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The present review examines the role of perirhinal cortex (PRC) in Pavlovian fear conditioning. The focus is on rats, partly because so much is known, behaviorally and neurobiologically, about fear conditioning in these animals. In addition, the neuroanatomy and neurophysiology of rat PRC have been described in considerable detail at the cellular and systems levels. The evidence suggests that PRC can serve at least two types of mnemonic functions in Pavlovian fear conditioning. The first function, termed "stimulus unitization," refers to the ability to treat two or more separate items or stimulus elements as a single entity. Supporting evidence for this perceptual function comes from studies of context conditioning as well as delay conditioning to discontinuous auditory cues. In a delay paradigm, the conditional stimulus (CS) and unconditional stimulus (US) overlap temporally and co-terminate. The second PRC function entails a type of "transient memory." Supporting evidence comes from studies of trace cue conditioning, where there is a temporal gap or trace interval between the CS offset and the US onset. For learning to occur, there must be a transient CS representation during the trace interval. We advance a novel neurophysiological mechanism for this transient representation. These two hypothesized functions of PRC are consistent with inferences based on non-aversive forms of learning., (Copyright © 2012 Wiley Periodicals, Inc.)

Intelligent behavior requires transient memory, which entails the ability to retain information over short time periods. A newly-emerging hypothesis posits that endogenous persistent firing (EPF) is the neurophysiological foundation for aspects or types of transient memory. EPF is enabled by the activation of muscarinic acetylcholine receptors (mAChRs) and is triggered by suprathreshold stimulation. EPF occurs in several brain regions, including the lateral amygdala (LA). The present study examined the role of amygdalar mAChRs in trace fear conditioning, a paradigm that requires transient memory. If mAChR-dependent EPF selectively supports transient memory, then blocking amygdalar mAChRs should impair trace conditioning, while sparing delay and context conditioning, which presumably do not rely upon transient memory. To test the EPF hypothesis, LA was bilaterally infused, prior to trace or delay conditioning, with either a mAChR antagonist (scopolamine) or saline. Computerized video analysis quantified the amount of freezing elicited by the cue and by the training context. Scopolamine infusion profoundly reduced freezing in the trace conditioning group but had no significant effect on delay or context conditioning. This pattern of results was uniquely anticipated by the EPF hypothesis. The present findings are discussed in terms of a systems-level theory of how EPF in LA and several other brain regions might help support trace fear conditioning.

Posttraumatic stress disorder (PTSD) is common following the experience of a natural disaster and sleep disturbance is an important influence on its course in adults, but little research is available examining sleep and PTSD in youths. This study's objective was to evaluate the role of sleep disturbance and the developmentally influenced factor of fear of sleeping alone in the maintenance of posttraumatic stress (PTS) symptoms in youths. Deidentified data of 191 Hurricane Katrina survivors ages 8 to 15 were used in this study. We found cross-sectional relationships of sleep disturbance and fear of sleeping alone with PTS symptom severity. Longitudinal analysis also indicated that general sleep disturbance at 24 months (T1) was predictive of PTS symptoms severity at 30 months (T2) even after adjusting for PTS symptom severity at T1, age, sex, and continued disrepair to the home. These results have implications for intervention strategies among youth exposed to traumatic events., (Copyright © 2011 International Society for Traumatic Stress Studies.)

Damage to rat perirhinal cortex (PR) profoundly impairs fear conditioning to 22kHz ultrasonic vocalizations (USVs), but has no effect on fear conditioning to continuous tones. The most obvious difference between these two sounds is that continuous tones have no internal temporal structure, whereas USVs consist of strings of discrete calls separated by temporal discontinuities. PR was hypothesized to support the fusion or integration of discontinuous auditory segments into unitary representations or "auditory objects". This transform was suggested to be necessary for normal fear conditioning to occur. These ideas naturally assume that the effect of PR damage on auditory fear conditioning is not peculiar to 22kHz USVs. The present study directly tested these ideas by using a different set of continuous and discontinuous auditory cues. Control and PR-damaged rats were fear conditioned to a 53kHz USV, a 53kHz continuous tone, or a 53kHz discontinuous tone. The continuous and discontinuous tones matched the 53kHz USV in terms of duration, loudness, and principle frequency. The on/off pattern of the discontinuous tone matched the pattern of the individual calls of the 53kHz USV. The on/off pattern of the 50kHz USV was very different from the patterns in the 22kHz USVs that have been comparably examined. Rats with PR damage were profoundly impaired in fear conditioning to both discontinuous cues, but they were unimpaired in conditioning to the continuous cue. The implications of this temporal discontinuity effect are explored in terms of contemporary ideas about PR function.

