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PubMed1992

Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala.

Data derived from in vitro preparations indicate that NMDA receptors play a critical role in synaptic plasticity in the CNS. More recently, in vivo pharmacological manipulations have suggested that an NMDA-dependent process may be involved in specific forms of behavioral plasticity. All of the work thus far has focused on the possible role of NMDA receptors in the acquisition of responses. However, there are many examples in the behavioral literature of learning-induced changes that involve the reduction or elimination of a previously acquired response. Experimental extinction is a primary example of the elimination of a learned response. Experimental extinction is well described in the behavioral literature, but has not received the same attention in the neurobiological literature. As a result, the neural mechanisms that underlie this important form of learning are not at all understood. In the present experiments, the fear-potentiated startle paradigm was employed to begin to investigate neural mechanisms of extinction. The results show that infusion of the NMDA antagonist D,L-2-amino-5-phosphonovaleric acid (AP5) into the amygdala, a limbic structure known to be important for fear conditioning, dose-dependently blocked extinction of conditioned fear. Control experiments showed that the blockade of extinction was neither the result of the permanent disruption of amygdaloid function nor the result of decreased sensitivity of the animals to the conditioned stimulus. Infusion of AP5 into the interpositus nucleus of the cerebellum, a control site, did not block extinction. Finally, intra-amygdala infusion of a selected dose of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione did not block extinction of conditioned fear. These results, together with a previous report from our laboratory (Miserendino et al., 1990), demonstrate the importance of the amygdala in the elaboration of conditioned fear and suggest that an NMDA-dependent process might underlie the extinction of conditioned fear.

2-Amino-5-phosphonovalerate↗

PubMed2005

Systemic administration of lipopolysaccharide and interleukin-1beta have different effects on memory consolidation.

Sickness behaviour is an adaptive response to infection that includes lethargy, anorexia and of direct relevance to this work, learning and memory impairments. It has been suggested that proinflammatory cytokines may disrupt learning and memory by interfering with memory consolidation [C.R. Pugh, K. Kumagawa, M. Fleshner, L.R. Watkins, S.F. Maier, J.R. Rudy, Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning, Brain Behav. Immun. 12 (1998) 212-229]. We tested whether systemic interleukin-1beta is sufficient to induce impairments in memory consolidation by comparing the effects of post-learning administration of interleukin-1beta with, the potent endotoxin, lipopolysaccharide; and saline, on retention of conditioned fear of a context. We administered an acute intraperitoneal injection of lipopolysaccharide, interleukin-1beta or saline immediately following a single conditioning episode in which rats received two tone-shock pairings. Two days following the learning episode, animals were tested for strength of conditioned responding to both the context and tone. Lipopolysaccharide-injected animals, but not interleukin-1beta-injected animals, exhibited less conditioned fear of context compared to saline-treated controls. All groups showed similar conditioned fear of tone. Our results suggest that systemic interleukin-1beta is not sufficient to disrupt memory consolidation, but rather, the synergistic actions of the proinflammatory cytokines released by lipopolysaccharide are required to disrupt memory consolidation.

Acoustic Stimulation↗

PubMed1979

Autoanalgesia: acquisition, blockade and relationship to opiate binding.

Acquisition of autoanalgesia (behaviorally activated antinociception) was assessed across 7 consecutive days by shocking rats 10 sec after the determination of their tail-flick latencies. Thus the effect of conditioned fear on antinociception was being investigated, since each shock preceded the subsequent tail-flick test by 24 h. Autoanalgesia was acquired by the second fear-conditioning trial. Although pretreatment with naltrexone or diazepam had no effect, spinal cord transection at the thoracic level effectively obviated autoanalgesia. Investigations of opiate and opioid binding indicated significantly less binding in the fear-conditioned rats as well as an inverse relationship between binding and antinociception. These changes in binding are suggestive of partial mediation of autoanalgesia by an endogenous opiate peptide that is released by the fear-conditioning procedure.

Analgesia↗

PubMed2005

Rat ultrasonic vocalization in aversively motivated situations and the role of individual differences in anxiety-related behavior.

