NMDA receptor antagonism in the basolateral amygdala blocks enhancement of inhibitory avoidance learning in previously trained rats

Extensive evidence suggests that N-methyl-D-aspartate (NMDA) glutamate receptor channels in the amygdala are involved in fear-motivated learning, and infusion of NMDA receptor antagonists into the amygdala blocks memory of fear-motivated tasks. Recent studies have shown that previous training can prevent the amnestic effects of NMDA receptor antagonists on spatial learning. In the present study, we evaluated whether infusion of the NMDA antagonist D,L-2-amino-5-phosphonopentanoic acid (AP5) into the basolateral nucleus of the amygdala (BLA) impairs reinforcement of inhibitory avoidance learning in rats given previous training. Adult male Wistar rats (220-310 g) were bilaterally implanted under thionembutal anesthesia (30 mg/kg, i.p.) with 9.0-mm guide cannulae aimed 1.0 mm above the BLA. Infusion of AP5 (5.0 microg) 10 min prior to training in a step-down inhibitory avoidance task (0.4 mA footshock) blocked retention measured 24 h after training. When infused 10 min prior to a second training session in animals given previous training (0.2 mA footshock), AP5 blocked the enhancement of retention induced by the second training. Control experiments showed that the effects were not due to alterations in motor activity or footshock sensitivity. The results suggest that NMDA receptors in the basolateral amygdala are involved in both formation of memory for inhibitory avoidance and enhancement of retention in rats given previous training.     

Differential involvement of cortical muscarinic and NMDA receptors in short- and long-term taste aversion memory

In conditioned taste aversion, an animal avoids a taste previously associated with toxic effects, and this aversive memory formation requires an intact insular cortex. In this paper, we investigated the possible differential involvement of cholinergic and glutamatergic receptors in the insular cortex in short-term memory (STM) and long-term memory (LTM) of taste aversion in rats. Taste aversion was induced by intraperitoneal administration of lithium chloride (a malaise-inducing drug) 15 min after experience with an unfamiliar taste. In order to test STM and LTM of taste aversion, taste stimulus was again presented 4 h and 72 h after lithium injection, respectively. During the acquisition, microinjection of the muscarinic antagonist, scopolamine, in the insular cortex before, but not after, the presentation of the new taste, abolished STM as well as LTM. Blockade of the NMDA receptor, in the insular cortex, by AP5 before, but not after, the presentation of the taste stimulus, impaired LTM but left STM intact. Moreover, when injected 1 h after malaise induction (i.e., during taste-illness association), AP5 disrupted both STM and LTM. These results suggest that activation of muscarinic receptors in the insular cortex is involved in the acquisition of taste memory, whereas NMDA receptors participate in taste memory consolidation. These data demonstrate that different neurochemical mechanisms subserve different memory phases. NMDA receptors are also probably involved in processing the visceral input, thus allowing subsequent taste-illness association. This indicates that in the same cortical area the same neurotransmitter system can be involved in distinct processes: taste memory consolidation vs. taste-illness association.     

Blockade of noradrenergic receptors in the basolateral amygdala impairs taste memory

In conditioned taste aversion (CTA), a subject learns to associate a novel taste (conditioned stimulus, CS) with visceral malaise (unconditioned stimulus, US). Considerable evidence indicates that the noradrenergic system in the amygdala plays an important role in memory consolidation for emotionally arousing experiences. The specific aim of the present set of experiments was to determine the involvement of noradrenergic activity in the basolateral amygdala (BLA) during the US presentation and consolidation of CTA as well as during the consolidation of a nonaversive/incidental gustatory memory. Selective bilateral microinfusions of the beta-adrenergic antagonist propranolol administered into the BLA immediately before intraperitoneal (i.p.) lithium chloride (LiCl) injections disrupted CTA memory. Additionally, propranolol infused into the BLA immediately after a pre-exposure to the saccharin (CS) significantly attenuated latent inhibition. The present findings indicating that alterations in noradrenergic function in the BLA affect taste memory formation, provide additional evidence that the BLA plays a critical role in modulating the consolidation of memory and that the influence is mediated by interactions with other brain regions that support memory for different kinds of experiences.     