The hippocampus is well-known to be critical for trace fear conditioning, but nothing is known about the importance of perirhinal cortex (PR), which has reciprocal connections with hippocampus. PR damage severely impairs delay fear conditioning to ultrasonic vocalizations (USVs) and discontinuous tones (pips), but has no effect on delay conditioning to continuous tones. Here we demonstrate that trace auditory fear conditioning also critically depends on PR function. The trace interval between the CS offset and the US onset was 16s. Pre-training neurotoxic lesions were produced through multiple injections of N-methyl-D-aspartate along the full length of PR, which was directly visualized during the injections. Control animals received injections with phosphate-buffered saline. Three-dimensional reconstructions of the lesion volumes demonstrated that the neurotoxic damage was well-localized to PR and included most of its anterior-posterior extent. Automated video analysis quantified freezing behavior, which served as the conditional response. PR-damaged rats were profoundly impaired in trace conditioning to either of three different CSs (a USV, tone pips, and a continuous tone) as well as conditioning to the training context. Within both the lesion and control groups, the type of cue had no effect on the mean CR. The overall PR lesion effect size was 2.7 for cue conditioning and 3.9 for context conditioning. We suggest that the role of PR in trace fear conditioning may be distinct from some of its more perceptual functions. The results further define the essential circuitry underlying trace fear conditioning to auditory cues.

Pretraining lesions of rat perirhinal (PR) cortex impair fear conditioning to ultrasonic vocalizations (USVs) but have no effect on conditioning to continuous tones. This study attempted to deconstruct USVs into simpler stimulus features that cause fear conditioning to be PR-dependent. Rats were conditioned to one of three cues: a multicall 19-kHz USV, a 19-kHz discontinuous tone, and a 19-kHz continuous tone. The discontinuous tone duplicated the on/off pattern of the individual calls in the USV, but it lacked the characteristic frequency modulations. Well-localized neurotoxic PR lesions impaired conditioning to the USV, the discontinuous tone, and the training context. However, PR lesions had no effect on conditioning to the continuous tone. The authors suggest that the lesion effects on fear conditioning to both cues and contexts reflect the essential role of PR in binding stimulus elements together into unitary representations.

Rodent ultrasonic vocalizations (USVs) are ethologically critical social signals. Rats emit 22kHz USVs and 50kHz USVs, respectively, in conjunction with negative and positive affective states. Little is known about what controls emotional reactivity to these social signals. Using male Sprague-Dawley rats, we examined unconditional and conditional freezing behavior in response to the following auditory stimuli: three 22kHz USVs, a discontinuous tone whose frequency and on-off pattern matched one of the USVs, a continuous tone with the same or lower frequencies, a 4kHz discontinuous tone with an on-off pattern matched to one of the USVs, and a 50kHz USV. There were no differences among these stimuli in terms of the unconditional elicitation of freezing behavior. Thus, the stimuli were equally neutral before conditioning. During differential fear conditioning, one of these stimuli (the CS(+)) always co-terminated with a footshock unconditional stimulus (US) and another stimulus (the CS(-)) was explicitly unpaired with the US. There were no significant differences among these cues in CS(+)-elicited freezing behavior. Thus, the stimuli were equally salient or effective as cues in supporting fear conditioning. When the CS(+) was a 22kHz USV or a similar stimulus, rats discriminated based on the principal frequency and/or the temporal pattern of the stimulus. However, when these same stimuli served as the CS(-), discrimination failed due to generalization from the CS(+). Thus, the stimuli differed markedly in the specificity of conditioning. This strikingly asymmetrical stimulus generalization is a novel bias in discrimination.