Our previous work has shown that male Wistar rats, although identical in breeder, age and housing conditions, can differ systematically in their anxiety-related behavior as measured in the elevated plus-maze. Since such individual dispositions can affect the responsiveness in other aversively motivated situations, we asked in a 1st experiment whether such rats might also differ in a test of conditioned fear. Based on their levels of spontaneous open arm avoidance in the elevated plus-maze, 20 adult male Wistar rats were divided into those with "high open arm" (HOA) versus "low open arm" (LOA) time. These rats were then tested in a standard fear conditioning paradigm. During the conditioning procedure, they received 6 tone (3 kHz, 20 s) and shock (0.5 mA, 0.5 s) pairings, each followed by a 60 s inter-stimulus interval. Conditioned responses to the tone were tested 24 h thereafter. During both days, freezing behavior and ultrasonic vocalization were measured. Differences in ultrasonic vocalization between HOA and LOA rats were detected during the conditioning day, where vocalization was more likely in LOA rats. Furthermore, LOA rats emitted calls with higher frequency components than HOA rats. On the subsequent day of testing, the number of animals vocalizing, and the rate of vocalization was decreased, and call differences between groups were no longer detectable. In freezing, differences between HOA and LOA rats were observed on the conditioning day, where LOA rats showed more freezing behavior during the tone/shock intervals. Also, on the test day, they showed more freezing behavior during the tone intervals compared to HOA rats. These results indicate that acute and conditioned responses of rats in a conventional fear conditioning paradigm can depend on individual dispositions of anxiety-related behavior as measured with the elevated plus-maze. In a 2nd experiment, we asked whether exposure to an elevated plus-maze would lead to ultrasonic vocalization, which we tested in rats which had been handled or non-handled prior to testing. Most importantly, we found that none of the animals displayed any vocalization in the plus-maze, neither during a 1st nor a repeated test 1 day later. These data are discussed with respect to the presumed role of ultrasonic vocalization in aversively motivated situations, and the mechanisms, which may account for the behavioral differences between HOA and LOA rats in such tests.

Analysis of Variance↗

PubMed2003

Temporally massed CS presentations generate more fear extinction than spaced presentations.

Rodent fear conditioning models both excitatory learning and the pathogenesis of human anxiety, whereas extinction of conditional fear is a paradigm of inhibitory learning and the explicit model for behavior therapy. Many studies support a general learning rule for acquisition: Temporally spaced training is more effective than massed training. The authors asked whether this rule applies to extinction of conditional fear in mice. The authors find that both short- and long-term fear extinction are greater with temporally massed presentations of the conditional stimulus (CS). The data also indicate that once CS presentations are sufficiently massed to initiate, or "induce," extinction learning, further CS presentations are more effective when spaced.

Animals↗

PubMed2005

Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder.

Fear is an adaptive response that initiates defensive behavior to protect animals and humans from danger. However, anxiety disorders, such as Posttraumatic Stress Disorder (PTSD), can occur when fear is inappropriately regulated. Fear conditioning can be used to study aspects of PTSD, and we have developed a model in which pre-exposure to a stressor of repeated footshock enhances conditional fear responding to a single context-shock pairing. The experiments in this chapter address interpretations of this effect including generalization and summation or fear, inflation, and altered pain sensitivity. The results of these experiments lead to the conclusion that pre-exposure to shock sensitizes conditional fear responding to similar less intense stressors. This sensitization effect resists exposure therapy (extinction) and amnestic (NMDA antagonist) treatment. The pattern predicts why in PTSD patients, mild stressors cause reactions more appropriate for the original traumatic stressor and why new fears are so readily formed in these patients. This model can facilitate the study of neurobiological mechanisms underlying sensitization of responses observed in PTSD.

2-Amino-5-phosphonovalerate↗

PubMed2005

Activation of group II metabotropic glutamate receptors induces depotentiation in amygdala slices and reduces fear-potentiated startle in rats.

There is a close correlation between long-term potentiation (LTP) in the synapses of lateral amygdala (LA) and fear conditioning in animals. We predict that reversal of LTP (depotentiation) in this area of the brain may ameliorate conditioned fear. Activation of group II metabotropic glutamate receptors (mGluR II) with DCG-IV induces depotentiation in the LA. The induction of depotentiation is independent of NMDA receptors, L-type Ca++ channels, and calcineurin activity, but requires presynaptic activity and extracellular Ca++. (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) depotentiation is accompanied by a decrease in the frequency but not the amplitude of miniature excitatory post-synaptic currents (mEPSCs) and could be mimicked by endogenously released glutamate. DCG-IV inhibited the release of glutamate evoked by 4-AP but not that evoked by ionomycin, suggesting that the effect of DCG-IV is not mediated by an action downstream of Ca++ entry. Intra-amygdala infusion of mGluR II agonist blocks the consolidation of fear memory measured with fear-potentiated startle. Taken together, the present results characterize the properties of DCG-IV depotentiation and reveal a close parallel between depotentiation in the amygdala slice and the reduction of conditioned fear in animals.

