Alteration of synaptic transmission in the hippocampal‐mPFC pathway during extinction trials of context‐dependent fear memory in juvenile rat stress models

The medial prefrontal cortex (mPFC) has been proposed to be essential for extinction of fear memory, but its neural mechanism has been poorly understood. The present study examined whether synaptic transmission in the hippocampal‐mPFC pathway is related to extinction of context‐dependent fear memory in freely moving rats using electrophysiological approaches combined with behavioral analysis. Population spike amplitude in the mPFC was decreased during the first extinction trial by exposure to contextual fear conditioning. This synaptic inhibition was reversed by repeated extinction trials, accompanied by decreases in fear‐related freezing behavior. These results suggest that alteration of synaptic transmission in the hippocampal‐mPFC pathway is associated with the extinction processes of context‐dependent fear memory. Further experiments were performed to elucidate whether early postnatal stress alters the synaptic response in the mPFC during extinction trials using a juvenile stress model, based on our previous findings that early postnatal stress affects the behavioral response to emotional stress. Adult rats that previously were exposed to five footshocks (FS) (shock intensity, 0.5 mA; intershock interval, 28 seconds; shock duration, 2 seconds) at postnatal day 21 to 25 (week 3; 3W‐FS) exhibited impaired reversal of both inhibitory synaptic transmission and freezing behavior induced by repeated extinction trials. The neuronal and behavioral deficits observed in the 3W‐FS group were prevented by pretreatment with the serotonin_1A receptor agonist tandospirone (1 mg/kg, i.p.). These results indicate the possiblity that aversive stress exposure during the third postnatal week impaired extinction processes of context‐dependent fear memory. The deficits in extinction observed in the 3W‐FS group might be attributable to dysfunction of hippocampal‐mPFC neural circuits involving 5‐HT_1A receptor mechanisms. Synapse 63:805–813, 2009. © 2009 Wiley‐Liss, Inc.     

Prefrontal infusion of PD098059 immediately after fear extinction training blocks extinction-associated prefrontal synaptic plasticity and decreases prefrontal ERK2 phosphorylation

A previous study has demonstrated that disruption of fear extinction-induced long-term potentiation (LTP) in the medial prefrontal cortex (mPFC) is associated with the return of fear responding. Given that immediate posttraining infusion of PD098059, an inhibitor of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) cascade, into the mPFC also promotes recovery of fear, we investigated whether impairment of mPFC ERK/MAPK cascade also interferes with development of extinction-related LTP in the mPFC in rats. In Experiment 1, extinction training consisting of repetitive presentations of a tone previously associated with eyelid-shock application induced LTP-like changes at hippocampal inputs to the mPFC that were evident for approximately 2 h following fear extinction. Infusion of PD098059 into the mPFC immediately after extinction training abolished training-related prefrontal LTP and impaired retention of extinction memory tested on the following day. In Experiment 2, immunoblotting assays revealed that posttraining infusion of PD098059 into the mPFC produced a significant reduction of mPFC ERK2. These data, along with previous findings, suggest that low levels of ERK2 phosphorylation in the mPFC may interfere with mechanisms of retention of extinction training. The involvement of mPFC LTP in fear extinction is discussed.     

Lack of experience‐dependent intrinsic plasticity in the adolescent infralimbic medial prefrontal cortex

Fear extinction, an inhibitory learning that suppresses a previously learned fear memory, is diminished during adolescence. Earlier studies have shown that this suppressed fear extinction during adolescence involves an altered glutamatergic plasticity in infralimbic medial prefrontal cortical (IL‐mPFC) pyramidal neurons. However, it is unclear whether the excitability of IL‐mPFC pyramidal neurons plays a role in this development‐dependent suppression of fear extinction. Therefore, we examined whether fear conditioning and extinction affect the active and passive membrane properties of IL‐mPFC layer 5 pyramidal neurons in preadolescent, adolescent and adult mice. Both preadolescent and adult mice exhibited a bidirectional modulation of the excitability of IL‐mPFC layer 5 pyramidal neurons following fear conditioning and extinction, i.e., fear conditioning reduced membrane excitability, whereas fear extinction reversed this effect. However, the fear conditioning‐induced suppression of excitability was not reversed in adolescent mice following fear extinction training. Neither fear conditioning nor extinction affected GABAergic transmission in IL‐mPFC layer 5 pyramidal neurons, suggesting that GABAergic transmission did not play a role in experience‐dependent modulation of neuronal excitability. Our results suggest that the extinction‐specific modulation of excitability is impaired during adolescence.     

