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Rats emit 22 kHz ultrasonic vocalizations (USVs) in association with pain, fear, or distress. Whereas the capacity to produce USVs is innate, reactivity to them appears to require experience. Specifically, 22 kHz USVs fail to elicit freezing behavior in naïve laboratory rats. However, these "alarm calls" do elicit freezing in rats that previously experienced foot shocks. These findings led to the hypothesis that acquired reactivity is based on "autoconditioning"-learning in which self-generated 22 kHz USVs serve as Pavlovian cues that become associated with foot shocks. The current study tested the autoconditioning hypothesis by devocalizing rats through a unilateral transection of the recurrent laryngeal nerve (Experimental group). Subsequently, animals in both the Experimental and sham-operated Control groups received five unsignaled foot shocks. One or two days later, both groups were tested for USV-elicited freezing in a novel context. Recurrent laryngeal nerve transection failed to prevent or even diminish USV-elicited freezing. In fact, both groups showed large and comparable increases in freezing to USV presentations. A subset of Control animals failed to vocalize during conditioning, while some Experimental animals did vocalize during conditioning. Animals were therefore re-grouped and reanalyzed based on whether they vocalized during conditioning. Again, both groups showed large and comparable increases in USV-elicited freezing. These results disconfirm the essential tenet or prediction of the autoconditioning hypothesis. Alternative mechanisms for acquired reactivity to 22 kHz USVs are therefore considered., (Published by Elsevier Inc.)

Rats emit ultrasonic vocalizations (USVs) at ∼22kHz and ∼50kHz, respectively, during negative and positive affective states. Among rats raised in a naturalistic social context, 22-kHz USVs serve as "alarm cries" that can elicit freezing behavior. By contrast, several studies show that naïve laboratory rats do not freeze in response to alarm cries. An obvious and consistent interpretation of these facts is that USV-elicited freezing depends on a type of social learning that ordinarily does not occur in the laboratory. However, the present study explored an alternative and explicitly non-social learning mechanism. Animals in the experimental group received multiple footshocks that elicited 22-kHz USVs. Animals in the control group were exposed to the same chamber but did not receive footshocks and, therefore, did not vocalize. When subsequently tested in a novel context, experimental animals froze in response to a novel 22-kHz USV but were unresponsive to a novel 50-kHz USV. Vocalizing during the aversive experience was predictive of subsequent freezing to the 22-kHz USV. As expected from previous studies, control animals failed to freeze to either USV. We propose that the experimental animals learned to associate their own 22-kHz USVs with an internal fear state and selectively generalized this "autoconditioning" to a novel 22-kHz USV. This non-social form of learning seems sufficiently rapid, reliable, and stimulus-specific to be ethologically adaptive., (Copyright © 2012 Elsevier B.V. All rights reserved.)

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.

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.

An electrophysiological stimulation paradigm similar to one that produces Pavlovian conditioning was applied to synaptic inputs to pyramidal neurons of hippocampal brain slices. Persistent synaptic enhancement was induced in one of two weak synaptic inputs by pairing high-frequency electrical stimulation of the weak input with stimulation of a third, stronger input to the same region. Forward (temporally overlapping) but not backward (temporally separate) pairings caused this enhancement. Thus hippocampal synapses in vitro can undergo the conditional and selective type of associative modification that could provide the substrate for some of the mnemonic functions in which the hippocampus is thought to participate.