Amygdala↗

PubMed1999

Plasticity in the mediodorsal thalamo-prefrontal cortical transmission in behaving mice.

We studied changes in thalamo-prefrontal cortical transmission in behaving mice following both low-frequency stimulation of the mediodorsal thalamus (MD) and during extinction of a conditioned fear response. Electrical stimulation of the MD induces a field potential in the medial prefrontal cortex (mPFC) characterized by two initial negative-positive complexes (N1-P1 and N2-P2) followed by two positive-negative complexes (P2-N3 and P3-N4). The N1-P1 and N2-P2 complexes were identified as resulting from orthodromic and antidromic prefrontal activation, respectively. Because the two complexes were not often easily dissociated, plasticity in the prefrontal synaptic transmission was considered to result from changes in N1-P2 amplitude. Low-frequency thalamic stimulation (1, 200 pulses at 2 Hz) produced either long-term (at least 32 min) depression or potentiation of the N1-P2 amplitude. Mice submitted to fear conditioning (tone-shock association), displayed on the first day of extinction (tone-alone presentations) a strong freezing behavior, which decreased progressively, but was still high the following day. Extinction of conditioned fear was accompanied the first day by a depression of prefrontal transmission, which was converted into potentiation the following day. Potentiation of prefrontal transmission lasted at least 24 h following the second day of the fear extinction procedure. In conclusion, low-frequency thalamic stimulation can produce, in behaving mice, either depression or potentiation of prefrontal synaptic transmission. Decrease in prefrontal synaptic transmission observed during the first day of extinction may reflect processing of the high degree of predictiveness of danger (unconditioned stimulus: US) by the aversive conditioned stimulus (CS). However, the subsequent potentiation of transmission in the mPFC may be related to processing of cognitive information such as the CS will no longer be followed by the US, even if emotional response (freezing) to the CS is still high.

Acoustic Stimulation↗

PubMed2005

The lateral amygdala processes the value of conditioned and unconditioned aversive stimuli.

The amygdala is critical for acquiring and expressing conditioned fear responses elicited by sensory stimuli that predict future punishment, but there is conflicting evidence about whether the amygdala is necessary for perceiving the aversive qualities of painful or noxious stimuli that inflict primary punishment. To investigate this question, rats were fear conditioned by pairing a sequence of auditory pips (the conditioned stimulus, or CS) with a brief train of shocks to one eyelid (the unconditioned stimulus, or US). Conditioned responding to the CS was assessed by measuring freezing responses during a test session conducted 24 h after training, and unconditioned responding to the US was assessed by measuring head movements evoked by the eyelid shocks during training. We found that pre-training electrolytic lesions of the amygdala's lateral (LA) nucleus blocked acquisition of conditioned freezing to the CS, and also significantly attenuated unconditioned head movements evoked by the US. Similarly, bilateral inactivation of the amygdala with the GABA-A agonist muscimol impaired acquisition of CS-evoked freezing, and also attenuated US-evoked responses during training. However, when amygdala synaptic plasticity was blocked by infusion of the NR2B receptor antagonist ifenprodil, acquisition of conditioned freezing was impaired but shock reactivity was unaffected. These findings indicate that neural activity within the amygdala is important for both predicting and perceiving the aversive qualities of noxious stimuli, and that synaptic plasticity within LA is the mechanism by which the CS becomes associated with the US during fear conditioning.

Acoustic Stimulation↗

PubMed1995

Intra-amygdaloid projections of the basolateral and basomedial nuclei in the cat: Phaseolus vulgaris-leucoagglutinin anterograde tracing at the light and electron microscopic level.

The amygdaloid complex plays an essential role in auditory fear conditioning of the Pavlovian type. The available evidence suggests that the lateral nucleus is the input station of the amygdala for auditory conditioned stimuli, whereas the central medial nucleus is the output for conditioned fear responses. However, the intrinsic pathway transmitting auditory information about the conditioned stimulus from the lateral to the central medial nuclei is unknown as there are no direct projections between these nuclei. The present study was undertaken to determine if the main intra-amygdaloid targets of the lateral nucleus, namely the basomedial and basolateral nuclei, project to the central medial nucleus. To this end, iontophoretic injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin were performed in these nuclei. To rule out the possibility that the anterograde labeling reflected passing fibers merging with the major fiber bundles that course in and around the central medial nucleus, labeled terminals and varicosities were observed in the electron microscope. It was determined that the basolateral and basomedial nuclei have partially overlapping intraamygdaloid targets. They both project to the central medial nucleus, nucleus of the lateral olfactory tract and peri-amygdaloid cortex, but have limited projections to each other. Small Phaseolus vulgaris-leucoagglutinin injections in both nuclei gave rise to prominent intranuclear projections but only the basomedial nucleus was found to project to the lateral and anterior cortical nuclei. At the electron microscopic level, all labeled axon terminals and varicosities formed asymmetric synapses (n = 245) with dendritic spines (83%) or with dendritic shafts (17%). This is the first unambiguous demonstration that the basolateral and basomedial nuclei project to the central medial nucleus. Since these nuclei constitute the main intra-amygdaloid targets of the lateral nucleus, they represent likely candidates for the transmission of auditory conditioned stimuli to the central medial nucleus in auditory fear conditioning.