Fear learning induces persistent facilitation of amygdala synaptic transmission

In the maintenance phase of fear memory, synaptic transmission is potentiated and the stimulus requirements and signalling mechanisms are altered for long-term potentiation (LTP) in the cortico-lateral amygdala (LA) pathway. These findings link amygdala synaptic plasticity to the coding of fear memories. Behavioural experiments suggest that the amygdala serves to store long-term fear memories. Here we provide electrophysiological evidence showing that synaptic alterations in rats induced by fear conditioning are evident in vitro 10 days after fear conditioning. We show that synaptic transmission was facilitated and that high-frequency stimulation dependent LTP (HFS-LTP) of the cortico-lateral amygdala pathway remained attenuated 10 days following fear conditioning. Additionally, we found that the low-frequency stimulation dependent LTP (LFS-LTP) measured 24 h after fear conditioning was absent 10 days post-training. The persistent facilitation of synaptic transmission and occlusion of HFS-LTP suggests that, unlike hippocampal coding of contextual fear memory, the cortico-lateral amygdala synapse is involved in the storage of long-term fear memories. However, the absence of LFS-LTP 10 days following fear conditioning suggests that amygdala physiology 1 day following fear learning may reflect a dynamic state during memory stabilization that is inactive during the long-term storage of fear memory. Results from these experiments have significant implications regarding the locus of storage for maladaptive fear memories and the synaptic alterations induced by these memories.     

Behavioral and paired-pulse facilitation analyses of long-lasting depression at excitatory synapses in the medial prefrontal cortex in mice

Accumulative evidence indicates that acute (before extinction) and long-lasting (during extinction) depression can occur at excitatory synapses in mouse medial prefrontal cortex (mPFC) during re-exposure to a tone (conditioned stimulus: CS), previously paired with footshock (unconditioned stimulus: US). As recently shown, the long-term depression (LTD)-like plasticity in the mPFC does not interfere with extinction of CS-evoked freezing but predicts spontaneous recovery of this fear response. Here, the objectives were to investigate: (i). whether a resistance to extinction without any prefrontal acute synaptic plasticity could produce LTD-like changes, and (ii). by the use of paired-pulse facilitation (PPF) analyses, whether pre- or post-synaptic mechanisms were involved in this LTD phenomenon. Preliminary analyses indicated that levels of acute depression did not correlate with the degree of fear acquisition (effects of number of CS-US pairings). As a consequence, mice conditioned with 2CS+ or 2CS+/2CS- (partial reinforcement of the CS known to induce resistance to extinction) exhibited CS-associated freezing without any acute synaptic depression in the mPFC. However, during further CS-alone presentations, the 2CS+/2CS- group developed LTD-like changes that accompanied their resistance to extinguish freezing to the CS. In contrast, the 2CS+ group normally extinguished their conditioned freezing with synaptic transmission remaining at baseline levels. PPF analyses revealed that facilitation was unchanged following prefrontal LTD. These data, combined with our previous findings, (i). support a critical involvement of prefrontal LTD-like changes in spontaneous recovery of fear responses, and (ii). suggest a post-synaptic site for these changes.     

