N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats.

Three experiments examined the effects of intra-amygdaloid infusions of an N-methyl-D-aspartate (NMDA) receptor antagonist, D,L-2-amino-5-phosphonovalerate (APV), on contextual fear conditioning in rats. In Experiment 1, APV infusion into the basolateral amygdala (BLA), before training, disrupted the acquisition of contextual fear. In Experiment 2, APV produced a disruption of both the acquisition and expression of contextual fear. This blockade of contextual fear was not state dependent, not due to a shift in footshock sensitivity, and not the result of increased motor activity in APV-treated rats. In Experiment 3, fear conditioning was not affected by a posttraining APV infusion into the BLA. These results indicate that NMDA receptors in the BLA are necessary for both the acquisition and expression of Pavlovian fear conditioning to contextual cues in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amygdalar NMDA receptors are critical for new fear learning in previously fear-conditioned rats

NMDA receptors in the amygdala seem to be critical for fear conditioning in naive rats. Recent spatial-learning studies suggest that previous learning protected animals from the amnesic effect of NMDA antagonists on new learning (of a similar behavioral task). Therefore, the present study examined whether blocking of NMDA receptors in the basolateral nucleus of the amygdala (BLA) prevents new fear learning in previously fear-conditioned rats, as measured by freezing behavior. Intra-BLA infusions of the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) completely blocked fear conditioning to a tone stimulus in animals that had previously been fear-conditioned to a light stimulus. Similar results were obtained with intra-BLA infusions of APV before contextual fear conditioning in rats that had been fear-conditioned to a different context. Additional experiments showed that intra-BLA APV infusions substantially interfere with the expression and extinction of conditioned fear to tone, light, and context stimuli. Together, these results indicate that NMDA receptors in the BLA are crucial for the encoding of new fear memories (i.e., the formation of specific conditioned stimulus-unconditioned stimulus association), the expression of conditioned fear responses, and the extinction of acquired fear.     

Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid to the basolateral amygdala.

24 female rats, with chronic cannula placed bilaterally in the amygdala, received infusions of the N-methyl-{d}-aspartate (NMDA) receptor antagonist {d},{l}-2-amino-5-phosphonovaleric acid (APV) before contextual Pavlovian fear conditioning. Administration of APV to the basolateral nucleus prevented acquisition of fear. Central nucleus infusions had no effect. It is concluded that an NMDA-mediated process near the basolateral region of the amygdala (e.g., lateral or basolateral nucleus) is essential for the learning of fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of dorsal hippocampus and basolateral amygdala NMDA receptors in the acquisition and retrieval of context and contextual fear memories.

The authors used 3-phase context preexposure facilitation methodology to study the contribution of N-methyl-D-aspartate (NMDA) receptors in dorsal hippocampus (DH) and the basal lateral region of the amygdala (BLA) to (a) acquisition of the context memory, (b) retrieval of the context memory, (c) acquisition of context-shock association, and (d) retrieval of the context-shock association. The NMDA receptor antagonist D-2-amino-5 phosphonopentanoic acid (D-AP5) was injected into either the DH or BLA prior to (a) the context preexposure phase, (b) the immediate shock phase, or (c) the test for contextual fear. Antagonizing NMDA receptors in the DH impaired the acquisition of the context memory but did not affect its retrieval or retrieval of the fear memory. Antagonizing NMDA receptors with D-AP5 in the BLA impaired acquisition of the context-shock association but had no effect on the expression of fear. However, both DL-AP5 and L-AP5 reduced the expression of fear when they were injected into the amygdala prior to testing for contextual fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amygdalar NMDA Receptors Control the Expression of Associative Reflex Facilitation and Three Other Conditional Responses.