Amygdala↗

PubMed1997

Fear-potentiated startle conditioning in humans: explicit and contextual cue conditioning following paired versus unpaired training.

Conditioned fear in response to explicit and contextual cues was examined using the startle reflex in three groups of participants over two sessions separated by 4-5 days. The conditioned stimulus (CS) was paired with an aversive unconditioned stimulus (US) (shock) during conditioning in the paired but not in the unpaired group. In the reaction time (RT) group, the US was a nonaversive visual signal for an RT task. In the paired group, the CS potentiated startle in the postconditioning phase. This conditioned response was fully retained over the retention interval. There was no substantial change in baseline startle (startle delivered in the absence of CS). By contrast, startle was not potentiated by the CS in the unpaired group, but baseline startle was increased from Session 1 to Session 2. In the RT group, startle was not affected by the CS, and baseline startle was reduced from Session 1 to Session 2. These results suggest that paired presentations of a CS and an aversive US result in conditioned fear in response to the CS but little contextual fear, whereas unpaired presentations of a CS and US leads to poor explicit cue conditioning but substantial contextual fear.

Adolescent↗

PubMed2003

Mitogen-activated protein kinase signaling in the hippocampus and its modulation by corticotropin-releasing factor receptor 2: a possible link between stress and fear memory.

A coordinated activation of multiple interlinked signaling pathways involving cAMP-dependent protein kinase (PKA) and mitogen-activated extracellular signal-regulated kinases (Mek-1/2) regulates gene expression and neuronal changes underlying memory consolidation. In the present study we investigated whether these molecular cascades might mediate the effects of stress on memory formation. We also investigated the role of hippocampal corticotropin-releasing factor receptor 2 (CRF2) in stress-enhanced learning and molecular signaling mediated by PKA, Mek-1/2, and their downstream targets extracellularly regulated kinases 1 and 2 (Erk-1/2) and p90-ribosomal-s-kinase-1 (p90Rsk-1). Acute 1 hr immobilization was used as a stressful stimulus, and one-trial context-dependent fear conditioning was used as a model for associative learning. Training of BALB/c mice 3 hr after the end of immobilization resulted in an enhancement of conditioned fear, as indicated by significantly increased freezing behavior of stressed when compared with nonstressed mice. Interestingly, Erk-1/2 phosphorylation after conditioning of nonstressed and stressed mice depended on PKA and Mek-1/2, respectively. Intrahippocampal injection of the selective Mek-1/2 inhibitor U0126 or CRF2 antagonist antisauvagine-30 (aSvg-30) prevented stress-enhanced fear conditioning and Mek-1/2-dependent activation of Erk-1/2 and p90Rsk-1. aSvg-30 did not affect the phosphorylation of the PKA regulatory subunit II of stressed mice. The molecular and behavioral effects of CRF2 coincided with stress-induced upregulation of CRF2 mRNA. These results suggest that modulation of Mek-1/2-dependent signaling by hippocampal CRF2 can be selectively involved in the delayed effects of stress on memory consolidation.

Animals↗

PubMed2006

Human amygdala activity during the expression of fear responses.

The initial learning and subsequent behavioral expression of fear are often viewed as independent processes with potentially unique neural substrates. Laboratory animal studies of Pavlovian fear conditioning suggest that the amygdala is important for both forming stimulus associations and for subsequently expressing learned behavioral responses. In the present article, human amygdala activity was studied during the autonomic expression of conditional fear in two differential conditioning experiments with event-related functional magnetic resonance imaging and concurrent recording of skin conductance responses (SCRs). Trials were classified on the basis of individual participants' SCRs. Significant amygdala responding was detected only during trials on which a signal both predicted shock and elicited significant conditional SCR. Conditional stimulus presentation or autonomic activity alone was not sufficient. These results indicate that amygdala activity may specifically reflect the expression of learned fear responses and support the position that this region plays a central role in the expression of emotional reactions.