Mouse models of impaired fear memory exhibit deficits in amygdalar LTP

Inbred mouse strains have different genetic backgrounds that can result in impairments of synaptic plasticity and memory. They are valuable models for probing the mechanisms of memory impairments. We examined fear memory in several inbred strains, along with synaptic plasticity that may underlie fear memory. Long-term potentiation (LTP) is a form of activity-dependent synaptic plasticity that is a candidate cellular mechanism for some forms of learning and memory. Strains with impaired contextual or cued fear memory may have selective LTP deficits in different hippocampal subregions, or in the amygdala. We measured fear memory and its extinction in five inbred strains: C57BL/6NCrlBR (B6), A/J, BALB/cByJ (BALB), C57BL/10J (B10), and SM/J (SM). We also measured LTP in the basolateral amygdala and in the hippocampal Schaeffer collateral-commissural (SC) and medial perforant pathways (MPP). All strains exhibited intact contextual fear memory 24 h post-training, but cued fear memory was impaired in strains A/J, BALB, and SM. At 1 h post-training, both contextual and cued fear memory deficits were more widespread: all strains except for B6 and B10 showed impairments of both types of memory. Contextual fear extinction was impaired in BALB and SM. We found that amygdalar LTP was reduced in strains A/J and BALB, but SC LTP was intact in all strains (except for a selective multi-train LTP impairment in BALB). MPPLTP was similar in all five strains. Thus, reduced amygdalar LTP is correlated with impaired cued fear memory in strains A/J and BALB. Also, hippocampal SC LTP is more strongly correlated with 24-h (long-term) than with 1-h (short-term) contextual fear memory. In this first conjoint study of amygdala-dependent memory and amygdalar LTP in inbred mice, we identified specific hippocampal and amygdalar LTP deficits that correlate with fear memory impairments. These deficits should be considered when selecting inbred strains for genetic modification.     

Active Transition of Fear Memory Phase from Reconsolidation to Extinction through ERK-Mediated Prevention of Reconsolidation

The retrieval of fear memory induces two opposite memory process, i.e., reconsolidation and extinction. Brief retrieval induces reconsolidation to maintain or enhance fear memory, while prolonged retrieval extinguishes this memory. Although the mechanisms of reconsolidation and extinction have been investigated, it remains unknown how fear memory phases are switched from reconsolidation to extinction during memory retrieval. Here, we show that an extracellular signal-regulated kinase (ERK)-dependent memory transition process after retrieval regulates the switch of memory phases from reconsolidation to extinction by preventing induction of reconsolidation in an inhibitory avoidance (IA) task in male mice. First, the transition memory phase, which cancels the induction of reconsolidation, but is insufficient for the acquisition of extinction, was identified after reconsolidation, but before extinction phases. Second, the reconsolidation, transition, and extinction phases after memory retrieval showed distinct molecular and cellular signatures through cAMP responsive element binding protein (CREB) and ERK phosphorylation in the amygdala, hippocampus, and medial prefrontal cortex (mPFC). The reconsolidation phase showed increased CREB phosphorylation, while the extinction phase displayed several neural populations with various combinations of CREB and/or ERK phosphorylation, in these brain regions. Interestingly, the three memory phases, including the transition phase, showed transient ERK activation immediately after retrieval. Most importantly, the blockade of ERK in the amygdala, hippocampus, or mPFC at the transition memory phase disinhibited reconsolidation-induced enhancement of IA memory. These observations suggest that the ERK-signaling pathway actively regulates the transition of memory phase from reconsolidation to extinction and this process functions as a switch that cancels reconsolidation of fear memory.SIGNIFICANCE STATEMENT Retrieval of fear memory induces two opposite memory process; reconsolidation and extinction. Reconsolidation maintains/enhances fear memory, while extinction weakens fear memory. It remains unknown how memory phases are switched from reconsolidation to extinction during retrieval. Here, we identified an active memory transition process functioning as a switch that inhibits reconsolidation. This memory transition phase showed a transient increase of extracellular signal-regulated kinase (ERK) phosphorylation in the amygdala, hippocampus and medial prefrontal cortex (mPFC). Interestingly, inhibition of ERK in these regions at the transition phase disinhibited the reconsolidation-mediated enhancement of inhibitory avoidance (IA) memory. These findings suggest that the transition memory process actively regulates the switch of fear memory phases of fear memory by preventing induction of reconsolidation through the activation of the ERK-signaling pathway.     