Four conditional responses (CRs) were measured in rats implanted with bilateral cannulas in the basolateral nuclear complex of the amygdala (BLA). During retention testing in either the original training context or a shifted context, BLA was infused with artificial cerebral spinal fluid (ACSF) or ACSF containing an N-methyl-D-aspartate receptor antagonist (APV). Regardless of the testing context, APV infusion into BLA completely blocked the expression of conditional eyeblink facilitation and significantly attenuated the expression of conditional freezing, ultrasonic vocalization, and defecation. Discriminant analysis found eyeblink facilitation to be comparable to freezing in predicting group membership (APV vs. ACSF) and both to be better predictors than the other two CRs. The APV effect did not depend on the exact cannula positions within BLA. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Basolateral amygdala NMDA receptors are selectively involved in the acquisition of taste-potentiated odor aversion in the rat.

In the taste-potentiated odor aversion (TPOA) paradigm, animals acquire a strong aversion to an odor that is followed by delayed intoxication only if a gustatory stimulus is presented with the odor during conditioning. Although previous work has shown that N-methyl-D-aspartate (NMDA) receptors in the basolateral nucleus of the amygdala (BLA) play a role in the acquisition of TPOA, the present study aimed at.describing the process in which NMDA receptors in the BLA are involved during acquisition of TPOA. Male Long-Evans rats received intra-BLA infusions of the competitive NMDA receptor antagonist {d},{l}-2-2-amino-5-phosphonovalerate ({d}-APV; 0.05 and 0.50 μg) immediately before or after the odor–taste conditioned stimulus (CS) presentation, or immediately before the test. Results showed that {d}-APV impaired acquisition of TPOA when infused before, but not after, the CS presentation, but did not affect retrieval. These results suggest that NMDA receptors of the BLA are involved in the formation of potentiation—by taste—of the olfactory memory trace, but not in the maintenance of this process. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Associative structure of fear memory after basolateral amygdala lesions in rats.

The authors have recently demonstrated that rats with basolateral amygdala (BLA) lesions acquire Pavlovian fear conditioning after overtraining. However, it is not known whether the associative basis of Pavlovian fear memory acquired by rats with BLA lesions is similar to that of intact rats. Associations are typically formed between the conditional (CS) and unconditional (US) stimuli (stimulus-stimulus; S-S), although it is possible for stimuli to enter into association with the responses they produce (stimulus-response; S-R). Indeed, the central nucleus of the amygdala, which is essential for fear conditioning in rats with BLA lesions, may mediate S-R associations in some Pavlovian tasks. The authors therefore used a postconditioning US inflation procedure (i.e., exposure to intense footshock USs) to assess the contribution of S-S associations to fear conditioning after overtraining in rats with BLA lesions. In Experiment 1, intact rats that were overtrained and later inflated displayed elevated freezing levels when tested, indicating that S-S associations contribute to overtrained fear memories. Interestingly, neither neurotoxic BLA lesions nor temporary inactivation of the BLA during overtraining prevented the inflation effect (Experiment 2 and 3, respectively). These results reveal that S-S associations support Pavlovian fear memories after overtraining in both intact rats and rats with BLA lesions, and imply that the central nucleus of the amygdala encodes CS-US associations during fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: Absence of a temporal gradient.

The role of the basolateral amygdala (BLA) in the acquisition and expression of Pavlovian fear conditioning was examined in 80 rats. Excitotoxic lesions were made in the BLA using N-methyl-{d}-aspartate 7 days before or 1, 14, or 28 days after Pavlovian fear conditioning. Conditioning consisted of three pairings of a tone with an aversive footshock in a novel chamber, and freezing behavior served as an index of conditional fear. BLA lesions abolished conditional freezing to both the contextual and acoustic conditional stimuli at all training-to-lesion intervals, and the magnitude of the impairment did not vary as a function of the training-to-lesion interval. Reacquisition training elevated levels of freezing in rats with BLA lesions but did not reduce the magnitude of their deficit in relation to that of controls. These results reveal that neurons in the BLA have an enduring role in the expression of conditional fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Basolateral amygdala lesions block glucocorticoid-induced modulation of memory for spatial learning.

