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PubMed1986

The effects of clonidine on the partial reinforcement extinction effect (PREE).

Clonidine has been reported to exert anti-anxiety effects in animals and man similar to those of benzodiazepines. The present experiment examined the effects of clonidine administration on the partial reinforcement extinction effect (PREE) which is known to be sensitive to benzodiazepine action. Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Clonidine 50 micrograms/kg was administered in a 2 X 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. The PREE, i.e., increased resistance to extinction exhibited by PRF animals as compared to CRF animals, was obtained in animals that received saline in acquisition, independently of drug treatment in extinction, as well as in animals that received clonidine in both acquisition and extinction, but not in animals that received clonidine in acquisition alone. The administration of clonidine in extinction alone increased resistance to extinction in both the CRF and PRF animals. The increase in resistance to extinction, typically obtained with benzodiazepine treatment, indicates that clonidine exerts anxiolytic effects, supporting the involvement of the noradrenergic system in anxiety. However, clonidine did not fully reproduce the effects of benzodiazepines on the PREE, suggesting that the two classes of drugs may act via different noradrenergic mechanisms.

Animals↗
PubMed1997

Lesions of the entorhinal cortex disrupt behavioral and neuronal responses to context change during extinction of discriminative avoidance behavior.

Rabbits given either electrolytic lesions of the entorhinal cortex or sham-lesions were trained to prevent a foot-shock by stepping in an activity wheel after one tone, a positive conditioned stimulus (CS+), and to ignore a different tone, a negative conditioned stimulus (CS-). Neuronal activity was recorded simultaneously in the basolateral nucleus of the amygdala, the CA1 cell field of hippocampus, anterior cingulate cortical area 24b and posterior cingulate cortical area 29c/d. The activity of neurons in the entorhinal cortex was recorded in the controls. Acquisition of conditioned avoidance responses (CRs) was not affected by lesions of the entorhinal cortex. Discriminative neuronal activity (greater neuronal responses to the CS+ than to the CS-) during CR acquisition was significantly enhanced in hippocampal area CA1 and attenuated in the basolateral amygdala in rabbits with lesions. Following acquisition to a criterion, two counterbalanced extinction tests were administered, one in the original context and the other in the presence of novel contextual stimuli. CR frequency was significantly reduced in controls but not in rabbits with lesions, during extinction with novel contextual stimuli, relative to performance in the original context. The rabbits with lesions also showed fewer inter-trial responses than controls during extinction in the original context but intertrial response frequency in rabbits with lesions did not differ from the frequency in controls during extinction in the novel context. Neurons in the basolateral amygdala in controls showed discriminative activity during extinction in the original context but not in the novel context. Amygdalar neurons in the rabbits with lesions did not show discriminative activity during extinction in either context. Posterior cingulate cortical neurons in control rabbits did not show discriminative activity during extinction in the original context but these neurons exhibited robust discriminative activity in the novel context. Posterior cingulate cortical neurons in rabbits with lesions showed discriminative activity in both extinction sessions. The results indicated that the entorhinal cortex does not play a significant role in the acquisition of discriminative avoidance behavior, under the employed conditions of training. However, the interactions of neurons in the entorhinal cortex, amygdala and cingulate cortex are essential for contextual modulation of CRs during extinction.

Amygdala↗
PubMed2005

Neural consequences of somatosensory extinction: an fMRI study.

There are currently two main interpretations proposing mechanisms underlying tactile extinction: sensory and attention deficit hypotheses. Kinsbourne proposed an opponent processor model to support the attention deficit hypothesis. He insisted that bilateral hemispheres interact reciprocally through contralaterally oriented vectors, and in patients presenting extinction, balance is impaired, causing inattention. From Kinsbourne's point of view, extinction is not caused by sensory disturbance but inattention, therefore even in extinction patients, simultaneous bilateral stimuli should reach the bilateral primary sensory cortices (SI). Using functional magnetic resonance imaging (fMRI), tactile stimuli were administered to both hands of healthy subjects as well as a tactile extinction patient. The patient with tactile extinction extinguished right palm stimuli following simultaneous palm stimulation. During the fMRI study, we gave tactile stimuli to the right palm, the left palm, and simultaneously to both palms. In normal subjects, simultaneous bilateral stimuli activated the bilateral SI and bilateral secondary sensory cortices (SII). In the patient with right tactile extinction, simultaneous bilateral stimuli activated the bilateral SI along with the bilateral SII and right superior parietal lobule. Our study suggests that activation of SI is insufficient to engender an awareness of sensory stimuli. From the view point of Kinsbourne, stimulus driven activity in one hemisphere suppresses activity in the other hemisphere via callosal connections. Our results support the notion that an undamaged superior parietal lobule in the patient with tactile extinction suppresses the damaged parietal lobe function and causes extinction.