Early postnatal stress alters extracellular signal-regulated kinase signaling in the corticolimbic system modulating emotional circuitry in adult rats

The present study elucidated whether early life stress alters the extracellular signal-regulated kinase (ERK) pathway that underlies fear retrieval and fear extinction based on a contextual fear conditioning paradigm, using a juvenile stress model. Levels of phospho-ERK (pERK), the active form of ERK, increased after fear retrieval in the hippocampal CA1 region but not in the medial prefrontal cortex (mPFC). ERK activation in the CA1 following fear retrieval was not observed in adult rats who received aversive footshock (FS) stimuli during the second postnatal period (2wFS), which exhibited low levels of freezing. In fear extinction, pERK levels in the CA1 were increased by repeated extinction trials, but they were not altered after extinction retrieval. In contrast, pERK levels in the mPFC did not change during extinction training, but were enhanced after extinction retrieval. These findings were compatible in part with electrophysiological data showing that synaptic transmission in the CA1 field and mPFC was enhanced during extinction training and extinction retrieval, respectively. ERK activation in the CA1 and mPFC associated with extinction processes did not occur in rats that received FS stimuli during the third postnatal period (3wFS), which exhibited sustained freezing behavior. The repressed ERK signaling and extinction deficit observed in the 3wFS group were ameliorated by treatment with the partial N-methyl-D-aspartate receptor agonist D-cycloserine. These findings suggest that early postnatal stress induced the downregulation of ERK signaling in distinct brain regions through region-specific regulation, which may lead to increased behavioral abnormalities or emotional vulnerabilities in adulthood.     

Memory consolidation of fear conditioning: Bi-stable amygdala connectivity with dorsal anterior cingulate and medial prefrontal cortex

Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms of fear acquisition and extinction. However, the neural mechanism of memory consolidation of fear conditioning is not well understood. To address this question, we measured brain activity and the changes in functional connectivity following fear acquisition using resting-state functional magnetic resonance imaging. The amygdala–dorsal anterior cingulate cortex (dACC) and hippocampus–insula functional connectivity were enhanced, whereas the amygdala–medial prefrontal cortex (mPFC) functional coupling was decreased during fear memory consolidation. Furthermore, the amygdala–mPFC functional connectivity was negatively correlated with the subjective fear ratings. These findings suggest the amygdala functional connectivity with dACC and mPFC may play an important role in memory consolidation of fear conditioning. The change of amygdala-mPFC functional connectivity could predict the subjective fear. Accordingly, this study provides a new perspective for understanding fear memory consolidation.     

Spontaneous recovery of fear differs among early – late adolescent and adult male mice

Adolescence is a vulnerable period for developing anxiety-related mental disorders such as post-traumatic stress disorder (PTSD), which requires a long-term course of therapy when a traumatic event has been experienced during childhood. However, the biological mechanism underlying these age-dependent characteristics remains unclear. In the present study, we used early adolescent, late adolescent and adult (4-, 8-, and 15-week old) male mice to examine age differences in fear memory, fear extinction, and spontaneous recovery of fear. We also measured the activation of extracellular signal-regulated kinase (ERK) 2 in the dorsal hippocampus (dHip) and the basolateral amygdala (BLA) following a spontaneous recovery test. Our major findings were as follows: (1) early adolescent and adult mice did not recover the fear response; only late adolescent mice recovered the fear response. (2) The ERK2 in the dHip was more activated after the spontaneous recovery test in late adolescent mice than in adult mice, and the ERK2 in the BLA was more activated after the spontaneous recovery test in adult mice than in late adolescent mice. These results suggest that there exists a unique period in which spontaneous recovery occurs and that these late adolescent behavioral signatures may be related to alteration in the ERK2 phosphorylation in the dHip and BLA.     

