Lesions of the central nucleus of the amygdala block conditioned excitation, but not conditioned inhibition of fear as measured with the fear-potentiated startle effect.

Lesions of the amygdala block the expression of fear-potentiated startle following either moderate or extensive light?+?shock training. The present experiment assessed whether lesions of the amygdala would also block the expression of conditioned inhibition of fear. Rats were given conditioned inhibition training in which a light was paired with shock and a noise and light compound was presented in the absence of shock. Then half of the rats were given bilateral electrolytic lesions of the amygdala and the remaining rats were sham operated. Lesions of the amygdala blocked the expression of fear-potentiated startle to the light. To assess whether conditioned inhibition was disrupted, rats were retrained with light?+?shock pairings with no further conditioned inhibition training. Amygdala lesioned rats reacquired fear-potentiated startle to the light (Kim & Davis, 1993). Importantly, the noise conditioned inhibitor retained its ability to inhibit fear-potentiated startle to the retrained light. These results indicate that areas of the amygdala critical for initial performance of fear-potentiated startle are not critical for the expression of conditioned inhibition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Posttraining lesions of the amygdala interfere with fear-potentiated startle to both visual and auditory conditioned stimuli in C57BL/6J mice.

The fear-potentiated startle paradigm has been used with great success to examine conditioned fear in both rats and humans. The purpose of the present experiment was to extend the authors' previous findings and further validate the fear-potentiated startle paradigm in mice. In Experiments 1 and 2, C57BL/6J mice were given Pavlovian fear conditioning with either an auditory or a visual conditioned stimulus. Similar to data collected with rats, fear-potentiated startle was observed for both stimulus modalities. In Experiment 3, posttraining lesions of the amygdala disrupted fear-potentiated startle in both conditioned stimulus modalities. These data are consistent with amygdala lesion studies in rats and suggest that fear-potentiated startle in mice requires an intact amygdala. Together, these results extend the authors' previous results and provide the basis for using this well-understood behavioral paradigm for examining the molecular mechanisms of conditioned fear in transgenic and knockout mice. (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)     

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.     

Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in startle increases produced by conditioned versus unconditioned fear

The amplitude of the acoustic startle response is reliably enhanced when elicited in the presence of bright light (light-enhanced startle) or in the presence of cues previously paired with shock (fear-potentiated startle). Light-enhanced startle appears to reflect an unconditioned response to an anxiogenic stimulus, whereas fear-potentiated startle reflects a conditioned response to a fear-eliciting stimulus. We examine the involvement of the basolateral nucleus of the amygdala, the central nucleus of the amygdala, and the bed nucleus of the stria terminalis in both phenomena. Immediately before light-enhanced or fear-potentiated startle testing, rats received intracranial infusions of the AMPA receptor antagonist 2, 3-dihydroxy-6-nitro-7-sulphamoylbenzo(F)-quinoxaline (3 microg) or PBS. Infusions into the central nucleus of the amygdala blocked fear-potentiated but not light-enhanced startle, and infusions into the bed nucleus of the stria terminalis blocked light-enhanced but not fear-potentiated startle. Infusions into the basolateral amygdala disrupted both phenomena. These findings indicate that the neuroanatomical substrates of fear-potentiated and light-enhanced startle, and perhaps more generally of conditioned and unconditioned fear, may be anatomically dissociated.     

Fear-potentiated startle in two strains of inbred mice.

The fear-potentiated startle paradigm has been used with great success to examine conditioned fear in both rats and humans. The purpose of this study was to examine fear-potentiated startle in inbred mice. One-month-old C57BL/6J (C57) and DBA/2J (DBA) mice were given tone?+?foot shock training trials. The amplitude of the acoustic startle reflex was measured in the presence and absence of the tone both before and after training. Both strains showed fear-potentiated startle after training as evidenced by larger startle amplitudes in the presence of the tone than in its absence. However, the magnitude of fear-potentiated startle was greater in DBA mice than in C57 mice. These results not only demonstrate fear-potentiated startle in mice for the first time but also suggest that fear-potentiated startle can be influenced by characteristics of the mouse strain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Normal conditioning inhibition and extinction of freezing and fear-potentiated startle following electrolytic lesions of medial prefrontal cortex in rats.