Adolescent↗

PubMed1984

Strain difference in fear between spontaneously hypertensive and normotensive rats is mediated by adrenal cortical hormones.

In the present study we sought to determine whether the strain difference in fear reactivity between spontaneously hypertensive rats (SHR) and strain-matched WKY controls might be related to adrenocortical function. SHR and WKY were subjected to adrenalectomy prior to classical fear conditioning. Adrenal cortical steroids were replaced in some animals. Adrenalectomy produced comparable effects on conditioned fear reactivity in SHR and WKY and steroid replacement reversed the effects of adrenalectomy in both strains. However, a larger dose was required to compensate for adrenalectomy in SHR. These date implicate functions related, directly or indirectly, to the adrenal cortex, in the maintenance of the strain difference in fear reactivity.

Adrenal Cortex Hormones↗

PubMed2005

Pavlovian conditioning: a functional perspective.

From a functional perspective, Pavlovian conditioning involves learning about conditioned stimuli (CSs) that have a pre-existing relation to an unconditioned stimulus (US) rather than learning about arbitrary or neutral CSs. In addition, the most important product of learning involves changes in how the organism responds to the US, not in how it responds to the CS, because the US is the more biologically relevant stimulus. These concepts are illustrated using examples from a variety of behavioral and physiological situations including caloric intake and digestion, breast feeding, poison-avoidance learning, eyeblink conditioning, sexual conditioning, fear conditioning, aggression, and drug tolerance and sensitization.

Adaptation, Psychological↗

PubMed1993

Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear.

The effects of amygdala, hippocampus, and periaqueductal gray (PAG) lesions on contextual fear conditioning in rats were examined. Freezing behavior served as the measure of conditioning. Unlesioned control animals showed reliable conditional freezing in the testing chamber when observed both immediately and 24 hr after footshocks. In contrast, rats with amygdala or ventral PAG lesions exhibited a significant attenuation in freezing both immediately and 24 hr after the shocks. Dorsal PAG lesions had no effect on freezing at either time. Animals with hippocampal lesions displayed robust freezing behavior immediately following the shock, even though they showed a marked deficit in freezing 24 hr after the shock. These results indicate that there are anatomically dissociable short- and long-term conditional fear states.

Amygdala↗

PubMed1987

The long-term effects of diazepam and pentylenetetrazol on behavioral sensitivity to a stressor.

Rats were trained to bar press for sucrose reinforcement following daily injections of 20 mg/kg pentylenetetrazol (PTZ), 5 mg/kg diazepam (DZ), or saline. At the end of 12 days of this training, all injections were suspended for the remainder of the experiment. Five days later, the rats were given 10 days of Pavlovian fear conditioning (two trials per day) to establish a light as a shock signal. Next, the rats were returned to the bar press situation to test the capacity of the light to suppress responding. Rats previously treated with DZ showed stronger conditioned fear of the light than did rats originally trained following injections of either PTZ or saline. In contrast, bar pressing by PTZ-treated rats was less suppressed by light than was control performance. The results indicate that modification of the behavioral effects of environmental stressors can be a long-term consequence of drug treatments. DZ treatments had the long-term effect of increasing behavioral disruption by a stressor, while treatment with PTZ reduced the stressor's negative behavioral impact. These findings appear compatible with the idea that behavioral sensitivity to stressors is dependent, in part, on learning about the stimulus properties of internal states.

Animals↗

PubMed2005

The temporal dynamics of retention of a context memory: something is missing.

We use a variation of contextual fear conditioning, called the context pre-exposure facilitation effect (CPFE) to study the rat's memory for context. In this paradigm, the rat is pre-exposed to a conditioning context and later returned to that context, where it is immediately shocked. The memory context is revealed by the fact that pre-exposure to the conditioning context, but not to a different context, greatly enhances conditioned fear produced by immediate shock. We report that rat's retention of the context memory is a nonmonotonic U-shaped function of the interval separating pre-exposure and immediate shock. Retention performance decays rapidly so that within 2 min of pre-exposure there is no evidence that the rat was pre-exposed to the context. Within a few hours, however, a strong CPFE was observed that persisted for at least 28 d. Two hypotheses are discussed: (1) the descending arm of the U represents a retrieval failure, and (2) the U-shaped function represents two discontinuous memory processes initiated in parallel-short-term synaptic changes that are rapidly initiated, but also decay rapidly, and long-term synaptic processes that take time to generate but can endure for days.

Animals↗