Pretraining lesions of rat perirhinal cortex (PR) severely impair pavlovian fear conditioning to a 22 kHz ultrasonic vocalization (USV) cue. However, PR lesions are without significant effect when the cue is a continuous tone at the same or a lower frequency. Here we examined fear-conditioning-produced changes in single-unit firing elicited in rat PR by a 22 kHz tone cue or a 22 kHz USV cue. Chronic recording electrodes were introduced from the lateral surface of the skull. Altogether, 200 well isolated units were studied in 28 rats. Overall, 73% of the recorded single units (145 of 200 units) evidenced statistically significant firing changes in response to the tone or USV conditional stimulus (CS) after it had been paired several times with an aversive unconditional stimulus (US). Interestingly, 33% of units (66 of 200 units) that were initially CS-unresponsive became CS-responsive after conditioning. After conditioning, there were two notable differences between single-unit responses elicited by the USV cue and those elicited by the tone cue. First, 11% of the units (14 of 123 units) recorded from the USV-conditioned group displayed a precisely timed increase in firing rate during the 260 ms interval in which the US had previously occurred. This US-timed response was unique to the USV-conditioned group. Second, the mean latency of cue-elicited firing was approximately 30 ms longer in the USV-conditioned group than in the tone-conditioned group. These cue-specific differences in acquired firing latencies and acquired firing patterns suggest that spectrotemporal properties of a CS can control the essential circuitry or neurophysiological mechanisms underlying fear conditioning.

Trace and contextual fear conditioning were evaluated in adult (3-6 months), early middle-aged (8-12 months), late middle-aged (16-20 months), and aged (24-33 months) Sprague-Dawley rats. After trace conditioning, aged animals exhibited significantly less freezing to the tone conditioned stimulus and training context. Levels of trace-cue and context conditioning were negatively correlated with age (r = -0.56 and -0.59, respectively) and positively correlated with each other (r = +0.52). Aged rats showed robust conditioning in short- and long-delay fear paradigms, suggesting that the trace interval, rather than the use of a long interstimulus interval, is responsible for the aging-related deficits in trace fear conditioning. The authors suggest that these aging-related conditioning deficits furnish useful indices of functional changes within hippocampus or perirhinal cortex., (Copyright 2006 APA, all rights reserved.)

Kamin blocking in fear conditioning is thought to reflect diminished processing of the unconditional stimulus (US) in the presence of a conditional stimulus (CS-super(+)) that was previously paired with this US. According to Fanselow's (1998) hypothesis, the CS-super(+) drives output from the amygdala that ultimately produces analgesia by causing opiate release onto afferent pain circuits. This hypothesis was explored quantitatively through neurophysiological simulations. The results suggest that opiate-mediated, negative-feedback control of US processing is too slow for efficient blocking of cue conditioning. The reason is that conditioning-produced synaptic modifications can be induced before the opiate-mediated inhibition has any substantial effect on US processing. The results suggest the existence of an additional, faster-acting, inhibitory neurotransmitter in the blocking circuit., (((c) 2006 APA, all rights reserved).)

Auditory information can reach the lateral nucleus of the amygdala (LA) through a monosynaptic thalamic projection or a polysynaptic cortical route. The polymodal input from the perirhinal cortex (PR) is a major informational gateway to the LA and nearby structures. Pretraining PR lesions impair fear conditioning to a context, but there have been no reports that they cause deficits in delay conditioning to an auditory cue. The direct subcortical projection to the LA seems sufficient to support delay conditioning to a tone conditional stimulus (CS). We examined the effect of PR lesions on delay conditioning to two different tone conditional stimuli (4 and 22 kHz tones; both 10 sec duration) and two different rat ultrasonic vocalization (USV) conditional stimuli (10 sec of "22 kHz USVs"). The two USV conditional stimuli were multi-call segments that were recorded (digitized at 100 kHz) from two different rats. One USV CS was a continuous sequence of eight calls, and the other was a portion of a continuous sequence of six calls. PR lesions significantly impaired conditioning to both USV conditional stimuli and to the training context but had no significant effect on conditioning to either tone CS. The role of PR in fear conditioning appears not to be determined by whether the conditional stimuli serve as contexts or cues, but instead by the nature or complexity of the stimuli or stimulus configurations. These cue-specific effects of PR lesions are suggested to reflect differences in the stimulus features that are encoded in the two CS pathways to the LA.

