us during extinction training . a fourth possibility is 
 that resistance to extinction is not related to sensitization or 
 to the enhancement of an unspecific fear response . accordingly , if 
 the enhanced fear memory is expressed only when stressed animals 
 are exposed to the cs , it may indicate that this response is 
 sustained by associative learning , and thus the increased freezing 
 behavior of stressed animals could be attributable to an 
 attenuation of the extinction process , rather than to enhanced 
 fear acquisition , although the latter remains a possibility 
 . it is usually assumed that stressful life events interfere with 
 our ability to acquire new information . yet , previous exposure to 
 both acute and chronic stressful events can positively affect 
 classical conditioning tasks , including fear conditioning 
 [ 2933 ] . reports to date regarding the effects of stress on fear extinction show that exposure to stress increases resistance to extinction , that is , it impairs extinction 
 acquisition and consolidation , which reduces the extent to which 
 extinction is able to offset a fear response . in contrast , studies 
 addressing the relationship between stress and the acquisition of 
 new fear memories show that exposure to a stressful experience 
 facilitates fear learning , so further enhancing the fear response . for example , previous exposure to a restraint session increased 
 fear conditioning in a contextual fear paradigm . similarly , rau et al .   have shown that preexposure to a stressor of repeated foot shocks enhanced conditional fear 
 responses to a single context - shock pairing . cordero 
 et al .   have shown that a single exposure to an aversive 
 stimulus is sufficient to facilitate context - dependent fear 
 conditioning , and suggested increased glucocorticoid release at 
 training in the mechanisms mediating the memory - facilitating 
 effects induced by prior stressful experiences . these studies 
 corroborate others showing that if an animal learns a stressful 
 task , then the consolidation of this task may be enhanced by 
 stress and that its end product , corticosterone , may be secreted 
 during the task [ 3537 ] . this was found to be the case in 
 a variety of emotionally arousing tasks , such as inhibitory 
 avoidance , spatial learning , discrimination learning , and fear 
 conditioning [ 3844 ] . the basolateral amygdala ( bla ) plays a pivotal role in the 
 consolidation of memories related to fear and emotions , and in the 
 initiation of responses to stressful events [ 37 , 4550 ] . moreover , the bla is significantly involved in both the formation and extinction of fear memory [ 17 , 5154 ] . for example , microinfusions of a protein synthesis inhibitor to the amygdala prevented recall of extinction 
 after 30 minutes , and infusion of n - methyl - d - aspartate ( nmda ) 
 receptor antagonists or mitogen - activated protein kinase 
 inhibitors to the bla prevented across - day extinction of 
 fear - potentiated startle [ 17 , 5456 ] . in another study , bla lesions severely attenuated expression of previously acquired fear memory . also , infusion of an nmda agonist 
 into the amygdala facilitated fear extinction [ 58 , 59 ] . another brain structure that is known to play an important role , 
 not only in the regulation of emotion , but also in the integration 
 of affective states with appropriate modulation of autonomic and 
 neuroendocrine stress regulatory systems , is the medial prefrontal cortex ( mpfc ) . the mpfc provides an interface between 
 limbic and cortical structures   and regulates the 
 stress - induced activity of the hypothalamus - pituitary - adrenal 
 ( hpa ) axis [ 62 , 63 ] . specifically , lesions or inhibition of protein synthesis in the 
 infralimbic part of the medial pfc impair recall of extinction of 
 conditioned fear [ 18 , 19 , 64 , 65 ] . furthermore , mpfc stimulation that mimics extinction - induced tone responses reduces conditioned fear [ 66 , 67 ] , and stimulating the mediodorsal thalamic inputs 
 to the mpfc is associated with extinction maintenance 
 [ 68 , 69 ] . moreover , functional imaging studies in human 
 subjects indicate that the mpfc is engaged during extinction 
  and that subjects with ptsd have reduced mpfc activity during trauma recall . have shown that one week of restrained stress had the effect of impairing recall of extinction of conditioned fear , and suggested that this is due to deficits in the mpfc caused by 
 exposure to stress . recently , it has been reported that stress 
 exposure that impairs fear extinction also caused retraction of 
 terminal branches of apical dendrites of infralimbic neurons 
 . in addition to evidence indicating that extinction of fear memory 
 requires plasticity in both the mpfc and the bla [ 1719 ] , recent studies further point to a dysfunctional interaction between the prefrontal cortex and the amygdala in the failure to 
 extinguish conditioned fear . these studies indicate that the mpfc 
 has a function in the inhibition of emotions through its projections to the amygdala   and are in line with pavlov 's   view that extinction learning involves 
 inhibitory cortical circuits that reduce the cs - evoked conditioned 
 response . the glutamatergic efferents from the mpfc synapse on amygdala 
 gamma - aminobutyric acid ( gaba)ergic neurons , and through this , may provide important inhibitory input to the amygdala . of 