Differential involvement of hippocampal and amygdalar NMDA receptors in contextual and aversive aspects of inhibitory avoidance memory in rats

Adult male rats bilaterally implanted with guide canullae aimed either at the dorsal hippocampus (dHIP) or the basolateral nucleus of the amygdala (BLA) were trained in a step-down inhibitory avoidance task (IA) and tested for retention 24 h after training. Immediately after training, animals were given a bilateral infusion of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP5) (5.0 microg) into the dHIP or the BLA. Both intrahippocampal and intraamygdala infusions of AP5 blocked IA retention. Preexposure to the training box, but not to a different environment 24 h prior to training prevented the impairing effect of intrahippocampal infusion of AP5 on retention. Preexposure did not affect the retention impairment induced by intraamygdala infusion of AP5. These data suggest that hippocampal NMDA receptors might be involved in the contextual and spatial aspects, while amygdalar NMDA receptors might be involved in the aversive aspects of memory for IA.     

In vivo effects of intracortical administration of NMDA and metabotropic glutamate receptors antagonists on neocortical long-term potentiation and conditioned taste aversion.

It has been proposed that long-term potentiation (LTP), a form of activity-dependent modification of synaptic efficacy, may be a synaptic mechanism for certain types of learning. Recent studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induce an N-methyl-D-aspartate (NMDA) dependent LTP in the IC of adult rats in vivo. Here we present experimental data showing that intracortical administration of the NMDA receptor competitive antagonists CPP (-3(-2 carboxipiperazin-4-yl)-propyl-1-phosphonic acid, 0.03 microg per hemisphere) and AP-5 (D(-)-2-amino-5-phosphonopentanoic, 2.5 microg per hemisphere) disrupt the acquisition of conditioned taste aversion, as well as IC-LTP induction in vivo. In contrast, administration of the metabotropic glutamate receptor antagonist MCPG ((RS)-alpha-methyl-4-carboxyphenylglycine, 2.5 microg per hemisphere) does not disrupt the acquisition of CTA nor IC-LTP induction. These findings are of particular interest since they provide support for the view that the neural mechanisms underlying NMDA-dependent neocortical LTP constitute a possible mechanism for the learning-related functions performed by the IC.     

Glucocorticoid enhancement of memory consolidation in the rat is blocked by muscarinic receptor antagonism in the basolateral amygdala

Glucocorticoid-induced memory enhancement is known to depend on beta-adrenoceptor activation in the basolateral amygdala (BLA). Additionally, inactivation of muscarinic cholinergic receptors in the rat amygdala blocks memory enhancement induced by concurrent beta-adrenergic activation. Together, these findings suggest that glucocorticoid-induced modulation of memory consolidation requires cholinergic as well as adrenergic activation in the BLA. Two experiments investigated this issue. The first experiment examined whether blockade of muscarinic cholinergic receptors in the BLA with atropine alters the memory-enhancing effects of the systemically administered glucocorticoid dexamethasone. Dexamethasone (0.3, 1.0 or 3.0 mg/kg, s.c.) administered to rats immediately after inhibitory avoidance training produced dose-dependent enhancement of 48-h retention. Concurrent bilateral infusions of the muscarinic cholinergic antagonist atropine (0.5 microg in 0.2 microL per side) into the BLA blocked the memory enhancement. The second experiment investigated whether the BLA is a locus of interaction between glucocorticoid and muscarinic activation. The specific glucocorticoid receptor (GR or type II) agonist RU 28362 (1.0, 3.0 or 10 ng) was infused into the BLA either alone or together with atropine immediately after training. The GR agonist produced dose-dependent memory enhancement and atropine blocked the memory enhancement. These findings indicate that muscarinic cholinergic activation within the BLA is critical for enabling glucocorticoid enhancement of memory consolidation and that enhancement of memory induced by GR activation in the BLA requires cholinergic activation within the BLA.     

Establishing aversive, but not safe, taste memories requires lateralized pontine-cortical connections

Aversive and safe taste memory processing is dramatically disrupted by bilateral lesions of the pontine parabrachial nucleus (PBN). To determine how such lesions affect patterns of neuronal activation in forebrain, lesions were combined with assessment of cFos-like immunoreactivity (FLI) in insular cortex (IC) and amygdala after conditioned taste aversion (CTA) training. Increases in FLI in amygdala and IC, which are normally seen following novel (versus familiar) CS-US pairing, were eliminated after PBN lesions. This suggests that PBN lesions prevent transmission of critical CS and US information to forebrain regions for the processing of both aversive and safe taste memories. Unilateral asymmetrical lesions of PBN and IC blocked CTA acquisition as well as normal patterns of FLI in amygdala after novel CS-US pairing, an effect not seen when unilateral lesions were confined to a single hemisphere. The crossed-disconnection experiments provide compelling evidence that functional interactions between PBN and IC are required for CTA acquisition, but not for safe taste memory formation and retrieval. The dissociation between effects of the different types of lesions on safe and aversive taste memories supports emerging evidence that the neural underpinnings of the two types of taste learning differ.     