The authors investigated the role of medial prefrontal cortex (mPFC) in the inhibition of conditioned fear in rats using both Pavlovian extinction and conditioned inhibition paradigms. In Experiment 1, lesions of ventral mPFC did not interfere with conditioned inhibition of the fear-potentiated startle response. In Experiment 2, lesions made after acquisition of fear conditioning did not retard extinction of fear to a visual conditioned stimulus (CS) and did not impair "reinstatement" of fear after unsignaled presentations of the unconditioned stimulus. In Experiment 3, lesions made before fear conditioning did not retard extinction of fear-potentiated startle or freezing to an auditory CS. In both Experiments 2 and 3, extinction of fear to contextual cues was also unaffected by the lesions. These results indicate that ventral mPFC is not essential for the inhibition of fear under a variety of circumstances. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Delayed development of fear-potentiated startle in rats.

Examined the developmental emergence of fear-potentiated startle in rats ranging in age from 16 to 75 days. In Exp 1, a pure tone served as the CS and an acoustic startle pulse served as the unconditioned stimulus (UCS) for fear conditioning. Fear-potentiated startle by the tone CS was observed in rats 23 days of age and older but not in rats 16 days of age. In Exp 2, a light served as the CS. Rats 30 days of age and older showed fear-potentiated startle, whereas 23-day-old rats did not. The final experiment demonstrated that another behavioral index of fear, stimulus-elicited freezing, was observed earlier in development than fear-potentiated startle, confirming the effectiveness of the training procedure for conditioning fear. Results suggest that fear-potentiated startle is a relatively late-emerging response system, parallelling the development of conditioned autonomic changes (e.g., heart rate) rather than that of freezing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Electrolytic lesions of the amygdala block acquisition and expression of fear-potentiated startle even with extensive training but do not prevent reacquisition.

Lesions of the amygdala have been shown to block the expression of fear-potentiated startle (increased acoustic startle in the presence of a cue previously paired with shock). In the present study, bilateral lesions of the central nucleus of the amygdala given after extensive training totally blocked the expression of fear-potentiated startle but did not prevent reacquisition. In contrast, when the lesions were made before any training, the lesioned rats did not show potentiated startle even with extensive training. Thus, the central nucleus of the amygdala normally seems to be required for the initial acquisition and expression of potentiated startle regardless of the degree of learning. However, reacquisition of potentiated startle can occur without the central nucleus, which implies the presence of a secondary brain system that can compensate for the loss of the central nucleus of the amygdala under some circumstances. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hyperexcitability: Exaggerated fear-potentiated startle produced by partial amygdala kindling.

The present study asked whether partial amygdala kindling would affect the expression of conditioned fear-potentiated startle. Rats were conditioned to be fearful of a light. They were then stimulated bilaterally in the amygdala or hippocampus on 2 consecutive days (partial kindling). Rats were tested 24 hr later for fear-potentiated startle. Amygdala-kindled rats had exaggerated fear-potentiated startle compared to sham-kindled rats. Hippocampus-kindled rats also displayed fear-potentiated startle. but no greater than that of sham-kindled rats. Partial amygdala kindling induced c-fos messenger RNA (mRNA) expression, a marker for neuronal activation, throughout the limbic and neocortices. In contrast, partial hippocampus kindling induced c-fos mRNA in the hippocampus only. The data suggest that kindled-induced hyperexcitability of the amygdala and limbic cortices produced exaggerated conditioned fear-potentiated startle. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lack of a temporal gradient of retrograde amnesia following NMDA-induced lesions of the basolateral anygdala assessed with the fear-potentiated startle paradigm.

M. Kim and M. Davis (see record 1994-28571-001) previously reported that electrolytic lesions of the central nucleus of the amygdala, made 6 or 30 days after training, complctcly blockcd the expression of fear potentiated startle in rats. The present study shows that excitotoxic lesions of the basolateral amygdala also block fear-potentiated startle and do so whether the lesions are made soon (i.e., 6 days) or long (i.e., 30 days) after training. The relevance of these findings to various theories of amygdala function is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intra-amygdala infusion of the N-methyl-D-aspartate receptor antagonist AP5 blocks acquisition but not expression of fear-potentiated startle to an auditory conditioned stimulus.

