Amygdalar Lateralization in Fear Conditioning: Evidence for Greater Involvement of the Right Amygdala.

The relative contribution of left and right amygdalae in the acquisition and retention of fear conditioning was investigated in rats. Pretraining bilateral electrolytic lesions blocked the acquisition of conditioned fear to tone and context, whereas unilateral lesions induced partial impairments with no left-right amygdala differences. In contrast, posttraining bilateral and unilateral lesions produced significant deficits in the retention of conditioned fear to tone and context. Although no left-right difference was observed to tone, the right amygdala lesions generated greater deficits in contextual fear than the left amygdala lesions. These results indicate that fear conditioning is partially disrupted with unilateral amygdalar lesions, but that the right amygdala has greater involvement than the left amygdala when conditioning occurs under a normal brain state. (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.     

Stimulation at a site of auditory-somatosensory convergence in the medial geniculate nucleus is an effective unconditioned stimulus for fear conditioning.

The medial division of the medial geniculate nucleus (MGm) and the posterior intralaminar nucleus (PIN) are necessary for conditioning to an auditory conditioned stimulus/stimuli (CS), receive both auditory and somatosensory input, and project to the amygdala, which is involved in production of fear conditioned responses (CRs). If CS–unconditioned stimulus (UCS) convergence in the MGm-PIN is critical for fear conditioning, then microstimulation of this area should serve as an effective UCS during classical conditioning, in place of standard footshock. Guinea pigs underwent conditioning (40–60 trials) using a tone as the CS and medial geniculate complex microstimulation as the UCS. Conditioning bradycardia developed when the UCS electrodes were in the PIN. However, microstimulation was not an effective UCS for conditioning in other parts of the medial geniculate or for sensitization training in the PIN or elsewhere. Learning curves were similar to those found previously for footshock UCS. Thus, the PIN can be a locus of functional CS–UCS convergence for fear conditioning to acoustic stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fear conditioning to tone, but not to context, is attenuated by lesions of the insular cortex and posterior extension of the intralaminar complex in rats.

C. Shi and M. Davis (see record 1999-00012-009) recently reported that combined lesions of the posterior extension of the intralaminar complex (PINT) and caudal insular cortex (INS) block acquisition but not expression of fear-potentiated startle to discreet conditioned stimuli (CSs) and a footshock unconditioned stimulus (US) and proposed that PINT-INS projections to the amygdala constitute the essential US pathways involved in fear conditioning. The present study further tested this hypothesis by examining whether PINT-INS lesions block fear conditioning (as measured by freezing) to diffuse-context and discrete-tone CSs, and whether posttraining lesions with continued CS–US training result in extinction to the CSs. Posttraining lesions resulted in a selective attenuation of tone conditoning, but context conditioning was unaffected by pre-and posttraining lesions. These results do not support the view that the PINT-INS represent the essential US pathway in fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Water deprivation enhances fear conditioning to contextual, but not discrete, conditional stimuli in rats.

Water-deprived and nondeprived rats were fear conditioned with a discrete tone CS and an aversive footshock unconditioned stimulus/stimuli (UCS). 24 and 48 hrs following conditioning, conditional fear to the tone CS and the context cues of the conditioning chamber, respectively, were assessed by measuring freezing behavior. Water deprivation had no effect on baseline responding to either tone or contextual stimuli. Following either 1 or 3 tone-shock pairings, however, water deprivation selectively enhanced conditional freezing to the contextual cues of the training chamber; conditional freezing to the tone was unaffected by water deprivation. These results are consistent with the view that water deprivation affects fear conditioning via an influence on the hippocampus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Partial disruption of fear conditioning in rats with unilateral amygdala damage: correspondence with unilateral temporal lobectomy in humans

Conditioned fear in rats was assessed for the effects of pretraining amygdala lesions (unilateral vs. bilateral) across unconditioned stimulus (US) modalities (white noise vs. shock). In contrast to sham controls, unilateral amygdala lesions significantly reduced conditioned freezing responses, whereas bilateral amygdala lesions resulted in a nearly complete lack of freezing to both the conditioned stimulus (CS) and the context. The lesion effects were more pronounced for CS conditioning but were consistent across US modalities. It was concluded that white noise can serve as an effective US and that unilateral amygdala lesions attenuate but do not eliminate conditioned fear in rats. The results support our interpretation of a recent fear conditioning study in humans (K. S. LaBar, J. E. LeDoux, D. D. Spencer, & E. A. Phelps, 1995).     

Electrical Stimulation of Medial Prefrontal Cortex Reduces Conditioned Fear in a Temporally Specific Manner.