Different disruptive effects on the acquisition and expression of conditioned taste aversion by blockades of amygdalar ionotropic and metabotropic glutamatergic receptor subtypes in rats

Conditioned taste aversion (CTA) is based on the gustatory long-term memory established after association of the taste of food (conditioned stimulus, CS) with visceral signals of poisoning (unconditioned stimulus, US). After the acquisition of CTA, hedonics of the taste CS changes from positive to negative as indicated by reduced ingestive and increased aversive taste reactivities in response to re-exposures to the CS. We examined the effects of reversible and selective blockades of the amygdalar glutamate receptor subtypes, AMPA, NMDA and metabotropic glutamate receptors, on the formation of CTA. Blockades of each of the three receptor subtypes between ingestion of saccharin (CS) and malaise-inducing LiCl (US) disrupted the acquisition of CTA. After the acquisition of CTA, however, blockades of only AMPA receptors, but not NMDA or metabotropic receptors, impaired the expression of CTA. This effect was seen only during the period when the antagonistic action to AMPA receptors lasted. These results indicate that both ionotropic and metabotropic glutamate receptor subtypes in the amygdala are indispensable for the acquisition of CTA, but that the expression of acquired CTA is mediated only by AMPA receptors. The present results also suggest that the amygdalar glutamatergic neural transmission is involved in the formation and storage of long-term gustatory memory associated with the altered hedonics from positive to negative.     

Substantia nigra glutamate antagonists produce contralateral turning and basal ganglia Fos expression: interactions with D1 and D2 dopamine receptor agonists

Experiments measuring behavior and immediate-early gene expression in the basal ganglia can reveal interactions between dopamine (DA) and glutamate neurotransmission. Nigrostriatal DA projections influence two striatal efferent pathways that, in turn, directly and indirectly influence the activity of the substantia nigra pars reticulata (SNr). This report tests the interactions between striatal DA receptors and nigral glutamate receptors on basal ganglia function by examining both contralateral turning and Fos immunoreactivity in striatum and pallidum following unilateral intranigral microinfusions of glutamate antagonists given to intact and 6-OHDA-lesioned rats. The NMDA antagonist AP5 (1 microg), or the AMPA/kainate antagonist DNQX (0.015-1.5 microg), injected into the SNr (0.5 microl) elicited contralateral turning as well as both striatal and pallidal Fos expression. Moreover, intranigral DNQX elicited more turning and greater numbers of Fos-positive striatal neurons in 6-OHDA-lesioned animals than in unlesioned controls, suggesting that the 6-OHDA injection induces functional changes in nigral glutamate transmission. In 6-OHDA-lesioned rats, systemic injections of the DA D1 receptor agonist SKF38393 (0.5 mg/kg, i.p.) increased striatal Fos expression due to intranigral DNQX. In contrast, the D2 agonist quinpirole (0.1 mg/kg, i.p.) decreased striatal Fos expression but increased the pallidal Fos arising from intranigral AP5. In additional experiments, both intact and 6-OHDA-lesioned rats were given simultaneous intranigral and intrastriatal infusions and turning and pallidal Fos expression were measured. 6-OHDA-lesioned rats given 5 microg of intrastriatal quinpirole exhibited both turning and pallidal Fos that was significantly increased by intranigral AP5. These results indicate that the opposing influences of D2 agonists and endogenous nigral glutamate transmission are mediated by striatal D2 receptors. Finally, the behavioral effects of intranigral glutamate antagonism can be dissociated from the effects on striatal or pallidal immediate-early gene expression.     

