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)     

Lesions of the amygdala, but not of the cerebellum or red nucleus, block conditioned fear as measured with the potentiated startle paradigm.

In Exp I, 97 male Sprague-Dawley albino rats were given 10 light–shock pairings on 2 successive days. At 24–48 hrs following training, groups of Ss received bilateral transection of the cerebellar peduncles, bilateral lesions of the red nucleus (which receives most of the cerebellar efferents), or bilateral lesions of the central nucleus of the amygdala. Controls were sham operated. At 3–4 days after surgery, Ss were tested for potentiated startle (PS [increased acoustic startle in the presence of the light previously paired with shock]). PS was blocked by lesions of the central nucleus of the amygdala but not by transection of the cerebellar peduncles or lesions of the red nucleus. Exp II, in which a visual prepulse test was used with 14 Ss, indicated that the blockade of PS observed in Ss with amygdala lesions could not be attributed to optic tract damage. Exp III, with 20 Ss, demonstrated that the absence of potentiation in Ss with amygdala lesions was not simply due to a lowered startle level ceiling, because these Ss could show increased startle with increased stimulus intensity and with administration of intraperitoneal strychnine, (0.75 mg/kg), a drug that increases startle. Results are consistent with the hypothesis that the amygdala is involved in fear conditioning. (64 ref) (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.     

Shock-induced hyperalgesia: III. Role of the bed nucleus of the stria terminalis and amygdaloid nuclei.

Rats exposed to a few moderately intense (1 mA) shocks subsequently exhibit lower vocalization thresholds to shock and thermal stimuli. They also exhibit facilitated learning in a Pavlovian conditioning paradigm. Together, these results suggest that shock exposure can enhance pain (hyperalgesia). The present study examined the role of the amygdala and bed nucleus of the stria terminalis (BNST), 2 systems that have been implicated in the induction and maintenance of negative affective states. Experiment 1 showed that lesions of the central, but not the basolateral, amygdala eliminate shock-induced hyperalgesia as measured by a decrease in vocalization thresholds to shock. Experiment 2 revealed that central nucleus lesions also prevent shock-induced sensitization of the vocalization response to heat. Anterior, but not posterior, BNST lesions had a similar effect. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

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.     

Sensitization of the acoustic startle reflex by footshock.

Administration of footshock (500-ms duration, 0.2–2.4 mA) increased the amplitude of the startle reflex for a long time after its presentation. The effect occurred with a single footshock, although its magnitude and consistency across animals were greater with 5 or 10 footshocks presented 1/s. The facilitatory effect came on within 2–4 min with a 0.6-mA shock, peaking in about 10 min and then dissipating over the next 40 min. Stronger shocks also increased startle, but with a more delayed onset of facilitation (8–20 min). Footshocks increased startle in rats not previously given startle-eliciting stimuli, indicating sensitization rather than dishabituation. The facilitatory effect may not be attributable to a rapid conditioning to the experimental context, because a change in lighting conditions from shock presentation to testing did not attenuate shock sensitization. This excitatory effect of shock on startle may represent the unconditioned effect of shock that can become associated with a neutral stimulus to support classical fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of the central nucleus of the amygdala in olfactory heart rate conditioning.

The role of the central nucleus of the amygdala on olfactory heart rate conditioning in the infant rat was investigated. The conditioned stimulus (CS) consisted of a 10-s presentation of grape juice odor that was immediately followed by a 0.5-s, 0.35-mA subcutaneous shock. A sensitization control group was also run. Three days prior to testing, Ss received either bilateral electrolytic lesions of the central nucleus of the amygdala, sham lesions, or were left unperturbed. Results show that damage to the central nucleus of the amygdala severely impaired olfactory heart rate conditioning but that it had no deleterious effect on the heart rate orienting response to that stimulus or on the heart rate unconditioned response (UCR) to shock. Results are analogous to those in previous research on auditory heart rate conditioning and suggest that the central nucleus of the amygdala may constitute a necessary stage in the transduction of the CS into a cardiac conditioned response (CR) regardless of sensory modality. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

N-methyl-D-aspartate lesions of the lateral and basolateral nuclei of the amygdaloid block fear-potentiated startle and shock sensitization of startle.