The fear-potentiated startle paradigm, in which the amplitude of the startle reflex is enhanced in the presence of a stimulus previously paired with footshock, was used to measure aversive conditioning after intra-amygdala infusion of the competitive N-methyl-{d}-aspartate (NMDA) receptor antagonist {dl}-2-amino-5-phosphonopentanoic acid (AP5). Infusion of 2.5 μg/side AP5 immediately before 5 noise–footshock pairings on each of 2 consecutive days dose-dependently blocked acquisition or consolidation of auditory fear-potentiated startle, consistent with previous results obtained with a visual stimulus. Somatosensory or auditory transmission deficits do not appear to be induced by intra-amygdala AP5, because rats reacted normally to footshocks and showed reliable potentiated startle expression after pretesting AP5 infusion at a dose that blocked acquisition. Together with earlier reports, these data suggest that an NMDA-dependent process localized in or near the amygdala may be necessary for the acquisition of conditioned fear across different sensory modalities. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Contribution of ventral tegmental area dopamine neurons to expression of conditional fear: Effects of electrical stimulation, excitotoxin lesions, and quinpirole infusion on potentiated startle in rats.

Potentiated startle was used in this study to determine the fear-motivational functions of the ventral tegmental area (VTA) in rats. In Experiment 1, electrical stimulation of the VTA increased acoustic startle amplitudes. In subsequent experiments fear-potentiated startle was assessed following axon-sparing N-methyl-D-aspartate (NMDA) lesions of the VTA and after bilateral intra-VTA infusion of the dopamine (DA) D2/3 receptor agonist quinpirole. The NMDA lesions produced substantial cell loss in the medial ventral tegmentum and suppressed fear expression. Similarly, inhibition of DA neuronal activity associated with locally administered quinpirole blocked fear-potentiated startle. It was suggested that VTA neurons and their forebrain DA projections regulate levels of aversive emotional arousal within the amygdala-based fear system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lesions of the bed nucleus of the stria terminalis block sensitization of the acoustic startle reflex produced by repeated stress, but not fear-potentiated startle

1. The effects of lesions of the bed nucleus of the stria terminalis (BST) on the acquisition of conditioned fear were examined. In Experiment 1, BST lesions did not block acquisition of fear-potentiated startle to an explicit visual conditioned stimulus (CS) over 20 days of training. However, BST lesions blocked a gradual elevation in baseline startle also seen over the course of training. 2. The gradual increase in baseline startle was replicated in Experiment 2 without the presence of an explicit CS, using unoperated subjects. Experiment 2 showed that the elevation was due to repetitive exposure to shock, because unshocked control subjects did not show any elevation over sessions. 3. In Experiment 3, lesions of the BST did not disrupt rapid sensitization of the startle reflex by footshock, showing that different neural substrates underlie sensitization of startle by acute and chronic exposure to footshock. 4. These data indicate that the BST, despite its anatomical continuity with the amygdala, is not critically involved in the acquisition of conditioned fear to an explicit CS. Nevertheless, the BST is involved in mediating a stress-induced elevation in the startle reflex. This suggests that the BST and the CeA, which constitute part of the "extended amygdala" have complementary roles in responses to stress.     

"Disruption of contextual freezing, but not contextual blocking of fear-potentiated startle, after lesions of the dorsal hippocampus": Correction to McNish et al (2000).

Reports an error in "Disruption of contextual freezing, but not contextual blocking of fear-potentiated startle, after lesions of the dorsal hippocampus" by Kenneth A. McNish, Jonathan C. Gewirtz and Michael Davis (Behavioral Neuroscience, 2000[Feb], Vol 114[1], 64-76). The captions for Figure 4 (p. 70) and Figure 5 (p. 72) were printed incorrectly. The caption used for Figure 4 should appear under Figure 5, and the caption used for Figure 5 should appear under Figure 4. (The following abstract of the original article appeared in record 2000-13470-005.) The role of the dorsal hippocampus in contextual fear conditioning was investigated with a contextual blocking paradigm. In Experiment 1, rats were given pairings of a light conditioned stimulus (CS) and footshock after preexposure either to footshock or to the context alone. The group preexposed to footshock showed poorer fear conditioning to the light CS, as measured by the fear-potentiated startle reflex. In Experiment 2, a group preexposed to footshock in the same context showed poorer fear conditioning to the light CS than did a group preexposed to footshock in a different context, indicating contextual blocking of fear-potentiated startle. In Experiment 3, lesions of the dorsal hippocampus had no effect on contextual blocking, even though contextual freezing was disrupted. The sparing of contextual blocking indicated that contextual memory was intact following hippocampal lesions, despite the disruption of contextual freezing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lesions of the Dorsal Hippocampus Block Trace Fear Conditioned Potentiation of Startle.