Glucocorticoid receptor activation in the rat nucleus of the solitary tract facilitates memory consolidation: involvement of the basolateral amygdala

These experiments examined the involvement of glucocorticoid receptors (GRs or type II) located in the A2-noradrenergic cell group of the rat nucleus of the solitary tract (NTS) in modulating memory storage. Bilateral intra-NTS infusions (0.5 microL) of the specific GR agonist RU 28362 (11beta, 17beta-dihydroxy-6, 21-dimethyl-17alpha-pregna-4,6-trien-20yn-3-one), in doses ranging from 0.01 to 10.0 ng, immediately after inhibitory avoidance training produced a dose-dependent enhancement of 48 h retention performance. Infusions of 0.1 or 1.0 ng of the agonist enhanced retention, whereas lower or higher doses were ineffective. Post-training infusions of the GR antagonist RU 38486 [17beta-hydroxy-11beta-(4-dimethylaminophenyl)-17alpha-(1-pr opynyl)-o estra-4,9-dien-3-one, 0.01-10.0 ng] into the NTS did not significantly affect retention performance, but shifted the dose-response effects of post-training systemic injections of the synthetic glucocorticoid dexamethasone to the right. These results indicate that activation of GRs in the NTS can influence memory formation for inhibitory avoidance training, and suggest that the effects of circulating glucocorticoids on memory are mediated, in part, by an activation of GRs in the NTS. Additionally, pretraining infusions of the beta1-adrenergic antagonist atenolol (0.5 microg in 0.2 microL) into the basolateral nucleus of the amygdala (BLA), a brain structure which receives noradrenergic projections from the NTS and is implicated in memory storage modulation, blocked the memory-enhancing effects of the GR agonist (1.0 ng) infused into the NTS. These findings provide evidence that memory storage is modulated by glucocorticoid binding to GRs in noradrenergic cell bodies in the NTS and suggest that these modulatory effects are conveyed by ascending projections to the BLA.     

Differential participation of temporal structures in the consolidation and reconsolidation of taste aversion extinction

The extinction process has been described as the decline in the frequency or intensity of the conditioned response following the withdrawal of reinforcement. Hence, experimental extinction does not reflect loss of the original memory, but rather reflects new learning, which in turn requires consolidation in order to be maintained in the long term. During extinction of conditioned taste aversion (CTA), a taste previously associated with aversive consequences acquires a safe status through continuous presentations of the flavor with no aversive consequence. In addition, reconsolidation has been defined as the labile state of a consolidated memory after its reactivation by the presentation of relevant information. In this study, we analyzed structures from the temporal lobe that could be involved in consolidation and reconsolidation of extinction of CTA by means of new protein synthesis. Our results showed that protein synthesis in the hippocampus (HC), the perirhinal cortex (PR) and the insular cortex (IC) of rats participate in extinction consolidation, whereas the basolateral amygdala plays no part in this phenomenon. Furthermore, we found that inhibition of protein synthesis in the IC in a third extinction trial had an effect on reconsolidation of extinction. The participation of the HC in taste memory has been described as a downmodulator for CTA consolidation, and has been related to a context–taste association. Altogether, these data suggest that extinction of aversive taste memories are subserved by the IC, HC and PR, and that extinction can undergo reconsolidation, a process depending only on the IC.     

Aversive stimulation of the inferior colliculus changes dopamine and serotonin extracellular levels in the frontal cortex: modulation by the basolateral nucleus of amygdala

We have shown that stimulation of the neural substrates in the inferior colliculus (IC) causes a significant increase in the extracellular levels of dopamine (DA) in frontal cortex (FC). Also, it has been reported that the basolateral complex of the amygdala (BLA) serves as a filter for unconditioned and conditioned aversive information that ascend to higher structures from the brainstem. Linking these two kinds of information, this work examines whether inactivation of BLA interferes with the activation of cortical dopaminergic outputs produced by aversive stimulation of the IC. To this end, rats were implanted with an electrode in the IC for the determination of the threshold of escape responses. Each rat also bore a cannula implanted in the BLA for injections of lidocaine (10 microg/0.5 microL), muscimol (0.5 microg/0.5 microL), or its vehicle and a microdialysis probe in the FC for determination of the amount of DA and serotonin (5-HT). The data obtained show that IC electrical stimulation caused an increase in the DA release while it reduced the 5-HT release in the FC. BLA inactivation with both lidocaine or muscimol enhanced the aversiveness of the electrical stimulation of the IC and attenuated the increase in DA, while the reduction in 5-HT release in the FC remained unaffected. These findings suggest that ascending aversive information from IC on their way up to higher structures in the SNC courses with opposite modulation by DA/5-HT mechanisms in the FC. These processes are regulated by filters located in the BLA. It is proposed that the loss of these BLA regulatory mechanisms prevents the expression of these modulatory mechanisms in the FC that are adaptive responses in order to cope with unconditioned aversive stimulus triggered at the brainstem level.     