 particular interest is the projection from the infralimbic region 
 of the pfc ( which , together with the prelimbic cortex , comprises 
 the ventromedial pfc ) to the capsular division of the central 
 nucleus of the amygdala . the capsular division of the 
 central nucleus contains gaba - ergic intercalated cells that have 
 been shown to exert powerful inhibitory control over central 
 nucleus neurons that project out of the amygdala [ 7779 ] . infralimbic input to intercalated cells could be a pathway by 
 which infralimbic tone responses inhibit the expression of 
 conditioned fear ( e.g. , reduce freezing ) . the anatomical data described for the interaction between these 
 two structures pinpoint the crucial role the neurotransmission of 
 gaba may play in the extinction of fear . indeed , a substantial 
 number of studies have demonstrated that the bla contains a 
 powerful inhibitory circuit that uses gaba as a neurotransmitter 
 [ 8183 ] . moreover , the bla has larger amounts of 
 benzodiazepine / gabaa receptors than any other amygdala 
 nucleus , explaining why the infusion of benzodiazepines 
 or gabaa agonists into the bla reduces fear 
 conditioning and anxiety [ 8588 ] . coincidently , local 
 blockade of these receptors attenuates the anxiolytic influence of 
 systemic benzodiazepines . recently , rodrguez manzanares et al . have shown that stress attenuates 
 inhibitory gaba - ergic control in the bla , leading to neuronal 
 hyperexcitability and increased plasticity that facilitates fear 
 learning . based on these data , it can be concluded that gaba - ergic 
 mechanisms in the amygdala play a major role in controlling the 
 emotional consequences of stress , and may thus affect extinction 
 of fear . benzodiazepines have long been used to treat anxiety and are 
 particularly appropriate in short - term treatment situations 
 . direct modulation of gaba - ergic neurons , through the 
 benzodiazepine - binding site , down regulates memory storage 
 processes and specifically affects learned fear responses . on the 
 other hand , benzodiazepine release could be modulated by the 
 anxiety and/or stress associated with different types of learning 
 . much research is directed at exploring the involvement of gaba in 
 inhibiting learned fear responses . although several studies 
 support the central role gaba neurotransmission plays in 
 extinction , there are different reports regarding whether this 
 role is to facilitate or impair extinction [ 26 , 9195 ] . using direct modulation of gaba - ergic neurons , it has been shown that the benzodiazepine inverse agonist fg7142 , which attenuates the effect of gaba at its receptor , 
 retards extinction of conditioned fear [ 91 , 96 ] . likewise , 
 mccabe et al . have shown that benzodiazepine agonists administered to mice following training significantly facilitated 
 extinction during a food - reinforced lever - press procedure . potentiation of gaba by the benzodiazepine agonist 
 chlordiazepoxide administered prior to extinction sessions 
 facilitated extinction in a paradigm of operant responding for 
 food reinforcement . by contrast , systemic administration of the gabaa antagonist picrotoxin , after the 
 extinction of inhibitory avoidance learning , enhanced extinction 
 retention during testing , and the gabaa - positive allosteric modulator diazepam impaired extinction retention when administered before extinction in a shuttle avoidance task . there are also a number of ways of modulating gaba - ergic functions 
 indirectly . for example , cannabinoid ( cb1 ) receptors and 
 gastrin - releasing peptide receptors are both located on 
 gaba - containing interneurons . endogenous cannabinoids , acting at 
 the cb1 receptor , facilitated the extinction of aversive memories 
 , and blocking the action of gastrin - releasing peptide , by genetically removing its receptor , retards extinction of 
 learned fear responses . recently , azad et al .   have shown that cb1 receptors reduce gaba - ergic synaptic transmission in the amygdale , and consequently facilitate 
 extinction of aversive memories . .   showed that gephyrin mrna and protein levels in the bla significantly 
 increased after fear extinction training , suggesting that the 
 modulation of gephyrin and gabaa receptor expression 
 in the bla may play a role in the experience - dependent plasticity 
 underlying extinction . using a low dose of the gabaa agonist muscimol , we 
 recently found   that muscimol infused to the infralimbic 
 area before extinction training ( see figure 2(a ) ) 
 resulted in long - term facilitation of extinction . by contrast , 
 where infusion of muscimol to the infralimbic area followed 
 extinction training , no such effect was observed , regardless of 
 the length of the extinction training period ( 5 or 15 trials ; data 
 not shown ) . however , infusion of muscimol to the bla following a 
 short ( 5-trial ) extinction session facilitated extinction for at 
 least 48 hours post - drug - infusion ( see figure 2(b ) ) . the differences between the temporal parameters of the effects of 
 muscimol in the infralimbic cortex compared to the bla suggest 
 differential involvement of these structures in long - term 
 extinction of fear memory . we propose that gabaa 
 neurotransmission in the infralimbic cortex plays a facilitatory 
 role in triggering the onset of fear extinction and its 