Role of the hippocampus in contextual modulation of fear extinction

Fear extinction is an important form of emotional learning, and affects neural plasticity. Cue fear extinction is a classical form of inhibitory learning that can be used as an exposure-based treatment for phobia, because the long-term extinction memory produced during cue fear extinction can limit the over-expression of fear. The expression of this inhibitory memory partly depends on the context in which the extinction learning occurs. Studies such as transient inhibition, electrophysiology and brain imaging have proved that the hippocampus - an important structure in the limbic system - facilitates memory retrieval by contextual cues. Mediation of the hippocampus-medial prefrontal lobe circuit may be the neurobiological basis of this process. This article has reviewed the role of the hippocampus in the learning and retrieval of fear extinction. Contextual modulation of fear extinction may rely on a neural network consisting of the hippocampus, the medial prefrontal cortex and the amygdala.     

NMDA receptor antagonism in the basolateral but not central amygdala blocks the extinction of Pavlovian fear conditioning in rats

Glutamate receptors in the basolateral complex of the amygdala (BLA) are essential for the acquisition, expression and extinction of Pavlovian fear conditioning in rats. Recent work has revealed that glutamate receptors in the central nucleus of the amygdala (CEA) are also involved in the acquisition of conditional fear, but it is not known whether they play a role in fear extinction. Here we examine this issue by infusing glutamate receptor antagonists into the BLA or CEA prior to the extinction of fear to an auditory conditioned stimulus (CS) in rats. Infusion of the α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate (AMPA) receptor antagonist, 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo[f]quinoxaline‐2,3‐dione (NBQX), into either the CEA or BLA impaired the expression of conditioned freezing to the auditory CS, but did not impair the formation of a long‐term extinction memory to that CS. In contrast, infusion of the N‐methyl‐d ‐aspartate (NMDA) receptor antagonist, d,l ‐2‐amino‐5‐phosphonopentanoic acid (APV), into the amygdala, spared the expression of fear to the CS during extinction training, but impaired the acquisition of a long‐term extinction memory. Importantly, only APV infusions into the BLA impaired extinction memory. These results reveal that AMPA and NMDA receptors within the amygdala make dissociable contributions to the expression and extinction of conditioned fear, respectively. Moreover, they indicate that NMDA receptor‐dependent processes involved in extinction learning are localized to the BLA. Together with previous work, these results reveal that NMDA receptors in the CEA have a selective role acquisition of fear memory.     

Extinction of auditory fear conditioning requires MAPK/ERK activation in the basolateral amygdala

Whereas the neuronal substrates underlying the acquisition of auditory fear conditioning have been widely studied, the substrates and mechanisms mediating the acquisition of fear extinction remain largely elusive. Previous reports indicate that consolidation of fear extinction depends on the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) signalling pathway and on protein synthesis in the medial prefrontal cortex (mPFC). Based on experiments using the fear-potentiated startle paradigm suggesting a role for neuronal plasticity in the basolateral amygdala (BLA) during fear extinction, we directly addressed whether MAPK/ERK signalling in the basolateral amygdala is necessary for the acquisition of fear extinction using conditioned freezing as a read-out. First, we investigated the regional and temporal pattern of MAPK/ERK activation in the BLA following extinction learning in C57Bl/6J mice. Our results indicate that acquisition of extinction is associated with an increase of phosphorylated MAPK/ERK in the BLA. Moreover, we found that inhibition of the MAPK/ERK signalling pathway by intrabasolateral amygdala infusion of the MEK inhibitor, U0126, completely blocks acquisition of extinction. Thus, our results indicate that the MAPK/ERK signalling pathway is required for extinction of auditory fear conditioning in the BLA, and support a role for neuronal plasticity in the BLA during the acquisition of fear extinction.     

Extinction is not a sufficient condition to prevent fear memories from undergoing reconsolidation in the basolateral amygdala

Consolidated memories when reactivated may return to a state that requires protein synthesis in order to be restabilized (reconsolidation). It has been shown in a variety of systems that if reactivation induces significant extinction then extinction is the protein synthesis dependent memory state, rather than reconsolidation. Thus, extinction consolidation may prevent the memory from undergoing reconsolidation. We investigated whether such an interaction also exists between extinction and reconsolidation of fear memories within the amygdala, by using a within subjects experimental design. We found that inhibition of protein synthesis in the basolateral amygdala (BLA) impaired reconsolidation for both the briefly reactivated and extinguished fear memories suggesting that extinction is not a sufficient condition to prevent induction of reconsolidation in the amygdala. These findings demonstrate that extinction consolidation does not always interact with reconsolidation. Therefore, under these conditions, extinction is not a boundary condition on reconsolidation of fear memories in the basolateral amygdala.     