Excitation of the pedunculopontine tegmental NMDA receptors induces wakefulness and cortical activation in the rat

Microinjection of the excitatory amino acid, L-glutamate into the brainstem pedunculo pontine tegmentum (PPT) has been shown to induce wakefulness, however, it has been unclear that receptors mediate this effect. The aim of this study was to test the hypothesis that in the PPT, L-glutamate induces cortical activation and wakefulness via activation of NMDA receptors. To test this hypothesis, three sets of micro-injections into the PPT were carried out on two different groups of rats that were then allowed to move freely although chronic instrumentation recorded sleep/wake states. Three days after the initial control injections of saline, in a contra-lateral site, Group I was micro-injected with saline + glutamate (saline first, and glutamate 15 min later); after another 3 days, the same rats were micro-injected with the NMDA-receptor-specific antagonist, 2-amino-5-phosphonopentanoic acid, (AP5) + glutamate. Group II received the same initial control injections (saline only), then AP5 + glutamate and the saline + glutamate micro-injections last. In rats that were not pretreated with AP5, microinjection of a 90 ng dose of L-glutamate (0.48 nmol in a volume of 0.1 microl vehicle) kept animals awake for 2-3 hr by eliminating both slow-wave sleep (SWS) and rapid eye movement (REM) sleep. These behavioral state changes were accompanied by concomitant increase in the power of gamma (gamma) frequency (20-60 Hz) waves in the cortical EEG. Pretreatment of L-glutamate injection sites with 0.48 nmol of AP5 blocked L-glutamate-induced-wakefulness and preserved a normal amount of wakefulness and sleep. Pretreatment with AP5 decreased the power of gamma-wave activity below its control level. These results support the hypothesis that the glutamate-induced-wakefulness and cortical activation effects are mediated via the NMDA receptors.     

Critical role of insular cortex in taste but not odour aversion memory

Conditioned odour aversion (COA) and conditioned taste aversion (CTA) result from the association of a novel odour or a novel taste with delayed visceral illness. The insular cortex (IC) is crucial for CTA memory, and the present experiments sought to determine whether the IC is required for the formation and the retrieval of COA memory as it is for CTA. We first demonstrated that ingested odour is as effective as taste for single-trial aversion learning in rats conditioned in their home cage. COA, like CTA, tolerates long intervals between the ingested stimuli and the illness and is long-lasting. Transient inactivation of the IC during acquisition spared COA whereas it greatly impaired CTA. Similarly, blockade of protein synthesis in IC did not affect COA but prevented CTA consolidation. Moreover, IC inactivation before retrieval tests did not interfere with COA memory expression when performed either 2 days (recent memory) or 36 days after acquisition (remote memory). Similar IC inactivation impaired the retrieval of either recent or remote CTA memory. Altogether these findings indicate that the IC is not necessary for aversive odour memory whereas it is essential for acquisition, consolidation and retrieval of aversive taste memory. We propose that the chemosensory stimulations modulate IC recruitment during the formation and the retrieval of food aversive memory.     

Basolateral amygdala lesions block the memory-enhancing effect of 8-Br-cAMP infused into the entorhinal cortex of rats after training

There is extensive evidence suggesting that the basolateral nucleus of the amygdala plays a critical role in modulating memory consolidation processes in other brain regions. The present experiments examined interactions between the basolateral amygdala and the entorhinal cortex in modulating memory consolidation for inhibitory avoidance training. Several studies have reported that activation of the second messenger system adenosine 3',5'-cyclic monophosphate (cAMP) in several brain regions enhances memory and induces long-term plasticity. In the present experiments, a unilateral infusion of the cAMP analogue, 8-Br-cAMP (0.25 or 1.25 microg in 0.5 microL), administered into the entorhinal cortex of male Sprague-Dawley rats immediately after training, enhanced 48-h retention. An N-methyl-d-aspartate-induced lesion of the ipsilateral basolateral amygdala did not impair retention, but blocked the memory-enhancing effect of 8-Br-cAMP (infused into the entorhinal cortex) post-training. A lesion of the contralateral basolateral amygdala did not block the 8-Br-cAMP-induced retention enhancement. These findings indicate that an intact basolateral amygdala is essential for modulation of memory consolidation involving the entorhinal cortex, and are consistent with evidence that the basolateral amygdala regulates memory consolidation mediated by other brain regions.     