This study examined the role of the amygdala in mediating the effects of glucocorticoids on spatial memory in rats. Adrenalectomy (ADX) induced 4–5 days prior to training impaired memory in a water-maze spatial task. This effect was reversed by a posttraining injection of dexamethasone (0.3 mg/kg sc) but not by corticosterone (0.3 mg/kg). Lesions of the basolateral (BLA), but not the central (CEA) or the medial (MEA), amygdala blocked the effects of ADX and dexamethasone. ADX also impaired acquisition. CEA, MEA, and BLA lesions blocked the ADX effect on acquisition. In adrenally intact rats, intracerebroventricular posttraining injections of a specific glucocorticoid receptor (GR or Type-ll) antagonist impaired retention, and BLA lesions blocked the effect of the GR antagonist. These findings provide evidence that the BLA is involved in mediating glucocorticoid influences on learning and memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of the N-methyl-D-aspartate antagonist DL-2-amino-5-phosphonovalerate on acquisition of fear of auditory and contextual cues.

Intracerebroventricular (icv) administration of the N-methyl-D-aspartate (NMDA) antagonist {dl}-2-amino-5-phosphonovalerate (APV) before tone-shock pairings caused a dose-dependent suppression of acquisition of fear of contextual cues associated with shock in 3 experiments involving 110 rats. Acquisition of fear of the tone was not impaired. Exp 2 showed that the fear of the tone was associative and that this tone-shock association was less affected by APV than was a context-shock association. Rats receiving APV before context-shock pairings showed an equivalent loss of fear regardless of whether testing occurred 1 or 28 days after training. It appears that icv administration of APV blocks acquisition of context conditioning by affecting NMDA receptors in the hippocampus. Activity at these receptors at the time of acquisition seems critical for later expression of both intermediate (1 day to 2 wks) and remote (4 wks) fear memories. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Involvement of NMDA receptors within the amygdala in short- versus long-term memory for fear conditioning as assessed with fear-potentiated startle.

Pretraining intra-amygdala infusions of the NMDA receptor antagonist, D,L-AP5, block fear-potentiated startle in rats tested 24+ hr after training. This may reflect a failure of either acquisition or retention. To evaluate these alternatives, rats were tested for fear-potentiated startle during fear conditioning (30 light-shock pairings [0.6 mA shock]), as well as 1–30 min and 48 hr after fear conditioning. Amygdala lesions abolishes fear-potentiated startle at all train-test intervals. Intra-amygdala AP5 infusions (25 nmol/side) abolished fear-potentiated startle during the long-term test and had partial effects at shorter train-test intervals. When the level of fear-potentiated startle during the short-term test was lowered to that of the 48-hr test (i.e., by training rats with a lower, 0.3 mA footshock), AP5 abolished fear-potentiated startle at each timepoint. Thus, amygdala NMDA receptors appear to participate in the initial acquisition of fear memories. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pre- and posttraining infusion of N-methyl-D-aspartate receptor antagonists into the amygdala impair memory in an inhibitory avoidance task

Involvement of amygdaloid N-methyl-D-aspartate (NMDA) receptors in memory processes was investigated. Rats with cannulas implanted in the basolateral amygdala were trained on a 1 trial step-through inhibitory avoidance task and tested for 24-hr retention. Pretraining infusion of 2-amino-5-phosphonovaleric acid (APV) into the amygdala, but not striatum or hippocampus, produced a dose-dependent retention deficit, which was attenuated by immediate posttraining intra-amygdala infusion of NMDA. Posttraining APV infusion also caused a dose- and time-dependent retention deficit. Pretest APV infusion had no effect on performance in the retention test. Further, pre- or posttraining infusion of 5.0 micrograms APV failed to affect acquisition and retention in the Morris water maze task. These findings suggest that amygdala NMDA receptors are normally activated by aversive training and play a critical role in memory formation for affective experience.     