Fear memories induce a switch in stimulus response and signaling mechanisms for long-term potentiation in the lateral amygdala

Activity-dependent modification of synapses is fundamental for information storage in the brain and underlies behavioral learning. Fear conditioning is a model of emotional memory and anxiety that is expressed as an enduring increase in synaptic strength in the lateral amygdala (LA). Here we analysed synaptic plasticity in the rat cortico-LA pathway during maintenance of fear memory. We show for the first time that the stimulus frequency for synaptic potentiation is switched during maintenance of fear memory, and the underlying signaling mechanisms are altered in the cortico-LA pathway. In slices from fear-conditioned animals, high-frequency stimulation-induced (HFS) long-term potentiation (LTP) was attenuated, whereas low-frequency stimulation (LFS) elicited a long-lasting potentiation. HFS generates robust LTP that is dependent on N-methyl-d-aspartate receptor (NMDAR) and L-type voltage-gated calcium channel (VGCC) activation in control animals, whereas in fear-conditioned animals HFS LTP is NMDAR- and VGCC-independent. LFS-LTP is partially NMDAR-dependent, but VGCCs are necessary for potentiation in fear memory. Collectively, these results show that during maintenance of fear memory the stimulus requirements for amygdala afferents and critical signaling mechanisms for amygdala synaptic potentiation are altered, suggesting that cue-engaged synaptic mechanisms in the amygdala are dramatically affected as a result of emotional learning.     

Fear conditioning enhances spontaneous AMPA receptor-mediated synaptic transmission in mouse hippocampal CA1 area

AMPA receptor-mediated synaptic modifications in the amygdala have been reported to sustain cued fear conditioning. However, the hippocampal formation is also critically involved in fear learning. Therefore, we examined whether fear conditioning is also accompanied by changes in AMPA receptor-mediated synaptic transmission in the hippocampus. We focused on spontaneous miniature excitatory post-synaptic currents (mEPSCs). Young adult mice were trained using tone/footshock pairings and contextual/cued memories were tested 3–4 h and 1 day later. We found that the mEPSC frequency was significantly enhanced when recorded 3 h, but not 24 h, after fear conditioning training. Fear training induced a slight enhancement in the mEPSC amplitude at 3 h after training. The increased mEPSC frequency and amplitude were absent in animals that were only exposed to footshock or novelty or unpaired tone/footshock training. This implies that learning the association between context, tone and footshock transiently enhances hippocampal CA1 spontaneous synaptic transmission, which may contribute to the encoding of the fearful event.     

Metabotropic glutamate receptors are involved in amygdaloid plasticity

The amygdala plays an important role in emotional learning. Synaptic plasticity underlying the acquisition of conditioned fear occurs in the lateral nucleus of the amygdala: long-term potentiation (LTP) of synapses in the pathway of the conditioned stimulus (CS) has shown to be a neural correlate of this kind of emotional learning. The present study is based on previous results of our laboratory showing an important role of the metabotropic glutamate receptor subtype 5 (mGluR5) in fear conditioning. Here, we explored whether mGlu5 receptors within the lateral nucleus of the amygdala are involved in the plasticity underlying fear conditioning. We used an in vivo approach investigating the acquisition, consolidation and expression of conditioned fear by the fear-potentiated startle paradigm and by the inhibition of motor activity during CS presentation. Additionally, we used an in vitro approach inducing LTP in the lateral amygdala by patch-clamp recordings in rat brain slices. Acquisition of conditioned fear, but not consolidation and expression, was blocked by intra-amygdaloid injections of the specific mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) in vivo. Furthermore, induction of amygdaloid LTP but not synaptic transmission was disrupted by MPEP application in vitro. These experiments show for the first time in vivo and in vitro that mGluR5 receptors are necessary for plasticity in the amygdala.     