Adolescent↗
PubMed2006

Prefrontal mechanisms in extinction of conditioned fear.

Interest in the medial prefrontal cortex (mPFC) as a source of behavioral inhibition has increased with the mounting evidence for a functional role of the mPFC in extinction of conditioned fear. In fear extinction, a tone-conditioned stimulus (CS) previously paired with a footshock is presented repeatedly in the absence of footshock, causing fear responses to diminish. Here, we review converging evidence from different laboratories implicating the mPFC in memory circuits for fear extinction: (1) lesions of mPFC impair recall of extinction under various conditions, (2) extinction potentiates mPFC physiological responses to the CS, (3) mPFC potentiation is correlated with extinction behavior, and (4) stimulation of mPFC strengthens extinction memory. These findings support Pavlov's original notion that extinction is new learning, rather than erasure of conditioning. In people suffering from posttraumatic stress disorder (PTSD), homologous areas of ventral mPFC show morphological and functional abnormalities, suggesting that extinction circuits are compromised in PTSD. Strategies for augmenting prefrontal function for clinical benefit are discussed.

Animals↗
PubMed2004

Effects of drugs that potentiate GABA on extinction of positively-reinforced operant behaviour.

Extinction following positively reinforced operant conditioning reduces response frequency, at least in part through the aversive or frustrative effects of non-reinforcement. According to J.A. Gray's theory, non-reinforcement activates the behavioural inhibition system which in turn causes anxiety. As predicted, anxiolytic drugs including benzodiazepines affect the operant extinction process. Recent studies have shown that reducing GABA-mediated neurotransmission retards extinction of aversive conditioning. We have shown in a series of studies that anxiolytic compounds that potentiate GABA facilitate extinction of positively reinforced fixed-ratio operant behaviour in C57B1/6 male mice. This effect does not occur in the early stages of extinction, nor is it dependent on cumulative effects of the compound administered. Potentiation of GABA at later stages has the effect of increasing sensitivity to the extinction contingency and facilitates the inhibition of the behaviour that is no longer required. The GABAergic hypnotic, zolpidem, has the same selective effects on operant extinction in this procedure. The effects of zolpidem are not due to sedative action. There is evidence across our series of experiments that different GABA-A subtype receptors are involved in extinction facilitation and anxiolysis. Consequently, this procedure may not be an appropriate model for anxiolytic drug action, but it may be a useful technique for analysing the neural bases of extinction and designing therapeutic interventions in humans where failure to extinguish inappropriate behaviours can lead to pathological conditions such as post-traumatic stress disorder.

Animals↗
PubMed2006

Extinction of conditioned eyeblink responses in patients with cerebellar disorders.

Extinction of conditioned eyeblink responses (CRs) was analyzed in sixteen patients with pure cortical cerebellar degeneration, 14 patients with lesions within the territory of the superior cerebellar artery (SCA), 13 patients with infarctions within the territory of the posterior inferior cerebellar artery (PICA) and 45 age-matched controls. Three-dimensional (3D) magnetic resonance (MRI) data sets were acquired in patients with focal lesions to identify affected cerebellar lobules and possible involvement of nuclei. Eyeblink conditioning was performed using a standard delay protocol. At the end of the experiment 10 CS-alone trials were presented as extinction trials. Controls showed significant effects of extinction that is a significant decline comparing CR-incidences in the extinction trials and the last block of 10 trials of the paired trials. In the group of all cerebellar patients, however, no significant effects of extinction were observed. In patients with unilateral lesions effects of extinction were present on the unaffected, but not on the affected side. Deficits of extinction were observed in PICA and SCA patients both with and without involvement of cerebellar nuclei. Extending previous reports in cerebellar patients the present findings show that the ipsilateral cerebellar hemisphere contributes to extinction of conditioned eyeblink responses in humans. It cannot be ruled out, however, that impaired acquisition affected the extinction results.

Adult↗
PubMed2004

Subtype-selective GABAergic drugs facilitate extinction of mouse operant behaviour.