The authors recently showed that extinction of auditory fear conditioning leads to potentiation of tone-evoked activity of neurons in the infralimbic (IL) subregion of the medial prefrontal cortex, suggesting that IL inhibits fear after extinction (M. R. Milad, & G. J. Quirk, 2002). In support of this finding, pairing conditioned tones with brief (300-ms) electrical stimulation of IL reduces conditioned freezing. The present study showed that IL stimulation inhibits freezing if given 0.1 s after tone onset (the latency of tone-evoked responses) but has no effect if given either 1 s before or 1 s after tone onset. This suggests that IL gates the response of downstream structures such as the amygdala to fear stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The psychobiological basis of posttraumatic stress disorder

Posttraumatic stress disorder is a disorder with an identifiable etiological factor (exposure to a traumatic event) and with a complex symptomatology (i.e. intrusive memories, avoidance, hyperarousal) that suggests dysfunction in multiple psychobiological systems. This review considers studies of the neurobiological consequences of acute and chronic stress showing that traumatic experiences can produce long-lasting alterations in multiple neurochemical systems. The role of the locus coeruleus noradrenergic system, prefrontal cortex dopaminergic system, endogenous opiates, hypothalamic-pituitary-adrenal axis, and cortico-releasing factors are reviewed. Several models of PTSD are highlighted, including fear conditioning, kindling, and sensitization. In particular, fear conditioning to explicit and contextual cues is proposed as a model for intrusive memories reactivated by trauma-related stimuli and hyperarousal, respectively. It is argued that the amygdala plays a crucial role in the encoding and retrieval of fear memories activated by specific stimuli that have been associated with aversive events. Association involving more complex environmental stimuli and aversive events may require the involvement of the hippocampus and the bed nucleus of the stria terminalis. Repeated activation of conditioned fear memories may produce a kindling-like process which results in spontaneous intrusive memories.     

An infusion of bupivacaine into the nucleus accumbens disrupts the acquisition but not the expression of contextual fear conditioning.

An infusion of the local anesthetic bupivacaine into the nucleus accumbens (Acb) impaired the acquisition but not the expression of fear responses (freezing) to a shocked context but spared both the acquisition and expression of these responses to an auditory conditioned stimulus (CS) paired with the shock. In contrast, an infusion of bupivacaine into the amygdala impaired the acquisition and the expression of fear responses to both the CS and the context. The results demonstrate a critical role for the Acb in the acquisition but not the expression of contextual fear conditioning and are consistent with the view that this structure is involved in the processes by which rats represent a context (Westbrook, Good, & Kiernan, 1997). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurotoxic lesions of basolateral, but not central, amygdala interfere with Pavlovian second-order conditioning and reinforcer devaluation effects

Considerable evidence suggests that various discrete nuclei within the amygdala complex are critically involved in the assignment of emotional significance or value to events through associative learning. Much of this evidence comes from aversive conditioning procedures. For example, lesions of either basolateral amygdala (ABL) or the central nucleus (CN) interfere with the acquisition or expression of conditioned fear. The present study examined the effects of selective neurotoxic lesions of either ABL or CN on the acquisition of positive incentive value by a conditioned stimulus (CS) with two appetitive Pavlovian conditioning procedures. In second-order conditioning experiments, rats first received light-food pairings intended to endow the light with reinforcing power. The acquired reinforcing power of the light was then measured by examining its ability to serve as a reinforcer for second-order conditioning of a tone when tone-light pairings were given in the absence of food. Acquisition of second-order conditioning was impaired in rats with ABL lesions but not in rats with CN lesions. In reinforcer devaluation procedures, conditioned responding of rats with ABL lesions was insensitive to postconditioning changes in the value of the reinforcer, whereas rats with CN lesions, like normal rats, were able to spontaneously adjust their CRs to the current value of the reinforcer. The results of both test procedures indicate that ABL, but not CN, is part of a system involved in CSs' acquisition of positive incentive value. Together with evidence that identifies a role for CN in certain changes in attentional processing of CSs in conditioning, these results suggest that separate amygdala subsystems contribute to a variety of processes inherent in associative learning.     

Hippocampectomy disrupts auditory trace fear conditioning and contextual fear conditioning in the rat