Synaptic transmission and plasticity in the amygdala. An emerging physiology of fear conditioning circuits

Numerous studies in both rats and humans indicate the importance of the amygdala in the acquisition and expression of learned fear. The identification of the amygdala as an essential neural substrate for fear conditioning has permitted neurophysiological examinations of synaptic processes in the amygdala that may mediate fear conditioning. One candidate cellular mechanism for fear conditioning is long-term potentiation (LTP), an enduring increase in synaptic transmission induced by high-frequency stimulation of excitatory afferents. At present, the mechanisms underlying the induction and expression of amygdaloid LTP are only beginning to be understood, and probably involve both the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) subclasses of glutamate receptors. This article will examine recent studies of synaptic transmission and plasticity in the amygdala in an effort to understand the relationships of these processes to aversive learning and memory.     

Intrahippocampal infusions of a metabotropic glutamate receptor antagonist block the memory of context-specific but not tone-specific conditioned fear.

The role of metabotropic glutamate receptors (mGluRs) in the acquisition of learning and memory using fear conditioning as a behavioral model was examined. The mGluR antagonist (R,S)-α-methyl-4-carboxyphenylglycine (MCPG) was infused into the hippocampus 30 min before fear conditioning, and freezing was measured during both acquisition and retention tests. The results show that pretraining antagonism of MCPG-sensitive mGluRs in the hippocampus impaired context-specific memory for an aversive event during testing. The memory for tone-specific fear, however, remained intact despite pretraining infusion of MCPG. Treating rats with MCPG did not affect context- or tone-specific fear during acquisition. Results suggest that mGluR activation may play an important role in hippocampally mediated memory consolidation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Amygdala Modulates Hippocampus-Dependent Context Memory Formation and Stores Cue-Shock Associations.

Preexposing rats to the context facilitates subsequent contextual fear conditioning. This effect depends on the hippocampus (J. W. Rudy, R. M. Barrientos, & R. C. O'Reilly, 2002). The authors report that inactivating the basolateral region of the amygdala (BLA) by injecting muscimol, a GABAA agonist, before or after preexposure reduced this effect. In contrast, bilateral injections of anisomycin, a protein synthesis inhibitor, into BLA did not impair the consolidation of the context memory. However, when injected after fear conditioning, anisomycin impaired consolidation of both contextual and auditory-cue fear conditioning. Results are consistent with 2 ideas about the amygdala's contribution to memory: (a) It modulates memory formation in other regions of the brain, and (b) it is a storage site for cue-shock associations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prolonged suppression of human immunodeficiency virus type 1 (HIV-1) viremia in persons with advanced disease results in enhancement of CD4 T cell reactivity to microbial antigens but not to HIV-1 antigens

In rats, the septo-hippocampal system is important for memory encoding. Previous reports indicate that muscimol, a specific GABAergic agonist induces learning and memory deficits when infused into the medial septal area. The basolateral nucleus of the amygdala (BLA) modulates memory encoding in other brain areas, including the hippocampus. To explore the interactions between the septo-hippocampal system and amygdala in memory, we studied the effects of intra-medial septal infusions of muscimol in rats with BLA lesions. Animals received sham surgery or excitotoxic BLA lesions and were given infusions of either vehicle or muscimol (5 nmol) into the medial septal area 5 min prior to training sessions in inhibitory avoidance and water maze tasks. In the inhibitory avoidance task, muscimol-induced memory impairment was potentiated by BLA amygdala lesions. Additionally, in the water maze task, BLA-lesioned rats given muscimol infusions into the medial septal also showed memory impairment. These findings indicate that the MSA interacts with the BLA in the processing of memory storage.     

Functional interaction between entorhinal cortex and basolateral amygdala during trace conditioning of odor aversion in the rat.