Several recent studies have shown that reducing gamma-aminobutyric acid (GABA)-mediated neurotransmission retards extinction of aversive conditioning. However, relatively little is known about the effect of GABA on extinction of appetitively motivated tasks. We examined the effect of chlordiazepoxide (CDP), a classical benzodiazepine (BZ) and two novel subtype-selective BZs when administered to male C57Bl/6 mice during extinction following training on a discrete-trial fixed-ratio 5 (FR5) food reinforced lever-press procedure. Initially CDP had no effect, but after several extinction sessions CDP significantly facilitated extinction, i.e. slowed responding, compared with vehicle-treated mice. This effect was not due to drug accumulation because mice switched from vehicle treatment to CDP late in extinction showed facilitation immediately. Likewise, this effect could not be attributed to sedation because the dose of CDP used (15 mg/kg i.p.) did not suppress locomotor activity. The two novel subtype-selective BZ partial agonists, L-838417 and TP13, selectively facilitated extinction in similar fashion to CDP. The non-GABAergic anxiolytic buspirone was also tested and found to have similar effects when administered at a non-sedating dose. These studies demonstrate that GABA-mediated processes are important during extinction of an appetitively motivated task, but only after the animals have experienced several extinction sessions.

Animals↗
PubMedDate not supplied

The effects of interpolated reinforcement on resistance to extinction in children diagnosed with autism: a preliminary investigation.

Studies on the "interpolation of reinforcement" effect (IRE) suggest that switching from an intermittent (INT) to a continuous (CRF) reinforcement schedule may result in less resistance to extinction than if extinction had followed INT alone. The finding has been examined with both human and animal participants using both free- and restricted-operant research preparations with equivocal results. In the present study, the IRE was examined in four young children diagnosed with autism using a free-operant preparation. Participants were matched into pairs and were exposed, in a counterbalanced order, to extinction following CRF "interpolated" between INT and extinction, and to extinction following INT alone. Resistance to extinction was examined by comparing the number of responses emitted during extinction and the number of sessions required to reach an extinction criterion. Responding may be less resistant to extinction following interpolated CRF reinforcement than following INT alone. Methodological refinements necessary for more conclusively demonstrating the IRE are discussed.

Autistic Disorder↗
PubMed1990

State-dependent fear extinction with two benzodiazepine tranquilizers.

Four experiments with rats were run to investigate whether fear extinction conducted under the influence of a benzodiazepine transfers to the undrugged state. Fear was conditioned by pairing an experimental chamber with footshock and was assessed by observing freezing, a characteristic response of the rat to stimuli associated with shock. In Experiment 1, extinction of the chamber cues under chlordiazepoxide (librium) or diazepam (valium) was compared with extinction under a placebo; both drugs interfered with extinction in a dose-dependent manner as indicated by freezing during an undrugged test. Further results with chlordiazepoxide suggested that the effect depended on the drug's specific combination with extinction and that it occurred even though the extinction procedure otherwise eliminated fear completely (Experiment 2). Repeated preexposure to the drug, and the development of partial tolerance to its sedative effects, did not weaken the interference effect (Experiment 3). Other evidence suggested that the drug signaled or retrieved extinction instead of disrupting learning or consolidation (Experiment 4). The results are consistent with research suggesting that extinguished fear can be "renewed" if the exteroceptive contextual stimuli are changed after extinction. Extinction combined with either unique exteroceptive or interoceptive cues may be specific to its context.

Animals↗
PubMed2002

Neurons in medial prefrontal cortex signal memory for fear extinction.

Conditioned fear responses to a tone previously paired with a shock diminish if the tone is repeatedly presented without the shock, a process known as extinction. Since Pavlov it has been hypothesized that extinction does not erase conditioning, but forms a new memory. Destruction of the ventral medial prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks recall of fear extinction, indicating that medial prefrontal cortex might store long-term extinction memory. Here we show that infralimbic neurons recorded during fear conditioning and extinction fire to the tone only when rats are recalling extinction on the following day. Rats that froze the least showed the greatest increase in infralimbic tone responses. We also show that conditioned tones paired with brief electrical stimulation of infralimbic cortex elicit low freezing in rats that had not been extinguished. Thus, stimulation resembling extinction-induced infralimbic tone responses is able to simulate extinction memory. We suggest that consolidation of extinction learning potentiates infralimbic activity, which inhibits fear during subsequent encounters with fear stimuli.

Acoustic Stimulation↗
PubMed2006

NMDA Partial agonist reverses blocking of extinction of aversive memory by GABA(A) agonist in the amygdala.

The ability to extinguish aversive memories is of significant clinical interest. The amygdala plays an important role in emotional conditioning and its experimental extinction. It has been suggested that gamma-aminobutyric acid (GABA) agonists retard extinction and that consolidation of extinction involves N-methyl-D-aspartate receptor (NMDAR)-mediated plasticity. The aim was to further explore the interaction between GABA and NMDA in the amygdala in consolidation of experimental extinction in the rat. To that end conditioned taste aversion (CTA) was used. In CTA, the amygdala has been reported to subserve both acquisition and extinction. The GABA(A) receptor agonist, muscimol, administered into the amygdala immediately after the first extinction session, caused lasting disruption of extinction of CTA for at least 2 weeks. However, the administration of GABA(A) receptor antagonists had no effect on extinction kinetics. Microinfusing the partial NMDA agonist D-cycloserine together with or after muscimol infusion reversed the blocking effects of muscimol. These findings could bear relevance to the potential involvement of extinction abnormalities in behavioral disorders, and their amelioration.