Destroyed cell bodies in the lateral and basolateral amygdaloid nuclei by local infusion of N-methyl-{d}-aspartate. Adjacent areas, such as the central amygdaloid nucleus, were largely spared. Lesions were carried out before training and testing (Exp 1) or after training but before testing (Exp 2). In both cases, the lesions completely blocked fear-potentiated startle (increased acoustic startle in the presence of a light previously paired with footshock). They also blocked increased startle after a series of footshocks, provided they damaged the most anterior part of the basolateral nucleus. It is suggested that the lateral or basolateral amygdaloid nuclei (or both) relay visual information to the central amygdaloid nucleus, which is also critical for fear-potentiated startle. In addition, activation of the most anterior part of the basolateral nucleus may be critical for processing shock information during fear conditioning. (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)     

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)     

Enhancement of acoustic startle by electrical stimulation of the amygdala.

The present study demonstrated that electrical stimulation of the amygdala enhanced the acoustic startle response. A 25-ms train of 0.1-ms pulses initiated 5 ms before the onset of a 20-ms noise burst significantly increased startle at currents from 40 to 400 μA. Electrode placements just medial to the amygdala (in the pathway connecting the amygdala to the brain stem) increased startle with the lowest currents. Startle was also increased in all animals with stimulation in the central, medial, and intercalated nuclei of the amygdala. Stimulation in areas surrounding the amygdaloid complex was ineffective. In a second experiment, paired pulses with interpulse intervals between 0.1 and 20.0 ms delivered to the amygdala demonstrated that the stimulated axons had a distribution of refractory periods between 0.6 and 1.0 ms. This suggests that the population of neurons which subserves the enhancement of acoustic startle is fairly homogeneous and has small, myelinated axons. (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)     

Role of the hippocampus, the bed nucleus of the stria terminalis, and the amygdala in the excitatory effect of corticotropin-releasing hormone on the acoustic startle reflex

Previously, we demonstrated that transection of the fimbria/fornix blocked the excitatory effect of corticotropin-releasing hormone (CRH) on startle (CRH-enhanced startle), suggesting that the hippocampus and its efferent target areas that communicate via the fimbria may be critically involved in CRH-enhanced startle. The bed nucleus of the stria terminalis (BNST) receives direct projections from the ventral hippocampus via the fimbria/fornix. Therefore, the role of the ventral hippocampus, the BNST, and the amygdala in CRH-enhanced startle was investigated. NMDA lesions of the BNST completely blocked CRH-enhanced startle, whereas chemical lesions of the ventral hippocampus and the amygdala failed to block CRH-enhanced startle. However, the same amygdala-lesioned animals showed a complete blockade of fear-potentiated startle, a conditioned fear response sensitive to manipulations of the amygdala. In contrast, BNST-lesioned rats had normal fear-potentiated startle. This indicates a double dissociation between the BNST and the amygdala in two different paradigms that enhance startle amplitude. Microinfusions of CRH into the BNST, but not into the ventral hippocampus, mimicked intracerebroventricular CRH effects. Furthermore, infusion of a CRH antagonist into the BNST blocked CRH-enhanced startle in a dose-dependent manner. Control studies showed that this blockade did not result from either leakage of the antagonist into the ventricular system or a local anesthetic effect caused by infusion of the antagonist into the BNST. The present studies strongly suggest that CRH in the CSF can activate the BNST, which could lead to activation of brainstem and hypothalamic BNST target areas involved in anxiety and stress responses.     

Neural systems involved in fear and anxiety measured with fear-potentiated startle.

A good deal is now known about the neural circuitry involved in how conditioned fear can augment a simple reflex (fear-potentiated startle). This involves visual or auditory as well as shock pathways that project via the thalamus and perirhinal or insular cortex to the basolateral amygdala (BLA). The BLA projects to the central (CeA) and medial (MeA) nuclei of the amygdala, which project indirectly to a particular part of the acoustic startle pathway in the brainstem. N-methyl-D-aspartate (NMDA) receptors, as well as various intracellular cascades in the amygdala, are critical for fear learning, which is then mediated by glutamate acting in the CeA. Less predictable stimuli, such as a long-duration bright light or a fearful context, activate the BLA, which projects to the bed nucleus of the stria terminalis (BNST), which projects to the startle pathway much as the CeA does. The anxiogenic peptide corticotropin-releasing hormone increases startle by acting directly in the BNST. CeA-mediated behaviors may represent stimulus-specific fear, whereas BNST-mediated behaviors are more akin to anxiety. NMDA receptors are also involved in extinction of conditioned fear, and both extinction in rats and exposure-based psychotherapy in humans are facilitated by an NMDA-partial agonist called D-cycloserine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Olfactory bulbectomy enhances sensitization of the acoustic startle reflex produced by acute or repeated stress.