 maintenance , whereas in the bla , gabaa 
 neurotransmission facilitates extinction consolidation . overall , the data suggest that manipulation of gaba transmission 
 may have very different effects depending on whether it is 
 administered pre- or postextinction training or before a retention 
 test , and depending also on the behavioral paradigm used . while examining the involvement of gaba in the effects of stress 
 on fear extinction , we found that systemic administration of the 
 benzodiazepine agonist diazepam reversed the resistance to 
 extinction induced by exposure to an out - of - context stressor ( see 
 figure 3 ) . after classical auditory fear conditioning 
 ( 3 cs - us pairings of a tone with a foot shock of 0.5 ma ) , 
 control rats that were exposed to the tone without shock gradually 
 extinguished their freezing ( cr ) in response to the tone during 
 extinction training . at the end of the third extinction session rats that were exposed to 
 an out - of - context stressor ( i.e. , animals that were placed on an 
 elevated platform for 30 minutes ) before the first extinction 
 training session showed increased levels of freezing in response 
 to the tone even 48 hours after the stressor ( i.e. , showed 
 resistance to extinction ) . a single injection of diazepam 
 ( 2 mg / kg , ip ) 20 minutes before exposure to the out - of - context 
 stressor significantly facilitated extinction compared with the 
 control and stress groups as manifested by reduced freezing levels 
 in the first extinction session . on the second and third sessions 
 of extinction training , the response of the diazepam - stress group was no different to that of the control group , with the former group also exhibiting significantly 
 less freezing than the stressed rats that had not first received 
 diazepam . hence , treatment with diazepam reversed the impairing effect of exposure to stress on fear extinction . further experiments to elucidate the possible role gaba plays in 
 the bla and the mpfc in preventing stress - associated impairments 
 of extinction are required . a problem associated with the use of anxiolytic and anxiogenic 
 compounds in studies of extinction , however , is the possibility of 
 state dependency as opposed to a true effect on the suppression of 
 the learning process . that is , it is possible that a 
 drug administered before or immediately following extinction 
 produces an internal state , or drug context , that is discriminable 
 to the animal . however , in our experiment , the effect was probably not due to state dependence because the stressed 
 animals that were treated with diazepam showed less freezing 
 ( i.e. , more extinction ) than the stressed animals that were 
 treated with saline , even 24 and 48 hours after a single 
 injection . to conclude , the present results demonstrate that pretreatment 
 with the benzodiazepine tranquilizer diazepam reverses the 
 cr - enhancing effects of the elevated platform experience . these 
 findings suggest that benzodiazepines may prevent the augmentation 
 of the trauma - related symptoms seen in phobia and ptsd patients 
 that are caused by exposure to a stressful experience . recent observations provide direct physiological support that the 
 mpfc reduces fear responses by reducing amygdala output 
 [ 66 , 103 , 104 ] . for example , milad and quirk 
  found that stimulation of the mpfc decreases 
 the responsiveness of central amygdala neurons that regularly fire 
 in response to the cs only when animals are recalling extinction 
 of a fear task learned using that cs . additionally , morgan 
 et al .   reported that rats with mpfc lesions had an 
 increased resistance to extinction . they proposed that connections 
 between the mpfc and amygdala normally allow the organism to 
 adjust its emotional behavior when environmental circumstances 
 change , and that some alteration in this circuitry , causing a loss 
 of prefrontal control of the amygdala , might underlie the 
 inability of persons with anxiety disorders to regulate their 
 emotions . if the mpfc normally inhibits the amygdala as an active component 
 of extinction of fear conditioning , then when the mpfc is 
 inhibited or suppressed , emotional associations mediated by the 
 amygdala may be not inhibited during nonreinforcement . as a 
 result , conditioned responding may be prolonged over time 
 . a combination of changes throughout this circuit is important in 
 generating stress - induced changes in emotionality . the mpfc may 
 have a regulatory role in stress - induced fear and anxiety - like 
 behaviors through inhibitory effects on amygdala output and 
 processing . indeed , extensive evidence supports the notion that the bla is a site of plasticity for fear conditioning 
 [ 104 , 106 ] , and that the bla is extensively connected with the 
 central nucleus of the amygdala [ 107 , 108 ] . in turn , the 
 central nucleus projects to the paraventricular nucleus of the 
 hypothalamus , thereby providing the most likely route 
 for any bla - dependent effects on stress - induced hpa output . we would like to take this a step further , and suggest a possible 
 mode of action for the mpfc - amygdala circuit in fear extinction 
 under stressful conditions . accordingly , under normal conditions 
 of fear suppression , the mpfc is activated and inhibits amygdala 