The hippocampus is believed to be an important structure for learning tasks that require temporal processing of information. The trace classical conditioning paradigm requires temporal processing because the conditioned stimulus (CS) and the unconditioned stimulus (US) are temporally separated by an empty trace interval. The present study sought to determine whether the hippocampus was necessary for rats to perform a classical trace fear conditioning task in which each of 10 trials consisted of an auditory tone CS (1 5-s duration) followed by an empty 30-s trace interval and then a fear-producing floor-shock US (0.5-s duration). Several weeks prior to training, animals were anesthetized and given aspiration lesions of the neocortex (NEO; n = 6), hippocampus and overlying neocortex (HIPP; n = 7), or no lesions at all (control; n = 6). Approximately 24 h after trace conditioning, NEO and control animals showed a significant decrease in movement to a CS-alone presentation that was indicative of a conditioned fear response. Animals in the HIPP group did not show conditioned fear responses to the CS alone, nor did a pseudoconditioning group (n = 7) that was trained with unpaired CSs and USs. Furthermore, all groups except the HIPP group showed conditioned fear responses to the original context in which they received shock USs. One week later, HIPP, NEO, and control animals received delay fear-conditioning trials with no trace interval separating the CS and US. Six of seven HIPP animals could perform the delay version, but none could perform the trace version. This result suggests that the trace fear task is a reliable and useful model for examining the neural mechanisms of hippocampally dependent learning.     

Central and basolateral amygdala neurons crash the aversive conditioning party: Theoretical comment on Rorick-Kehn and Steinmetz (2005).

Rorick-Kehn and Steinmetz (2005) (see record 2005-13804-012) report that neurons in the central and basolateral nuclei of the amygdala exhibit learning-related spike firing to conditional stimuli associated with shock in 3 different aversive conditioning paradigms: eyeblink conditioning, fear conditioning, and signaled avoidance conditioning. Central nucleus neurons responded in all 3 tasks, whereas basolateral nucleus neurons were more activated by fear and avoidance conditioning. These results reveal that amygdala neurons are differentially engaged by aversive conditioning, but questions remain concerning the associative basis and functional role for these unit responses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampal lesions alter conditioning to conditional and contextual stimuli

The control of conditioned fear behaviour by a conditional stimulus (CS) and contextual stimuli (CXT) was compared in rats with lesions to the hippocampus (HPC) or neocortex (CO), and operated controls (OC). After classical fear conditioning in a distinctive context, rats were subsequently tested in the presence of the CS and CXT (CS + CXT), the CS alone (CS-only), or context alone (CXT-only). Two experiments were conducted in which conditioned fear was measured by an active avoidance response (experiment 1) or by response suppression (experiment 2). Groups did not differ in acquiring the conditioned fear response, as measured in the CS + CON test but, in both experiments, hippocampal (HPC) groups exhibited more conditioned fear behaviour than controls in the CXT-Only and CS-Only conditions. It was suggested that control rats conditioned the fear response to a stimulus complex that incorporated the CS and CTX. Rats with HPC lesions did not form this association between the stimulus elements; instead they segregated the CS and CXT and formed independent associations between the conditioned response (CR) and each component. In showing that HPC damage disrupts the process of forming associations between environmental stimuli and that the effect is not restricted to contextual cues, the results help to resolve apparently contradictory findings regarding the role of HPC in contextual information processing.     

Isolation and characterization of the human prosaposin promoter

Male C57BL/6N mice were chosen to determine Fos production during acquisition of context-dependent fear and after re-exposure to the conditioning context. Fear-conditioning was induced by a single exposure of mice to a context followed by an electric shock. Control groups consisted of mice exposed to context only (Context group) or to an immediate electric shock. When contextual retention was measured 24 h after conditioning (retention test 1), significant contextual generalization was observed. However, when animals were exposed to a different context from days 2-5 after conditioning and then tested for retention on day 6 (retention test 2), generalization was markedly reduced. After the training, the fear-conditioned mice produced higher Fos levels than mice exposed to an immediate shock in the hippocampus, medial amygdaloid nucleus and parietal somatosensory cortex. Both shock groups produced significantly more Fos than the Context group in the central nucleus of the amygdala. After retention test 1, fear-conditioned mice generated more Fos in the hippocampus and central amygdaloid nucleus than the two control groups. However, all groups exhibited similarly low Fos production after retention test 2. The results demonstrated that simultaneous Fos production in the hippocampus, central and medial nuclei of amygdala and somatosensory parietal cortex closely paralleled the ability of mice to acquire conditioned fear. In contrast, Fos production after the retention tests did not correlate with the expression of conditioned fear.     

Differential modulation of changes in hippocampal-septal synaptic excitability by the amygdala as a function of either elemental or contextual fear conditioning in mice