Several studies show that the hippocampus is critical for the memories mediating trace and contextual fear conditioning. This study investigates whether N-methyl-D-aspartate-induced lesions of the dorsal hippocampus made prior to training affect context fear conditioning and trace fear conditioning measured with the fear-potentiated startle. Pretraining excitotoxic lesions of the dorsal hippocampus blocked acquisition of trace fear conditioning to a tone stimulus but did not affect context fear conditioning. These data indicate that without a dorsal hippocampus rats are unable to acquire trace conditioning but can acquire contextual fear when fear is measured by potentiation of the startle response. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fear-potentiated startle and electrically evoked startle mediated by synapses in rostrolateral midbrain.

Startle amplitudes are increased when acoustic startle responses are elicited in the presence of a stimulus that has previously been paired with shock. This "fear-potentiated" startle response appears to be mediated via the caudal ventral amygdalofugal pathway to the brainstem. Electrical stimulation of this pathway evokes unconditioned startlelike responses. Collision tests have shown that a monosynaptic connection from amygdala to midbrain mediates these responses. Collision tests here localize these synapses mediating electrically evoked startlelike responses to the rostrolateral midbrain in awake rats. To test whether rostrolateral midbrain synapses also mediate fear-potentiated startle, we lesioned cells in these sites with ibotenic acid. These lesions completely blocked fear potentiation of acoustic startle. These same lesions did not block potentiation of startle by d-amphetamine (6 mg/kg). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Central CRF receptor antagonist α-helical CRF9-41 blocks reinstatement of extinguished fear: The role of the bed nucleus of the stria terminalis.

The present experiments assessed the necessity of central CRF in reinstatement of extinguished fear. Using the fear-potentiated startle procedure, rats were given light-shock pairings (fear conditioning) followed by light-alone extinction training. Rats were then given unsignaled shocks to reinstate fear to the light conditioned stimulus (CS). Intracerebroventricular administration of the CRF antagonist α-Helical CRF9-41 prior to reinstatement training dose-dependently prevented reinstatement. Further, α-Helical CRF9-41 administration prior to reinstatement training or the test for reinstatement of fear to the extinguished CS prevented reinstatement at both treatment times, suggesting that CRF activity is critical for this type of return of fear to an extinguished CS. The abolition of reinstatement by drug administration was not due to state-dependent learning, as rats treated with the drug prior to both reinstatement training or testing also failed α-Helical CRF9-41 in the bed nucleus of the stria terminalis suggested that this area is a site at which central CRF is involved in this form of relapse. (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)     

Temporal specificity of fear conditioning: Effects of different conditioned stimulus--unconditioned stimulus intervals on the fear-potentiated startle effect.

Separate groups of rats were given 30 pairings of a light (conditioned stimulus, CS) and a 500-ms shock (unconditioned stimulus, US) at CS–US intervals of 0, 25, 50, 100, 200, 800, 3,200, 12,800, or 51,200 ms. Other groups had lights and shocks inconsistently paired. The startle reflex was elicited 2–4 days later with a noise burst alone or 25–51,200 ms after light onset. After CS–US pairings over a range of intervals (25–51,200 ms), startle was potentiated in testing, as rapidly as 50 ms after light onset. Magnitude of potentiation and resistance to extinction were generally greater with longer CS–US intervals. In several groups, potentiation was maximal at a test interval that matched the CS–US interval used in training. This temporal specificity sharpened with increasing numbers of training trials but even occurred with a single training trial in which a 51,200-ms CS–US interval was used. Data indicate that even during simple fear conditioning (FC), animals rapidly learn a temporal CS–US relationship. This has implications for understanding the neural mechanisms of FC. (PsycINFO Database Record (c) 2010 APA, all rights reserved)