 output . this dominance of the mpfc results in normal suppression 
 of fear , and in consequence promotes extinction of fear . however , 
 exposure to a stressful experience may reduce medial pfc 
 inhibition of the amygdala , and as a result the amygdala takes 
 control to assure defensive behaviors and becomes dominant . the 
 expected consequence is interference in the suppression of the 
 fear response , that is , impaired extinction learning . therefore , 
 exposure to a stressful experience would result in reduced mpfc 
 activity leading to resistance to extinction and inappropriate and 
 exaggerated fear responses , as seen in ptsd patients . indeed , 
 abnormally low pfc activity together with abnormally high amygdala 
 activity were found in ptsd patients , when reexposed to 
 traumatic reminders . accordingly , deficits in 
 extinction of conditioned fear as a result of exposure to a 
 stressful experience are proposed to contribute to the sustained 
 anxiety responses seen in ptsd . figure 4 schematically summarizes this idea and shows 
 that during extinction of fear , the mpfc is activated and acts to 
 inhibit the amygdala in order to reduce fear , resulting in less 
 freezing ( i.e. , extinction ) . however , exposure to stress at a 
 critical time with respect to extinction learning activates the 
 amygdala to increase fear and the result is more freezing ( i.e. , 
 resistance to extinction ) . therefore , according to our proposed 
 model , the stressor shifts the dominance from the mpfc to the 
 amygdala and , as a consequence , extinction of fear is impaired . our model is consistent with the data shown in 
 figure 1 , which demonstrate that exposure to a 
 stressful experience results in resistance to extinction in the 
 stressed group compared with the nonstressed group . whether this 
 effect is due to a reduction in mpfc modulation of amygdala 
 output , and to the involvement of gaba - based mechanisms acting on 
 the pfc - amygdala circuit , still needs to be examined . our model is 
 also consistent with the suggestion put forward by quirk and 
 gehlert   that deficient inhibitory tone in the 
 amygdala due to decreased inhibition from the prefrontal cortex 
 could lead to overexpression of conditioned responses , producing 
 pathological states such as anxiety disorders and drug - seeking 
 behavior . pathological fear and anxiety , such as that exhibited by ptsd 
 sufferers , may be the manifestation of abnormal modulations in the 
 activity of the amygdala and the mpfc , and in their interaction . ptsd is defined as symptoms of reexperiencing the trauma , 
 avoidance of associated stimuli and hyperarousal symptoms , 
 suggesting a heightened fear response , and it has been proposed 
 that ptsd symptoms reflect amygdala hyperresponsivity to 
 fear - related stimuli , with a concomitant lack of  top - down  
 prefrontal inhibition . this proposal is supported by neuroimaging 
 studies of ptsd patients , which observed abnormal reductions in 
 mpfc activity [ 71 , 112 , 113 ] , as well as enhanced and 
 distinctive amygdala engagement [ 114 , 115 ] , particularly for combat ptsd veterans . in line with this , fmri and pet 
 data have shown significant inverse correlations between the 
 functional activity of the mpfc and the amygdala [ 116 , 117 ] . collectively , these data provide strong support for the hypothesis 
 that ptsd is characterized by a failure of the mpfc to 
 sufficiently inhibit the amygdala . there is clinical interest in the effects of stress on fear 
 extinction learning as a model for the mechanisms operating in 
 ptsd , as well as interest in means to improve therapeutic outcomes 
 following fear - extinction - based strategies . future therapies aimed 
 at increasing the inhibitory tone in the amygdala , either locally 
 or via the prefrontal cortex , may accelerate extinction and may 
 help in the treatment of anxiety disorders .
stress exposure , depending on its intensity and duration , affects cognition and learning in an adaptive or maladaptive manner . 
 studies addressing the effects of stress on cognitive processes have mainly focused on conditioned fear , since it is suggested that fear - motivated learning lies at the root of affective and anxiety disorders . 
 inhibition of fear - motivated response can be accomplished by experimental extinction of the fearful response to the fear - inducing stimulus . 
 converging evidence indicates that extinction of fear memory requires plasticity in both the medial prefrontal cortex and the amygdala . 
 these brain areas are also deeply involved in mediating the effects of exposure to stress on memory . 
 moreover , extensive evidence indicates that gamma - aminobutyric acid ( gaba ) transmission plays a primary role in the modulation of behavioral sequelae resulting from a stressful experience , and may also partially mediate inhibitory learning during extinction . in this review , 
 we present evidence that exposure to a stressful experience may impair fear extinction   and the possible involvement of the gaba system . 
 impairment of fear extinction learning is particularly important as it may predispose some individuals to the development of posttraumatic stress disorder . 
 we further discuss a possible dysfunction in the medial prefrontal cortex - amygdala circuit following a stressful experience that may explain the impaired extinction caused by exposure to a stressor .