Memory consolidation of Pavlovian fear conditioning requires nitric oxide signaling in the lateral amygdala

Nitric oxide (NO) has been widely implicated in synaptic plasticity and memory formation. In studies of long-term potentiation (LTP), NO is thought to serve as a 'retrograde messenger' that contributes to presynaptic aspects of LTP expression. In this study, we examined the role of NO signaling in Pavlovian fear conditioning. We first show that neuronal nitric oxide synthase is localized in the lateral nucleus of the amygdala (LA), a critical site of plasticity in fear conditioning. We next show that NO signaling is required for LTP at thalamic inputs to the LA and for the long-term consolidation of auditory fear conditioning. Collectively, the findings suggest that NO signaling is an important component of memory formation of auditory fear conditioning, possibly as a retrograde signal that participates in presynaptic aspects of plasticity in the LA.     

Deep brain stimulation of the amygdala alleviates fear conditioning-induced alterations in synaptic plasticity in the cortical–amygdala pathway and fear memory

Deep brain stimulation (DBS) of the amygdala has been demonstrated to modulate hyperactivity of the amygdala, which is responsible for the symptoms of post-traumatic stress disorder (PTSD), and thus might be used for the treatment of PTSD. However, the underlying mechanism of DBS of the amygdala in the modulation of the amygdala is unclear. The present study investigated the effects of DBS of the amygdala on synaptic transmission and synaptic plasticity at cortical inputs to the amygdala, which is critical for the formation and storage of auditory fear memories, and fear memories. The results demonstrated that auditory fear conditioning increased single-pulse-evoked field excitatory postsynaptic potentials in the cortical–amygdala pathway. Furthermore, auditory fear conditioning decreased the induction of paired-pulse facilitation and long-term potentiation, two neurophysiological models for studying short-term and long-term synaptic plasticity, respectively, in the cortical–amygdala pathway. In addition, all these auditory fear conditioning-induced changes could be reversed by DBS of the amygdala. DBS of the amygdala also rescued auditory fear conditioning-induced enhancement of long-term retention of fear memory. These findings suggested that DBS of the amygdala alleviating fear conditioning-induced alterations in synaptic plasticity in the cortical–amygdala pathway and fear memory may underlie the neuromodulatory role of DBS of the amygdala in activities of the amygdala.     

Prevention of stress-impaired fear extinction through neuropeptide s action in the lateral amygdala

Stressful and traumatic events can create aversive memories, which are a predisposing factor for anxiety disorders. The amygdala is critical for transforming such stressful events into anxiety, and the recently discovered neuropeptide S transmitter system represents a promising candidate apt to control these interactions. Here we test the hypothesis that neuropeptide S can regulate stress-induced hyperexcitability in the amygdala, and thereby can interact with stress-induced alterations of fear memory. Mice underwent acute immobilization stress (IS), and neuropeptide S and a receptor antagonist were locally injected into the lateral amygdala (LA) during stress exposure. Ten days later, anxiety-like behavior, fear acquisition, fear memory retrieval, and extinction were tested. Furthermore, patch-clamp recordings were performed in amygdala slices prepared ex vivo to identify synaptic substrates of stress-induced alterations in fear responsiveness. (1) IS increased anxiety-like behavior, and enhanced conditioned fear responses during extinction 10 days after stress, (2) neuropeptide S in the amygdala prevented, while an antagonist aggravated, these stress-induced changes of aversive behaviors, (3) excitatory synaptic activity in LA projection neurons was increased on fear conditioning and returned to pre-conditioning values on fear extinction, and (4) stress resulted in sustained high levels of excitatory synaptic activity during fear extinction, whereas neuropeptide S supported the return of synaptic activity during fear extinction to levels typical of non-stressed animals. Together these results suggest that the neuropeptide S system is capable of interfering with mechanisms in the amygdala that transform stressful events into anxiety and impaired fear extinction.