Temporal encoding in Pavlovian fear conditioning was examined through conditional facilitation of the short-latency (Rl) component of the rat eyeblink reflex. Rats were fear-conditioned to a tone conditional stimulus (CS) with either a 3- or 9-s interstimulus interval (ISI) between CS onset and the onset of the grid-shock unconditional stimulus (US). Rl facilitation was tested over 2 days, in counterbalanced order, at a latency of 3 s and 9 s from CS onset. CS-produced Rl facilitation, the conditional response (CR), was 3-4 times larger when the test latency equaled the conditioning ISI. These results, coupled with the known neurophysiology of Rl facilitation, suggest that this CR could disclose differences in the time course of CS-generated output from the amygdala when driven by cortical versus subcortical CS-CR pathways.

Bilateral amygdala (AM) lesions prevent the acquisition of fear-related conditional responses (CRs) in rats, a result that is most commonly concluded to reflect a learning or memory deficit. An alternative hypothesis is that AM-lesioned animals fail to acquire certain fear CRs simply because they cannot perform these behaviors. This performance-deficit hypothesis is usually invoked in regard to studies in which the CR is freezing, the most commonly measured behavior. Here we explore this interpretation by measuring two different behaviors [freezing and 22 kHz ultrasonic vocalization (USV)] elicited under three conditions (during context conditioning, during subsequent retention testing, and after ejaculation) in experimental rats [that received electrolytic lesions of the central nucleus of the amygdala (ACe)] and control animals (that received a sham operation). If ACe damage produces a discrete motor deficit that specifically renders the animal unable to remain immobile, then freezing should be blocked or impaired when elicited under all three conditions, whereas USV should be spared. Alternatively, if ACe damage selectively interferes with CR formation, maintenance, or expression, then both freezing and USV should be blocked or impaired when elicited as CRs during acquisition and retention testing but spared when evoked as unconditional responses (URs) to ejaculation. ACe damage blocked or severely impaired both freezing and USV elicited as CRs but had no effect on either behavior elicited as URs. We reject the motor-deficit hypothesis and discuss some viable alternatives.

A tone conditioned stimulus (CS) previously paired with a grid shock unconditioned stimulus (US) can greatly enhance the early electromyographic (EMG) component (R1) of the rat eyeblink reflex. The hypothesis that the central nucleus of the amygdala (ACe) is an essential part of the circuitry mediating conditioned R1 enhancement was tested. After bilateral ACe lesions (L) or a sham operation (S), rats received paired presentations of the CS and US (P) or explicitly unpaired CS and US presentations (U), resulting in 4 groups: P/S, P/L, U/S, and U/L. ACe lesions completely prevented conditioned R1 enhancement, which was only exhibited in Group P/S. In the latter group, the "preextinction" conditioned enhancement effect was roughly a 2-fold increase in the R1 magnitude. Circuit-level mechanisms are discussed, and some advantages of the eyeblink EMG response in this general conditioning paradigm are considered.

There is conflicting evidence regarding the issue of whether NMDA receptors in the basolateral amygdalar complex (BLA) are critically involved in the expression of conditioned fear. This matter was addressed by infusing the rat BLA with d,l-2-amino-5-phosphonovaleric acid (APV), a competitive NMDA receptor antagonist. APV infusion into the BLA was reported to block the expression of conditioned fear when measured by freezing but not when measured by fear-potentiated startle response to a loud noise. To examine this issue further, here we used multiple indices of conditioned fear, including analgesia, 22 kHz ultrasonic vocalization (USV), defecation, and freezing. Rats with bilateral BLA cannula implants underwent fear conditioning consisting of 10 tone-footshock pairings. Before context and tone fear-retention tests, animals received intra-BLA infusions with APV (2.5 microg/side) or artificial CSF. Both tone and context tests demonstrated that the expression of conditioned freezing, USV, defecation, and analgesia were significantly impaired by intra-amygdalar infusions of APV. In a second set of experiments, intra-BLA infusions of APV markedly impaired the normal expression of postshock fear responses during training, as measured by freezing, USV, and defecation. Immediate postshock fear expression was predictive of subsequent fear retention to the tone and context when the animals were not infused. These results are consistent with the hypothesis that amygdalar NMDA receptors participate in normal synaptic transmission and therefore the overall functioning of the amygdala.