Long-term potentiation in the insular cortex enhances conditioned taste aversion retention

Long-lasting changes in synaptic strength, such as long-term potentiation (LTP), are thought to underlie memory formation. Recent studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and retention of conditioned taste aversion (CTA), have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induce LTP in the IC of adult rats in vivo, as well as, that blockade of N-methyl-D-aspartate (NMDA) receptors disrupts CTA and IC-LTP induction in vivo. Here, we present experimental data showing that induction of LTP in the Bla-IC projection previous to CTA training enhances the retention of this task. These findings are of particular interest since they provide support for the view that the neural mechanisms underlying neocortical LTP may contribute to memory related functions performed by the IC.     

The area postrema is involved in paraquat-induced conditioned aversion behavior and neuroendocrine activation of the hypothalamic-pituitary-adrenal axis

Paraquat is a herbicide capable of eliciting conditioned taste aversion (CTA), a behavioral response characteristic of toxicosis. The area postrema (AP) is a hindbrain circumventricular organ previously shown to be important in mediating signs of paraquat-induced toxicity, namely CTA and weight loss. The relationship between neural substrates for paraquat-induced CTA and activation of the hypothalamic-pituitary-adrenal (HPA) axis was investigated in Sprague-Dawley rats with lesions centered on the AP (APX) and sham-operated (SHM) rats administered paraquat (25 μmol/kg) or saline (1 ml/kg). Injection of paraquat at a dose sufficient to condition taste aversion, but produce no other signs of overt toxicity, significantly increased plasma corticosterone concentrations in SHM rats up to 4 h after administration. Paraquat-induced activation of the HPA axis was significantly attenuated in AP-lesioned rats as compared to sham-operated controls. These findings suggest the area postrema is a common neural substrate for the behavioral and neuroendocrine responses to paraquat.     

Role of glutamate in the amygdala and lateral hypothalamus in conditioned taste aversion

The role of glutamate in conditioned taste aversion was investigated. Both, in the amygdala (AMYG) and in the lateral hypothalamus (LH) extracellular levels of glutamate were assessed by microdialysis and capillary electrophoresis with laser induced fluorescence detection. Rats were conditioned by pairing a novel flavor (strawberry flavor) with an intraperitoneal injection of lithium chloride. When the conditioned stimulus (strawberry flavored solution) was injected into the mouth of conditioned rats, there was an increase of glutamate release in the AMYG, and a decrease in glutamate release in the LH. These results predicted that glutamate release in the AMYG and the LH was involved in CTA. This possibility was tested by MK-801 (glutamate antagonist) and glutamate microinjections. MK-801 injections in AMYG attenuated the rejection of the novel flavor, and in the LH did not cause any effect on CTA. Glutamate microinjections in the AMYG caused CTA. These results suggest that glutamatergic activity in the AMYG might be a relevant neurochemical correlate and cause of conditioned taste aversion.     

Dynamic processing of taste aversion extinction in the brain

While substantial advances have been made in discovering how the brain learns and remembers, less is known about how the brain discards information, reorganizes information, or both. These topics are not only relevant to normal brain functioning but also speak to pathologies in which painful memories do not wane but are evoked time and again (e.g., post-traumatic stress disorder; PTSD). Here, we measured brain activity (as indicated by the regional expression of c-Fos protein) in rats during acquisition and throughout extinction of a conditioned taste aversion (CTA). We compared that brain activity with animals that had intact CTA memories or those that experienced an explicitly unpaired (EU) conditioned stimulus (CS; saccharin, SAC) and unconditioned stimulus (US; lithium chloride, LiCl). The data show a dynamic and nonuniform pattern of c-Fos protein expression in brain nuclei known to mediate gustation and CTAs. In particular, brainstem nuclei (e.g., nucleus of the solitary tract; NTS) and the basolateral nucleus of the amygdala (BLA) are active early as CTAs are formed and as extinction of the learned response begins. Later in the extinction process, the BLA reduces c-Fos expression relative to nonextinguished controls. Finally, as almost full reacceptance of the taste is achieved, the gustatory neocortex (GNC) expresses enhanced levels of c-Fos protein. Thus, extinction of a CTA is not represented by a simple reversal of the c-Fos activity evoked by CTA conditioning. Rather, the data demonstrate that extinction of conditioned responses is a dynamic process in which the activity levels of particular nuclei along the brain's taste pathway change depending on the extent to which the conditioned response has been extinguished.     

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.