Recent data obtained using a classic fear conditioning paradigm showed a dissociation between the retention of associations relative to contextual information (dependent on the hippocampal formation) and the retention of elemental associations (dependent on the amygdala). Furthermore, it was reported that conditioned emotional responses (CERs) could be dissociated from the recollection of the learning experience (declarative memory) in humans and from modifications of the hippocampal-septal excitability in animals. Our aim was to determine whether these two systems ("behavioral expression" system and "factual memory" system) interact by examining the consequences of amygdalar lesions (1) on the modifications of hippocampal-septal excitability and (2) on the behavioral expression of fear (freezing) resulting from an aversive conditioning during reexposure to conditional stimuli (CSs). During conditioning, to modulate the predictive nature of the context and of a discrete stimulus (tone) on the unconditional stimulus (US) occurrence, the phasic discrete CS was paired with the US or randomly distributed with regard to the US. After the lesion, the CER was dramatically reduced during reexposure to the CSs, whatever the type of acquisition. However, the changes in hippocampal-septal excitability persisted but were altered. For controls, a decrease in septal excitability was observed during reexposure to the conditioning context only for the "unpaired group" (predictive context case). Conversely, among lesioned subjects this decrease was observed in the "paired group" (predictive discrete CS case), whereas this decrease was significantly reduced in the unpaired group with respect to the matched control group. The amplitude and the direction of these modifications suggest a differential modulation of hippocampal-septal excitability by the amygdala to amplify the contribution of the more predictive association signaling the occurrence of the aversive event.     

Evidence of contextual fear after lesions of the hippocampus: a disruption of freezing but not fear-potentiated startle

The roles of the dorsal hippocampus and the central nucleus of the amygdala in the expression of contextual fear were assessed using two measures of conditioned fear: freezing and fear-potentiated startle. A discriminable context conditioning paradigm was developed that demonstrated both conditioned freezing and fear-potentiated startle in a context paired previously with foot shock, relative to a context in which foot shock had never been presented. Post-training lesions of the central nucleus of the amygdala completely blocked both contextual freezing and fear-potentiated startle. Post-training lesions of the dorsal hippocampus attenuated contextual freezing, consistent with previous reports in the literature; however, these same lesions had no effect on fear-potentiated startle, suggesting preserved contextual fear. These results suggest that lesions of the hippocampus disrupt the freezing response but not contextual fear itself.     

Protein kinase Mzeta maintains fear memory in the amygdala but not in the hippocampus.

Recent work on the long-term stability of memory and synaptic plasticity has identified a potentially critical role for protein kinase Mzeta (PKMζ). PKMζ is a constitutively active, atypical isoform of protein kinase C that is believed to maintain long term potentiation at hippocampal synapses in vitro. In behaving animals, local inhibition of PKMζ disrupts spatial memory in the hippocampus and conditioned taste aversion memory in the insular cortex. The role of PKMζ in context fear memory is less clear. This study examined the role of PKMζ in amygdala and hippocampal neurons following a standard fear conditioning protocol. The results indicate that PKMζ inhibition in the amygdala, but not in the hippocampus, can disrupt fear memory. This suggests that PKMζ may only maintain select forms of memory in specific brain structures and does not participate in a universal memory storage mechanism. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of facial expressions on the classical conditioning of fear.

Previous research has demonstrated that particular facial expressions more readily acquire excitatory strength when paired with a congruent unconditioned stimulus than when paired with an incongruent outcome. The present study with a total of 36 undergraduates extends these findings on the excitatory inhibitory role of facial expressions by demonstrating that particular facial expressions (fear and happy), when paired with a neutral cue (tone), can influence conditioning to the neutral conditioned stimulus (CS). Ss who had a fear expression paired with the neutral CS responded more to the fear expression than to the neutral CS, whereas Ss who had a happy expression paired with the neutral CS responded more to the neutral cue than to the happy expression. These findings strongly support predictions from "overshadowing" or "blocking" models of classical conditioning. (12 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Microinjection of morphine into the nucleus accumbens impairs contextual learning in rats.

A unilateral microinjection of morphine into the amygdala impaired fear conditioning to both a conditioned stimulus (CS) paired with shock and the context where shock occurred, whereas a microinjection of morphine into the nucleus accumbens (NA) spared fear conditioning to the CS but impaired, in a dose-dependent and receptor-specific manner, fear conditioning to the context. Morphine in the NA also spared extinction and latent inhibition of a CS but abolished the context specificity of these effects and eliminated the increase in discriminability that results from preexposure to a to-be-shocked context. The results identify a role for the NA in the processes by which rats learn about a context and are discussed in terms of an opioid disruption of either within-context associations or of attentional processes that contribute to such associations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuronal plasticity induced by fear conditioning is expressed during paradoxical sleep: Evidence from simultaneous recordings in the lateral amygdala and the medial geniculate in rats.

The lateral amygdala (LA) and its afferent connections from the medial geniculate (MG) play a pivotal role in auditory fear conditioning. The authors evaluated whether those neurons could express in paradoxical sleep (PS) physiological plasticity acquired in waking. After a habituation session, rats received tone–footshock pairings in 3 sessions. After each session, the tone alone was presented during PS episodes. Multiunit activity was simultaneously recorded in the LA and the medial part of the MG. Both in LA and MG, conditioned responses emerged rapidly (within 5 trials), were expressed with short latency (