In rats, conditioned odor aversion (COA) occurs only if the time interval separating the odor from the subsequent intoxication is very short suggesting that the memory trace of the odor is subject to rapid decay. Recent results from our laboratory have found that lesion of the entorhinal cortex (EC), and activation of the basolateral nucleus of the amygdala (BLA) rendered COA tolerant to long interstimulus interval. The present study examined whether the odor memory trace depends on the interaction between the EC and the BLA. Rats lesioned in the EC received infusions of muscimol (a GABAA receptor agonist) into the BLA immediately after the odor presentation during acquisition of COA. Injection of muscimol into BLA prevented tolerance of COA to long interstimulus interval induced by EC lesions. This suggests that EC modulates the short-term memory trace of the odor by controlling the GABAergic activity of the BLA during acquisition of COA. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Predator odor-induced conditioned fear involves the basolateral and medial amygdala.

The basolateral (BLA) and medial nucleus (MeA) of the amygdala participate in the modulation of unconditioned fear induced by predator odor. However, the specific role of these amygdalar nuclei in predator odor-induced fear memory is not known. Therefore, fiber-sparing lesions or temporary inactivation of the BLA or MeA were made either prior to or after exposure to cat odor, and conditioned contextual fear behavior was examined the next day. BLA and MeA lesions produced significant reductions in cat odor-induced unconditioned and conditioned fear-related behavior. In addition, temporary pharmacological neural inactivation methods occurring after exposure to cat odor revealed subtle behavioral alterations indicative of a role of the BLA in fear memory consolidation but not memory retrieval. In contrast, the MeA appears to play a specific role in retrieval but not consolidation. Results show that the BLA participates in the conditioned and unconditioned cat odor stimulus association that underlies fear memory, underscore a novel role of the MeA in predator odor contextual conditioning, and demonstrate different roles of the BLA and MeA in modulating consolidation and retrieval of predator odor fear memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Activation of human neutrophil procollagenase by nitrogen dioxide and peroxynitrite: a novel mechanism for procollagenase activation involving nitric oxide

Electrolytic lesions of the dorsal hippocampus (DH) produce deficits in both the acquisition and expression of conditional fear to contextual stimuli in rats. To assess whether damage to DH neurons is responsible for these deficits, we performed three experiments to examine the effects of neurotoxic N-methyl-D-aspartate (NMDA) lesions of the DH on the acquisition and expression of fear conditioning. Fear conditioning consisted of the delivery of signaled or unsignaled footshocks in a novel conditioning chamber and freezing served as the measure of conditional fear. In Experiment 1, posttraining DH lesions produced severe retrograde deficits in context fear when made either 1 or 28, but not 100, days following training. Pretraining DH lesions made 1 week before training did not affect contextual fear conditioning. Tone fear was impaired by DH lesions at all training-to-lesion intervals. In Experiment 2, posttraining (1 day), but not pretraining (1 week), DH lesions produced substantial deficits in context fear using an unsignaled shock procedure. In Experiment 3, pretraining electrolytic DH lesions produced modest deficits in context fear using the same signaled and unsignaled shock procedures used in Experiments 1 and 2, respectively. Electrolytic, but not neurotoxic, lesions also increased pre-shock locomotor activity. Collectively, this pattern of results reveals that neurons in the DH are not required for the acquisition of context fear, but have a critical and time-limited role in the expression of context fear. The normal acquisition and expression of context fear in rats with neurotoxic DH lesions made before training may be mediated by conditioning to unimodal cues in the context, a process that may rely less on the hippocampal memory system.     

Selective impairment of long-term but not short-term conditional fear by the N-methyl-D-aspartate antagonist APV.

Previous research has indicated that the competitive N-methyl-D-aspartate (NMDA) antagonist APV ({dl}-2-amino-5-phosphonovalerate) prevents the Pavlovian conditioning of fear to contextual stimuli when tested 24 hrs, but not immediately, after training. The present study investigated this differential time-dependent effect of APV on fear conditioning. Rats were given either APV or saline and presented with 3 footshocks in a distinctive chamber. Promptly after the shock, rats that had received APV exhibited a species-typical fear response: freezing. However, the freezing lasted for only a short period of time (