The effects of olfactory bulbectomy on the acoustic startle reflex and shock-induced sensitization of the startle reflex were examined in 3 experiments. In Experiment 1, bulbectomized animals showed a modest increase in baseline startle responding following surgery, and normal acquisition of fear-potentiated startle, but a pronounced increase in baseline startle responding during the course of conditioning relative to sham-operated controls. In Experiments 2 and 3, bulbectomized animals showed shock-induced sensitization of the startle reflex to shock intensities that did not produce sensitization in sham and unoperated controls. These data suggest that olfactory bulbectomy results in an increased vulnerability to stressors, which may be mediated by a disinhibition of the amygdala or other structures involved in mediating stress and anxiety. Thus, the olfactory bulbectomy model of depression may share some similarities with other stress-induced models of depression. (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)     

Footshock-induced sensitization of electrically elicited startle reflexes.

Acoustic startle is a short-latency reflex mediated by a neural circuit consisting of the ventral cochlear nucleus (VCN), ventral nucleus of the lateral lemniscus (VLL), the nucleus reticularis pontis caudalis (RPC), and the spinal cord. The present study sought to determine the point along this pathway where footshocks might ultimately alter neural transmission to affect startle response. Rats were implanted bilaterally with stimulating electrodes in either the VCN, VLL, or RPC. Startle could be elicited acoustically with a noise burst or electrically with a single-pulse stimulus to either the VCN, VLL, or RPC before and after a train of ten 0.6-mA, 500-ms shocks presented at a rate of 1 shock/s. Startle elicited acoustically or electrically in the VCN or VLL was significantly elevated following shocks. Data suggest that footshock sensitization ultimately alters transmission in the startle circuit at the RPC. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ibotenic acid lesions of the dorsal prefrontal cortex disrupt the expression of behavioral sensitization to cocaine

The present study determined the effect of bilateral lesions of specific cortical or thalamic nuclei that provide excitatory amino acid afferents to the nucleus accumbens (i.e. the dorsal prefrontal cortex, ventral prefrontal cortex, amygdala, hippocampus and periventricular thalamus) on the expression of cocaine-induced behavioral sensitization. Lesions of these nuclei were made during a three-week withdrawal period following repeated daily injections of cocaine or saline. The results indicate that dorsal prefrontal cortex lesions block the expression of behavioral sensitization to cocaine, while ventral prefrontal cortex, fimbria fornix, amygdala and thalamic lesions have no effect. A subsequent microdialysis experiment was performed in order to evaluate the effect of dorsal prefrontal cortex lesions on glutamate transmission in the nucleus accumbens core of cocaine- and saline-pretreated rats. The systemic injection of cocaine produced a significant increase in extracellular glutamate in the nucleus accumbens core among animals with a sham surgery; this effect was blocked by a bilateral lesion of the dorsal prefrontal cortex. Taken together, these results indicate that the dorsal prefrontal cortex, which provides excitatory amino acid input selectively to the core region of the nucleus accumbens, enhances the expression of behavioral sensitization to cocaine by increasing glutamate transmission in this subnucleus.     

Peripheral and intraamygdalar administration of the dopamine D? receptor antagonist SCH 23390 blocks fear-potentiated startle but not shock reactivity or the shock sensitization of acoustic startle.

Central dopamine (DA) activity is thought to play a role in fear motivation. The aim of the present study was to assess the involvement of DA D? receptors in emotional learning. The authors report that peripheral and intraamygdalar administration of the specific D? receptor antagonist SCH 23390 blocked the acquisition of fear-potentiated startle. Analysis of shock reactivity during footshock administration revealed that the learning impairment could not be explained by a diminution in the aversive properties of the unconditioned stimulus. Additionally, systemic and intraamygdalar injection of SCH 23390 did not alter fear expression as measured with the shock sensitization of acoustic startle. The potential contribution of mesoamygdaloid DA to the acquisition and retrieval of conditioned fear responses is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)