Amygdala↗
PubMed2007

Acquisition of fear extinction requires activation of NR2B-containing NMDA receptors in the lateral amygdala.

N-methyl-D-aspartate receptors (NMDARs) contribute to synaptic plasticity underlying learning in a variety of brain systems. Fear extinction, which involves learning to suppress the expression of previously learned fear, appears to require NMDAR activation in the amygdala. However, it is unclear whether amygdala NMDARs are required for the acquisition of extinction learning, and it is unknown whether NR2B-containing NMDARs are required in fear extinction. Here, we assessed the effects of selective NR2B blockade with ifenprodil on fear extinction learning, and found that both systemic and intra-amygdala ifenprodil treatment, given before extinction training, impaired the initial acquisition, and subsequent retrieval of fear extinction. These results confirm previous evidence showing that NMDARs in the amygdala are involved in fear extinction, and additionally show that NR2B-containing NMDARs are required. Contrary to the conclusion of previous studies, our findings demonstrate NMDARs are required for the initial acquisition, rather than only the retention, of fear extinction learning. Thus, our results support a previously not known role for NMDA-dependent plasticity in the lateral amygdala during the acquisition of fear extinction.

Amygdala↗
PubMed2005

Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory.

The ventromedial prefrontal cortex (vmPFC) has been implicated in fear extinction [Phelps, E. A., Delgado, M. R., Nearing, K. I. & Ledoux, J. E. (2004) Neuron 43, 897-905; Herry, C. & Garcia, R. (2003) Behav. Brain Res. 146, 89-96]. Here, we test the hypothesis that the cortical thickness of vmPFC regions is associated with how well healthy humans retain their extinction memory a day after having been conditioned and then extinguished. Fourteen participants underwent a 2-day fear conditioning and extinction protocol. The conditioned stimuli (CSs) were pictures of virtual lights, and the unconditioned stimulus (US) was an electric shock. On day 1, participants received 5 CS+US pairings (conditioning), followed by 10 CS trials with no US (extinction). On day 2, the CS was presented alone to test for extinction memory. Skin conductance response (SCR) was the behavioral index of conditioning and extinction. Participants underwent MRI scans to obtain structural images, from which cortical thickness was measured. We performed a vertex-based analysis across the entire cortical surface and a region-of-interest analysis of a priori hypothesized territories to measure cortical thickness and map correlations between this measure and SCR. We found significant, direct correlation between thickness of the vmPFC, specifically medial orbitofrontal cortex, and extinction retention. That is, thicker medial orbitofrontal cortex was associated with lower SCR to the conditioned stimulus during extinction recall (i.e., greater extinction memory). These results suggest that the size of the vmPFC might explain individual differences in the ability to modulate fear among humans.

Adult↗
PubMedDate not supplied

Memory for extinction of conditioned fear is long-lasting and persists following spontaneous recovery.

Conditioned fear responses to a tone paired with footshock rapidly extinguish when the tone is presented in the absence of the shock. Rather than erase conditioning, extinction is thought to involve the formation of new memory. In support of this, extinguished freezing spontaneously recovers with the passage of time. It is not known, however, how long extinction memory lasts or whether extinction interferes with consolidation of conditioning if given on the same day. To address this, we gave rats 7 trials of auditory fear conditioning followed 1 h later by 20 extinction trials, and tested for spontaneous recovery after a delay of 0, 1, 2, 4, 6, 10, or 14 d. Conditioned freezing to the tone gradually recovered with time to reach 100% by day 10. No-extinction controls indicated that the increase in freezing with time was not owing to incubation of conditioning memory. Complete spontaneous recovery indicates that extinction training given 1 h after conditioning does not interfere with the consolidation of conditioning memory. Despite complete recovery of freezing, rats showed savings in their rate of re-extinction, indicating persistence of extinction memory. These data support the idea that conditioning and extinction of fear are learned by independent systems, each able to retain a long-term memory.

Acoustic Stimulation↗
PubMed2006

Electrolytic lesions of the medial prefrontal cortex do not interfere with long-term memory of extinction of conditioned fear.

Lesion studies indicate that rats without the medial prefrontal cortex (mPFC) have difficulty recalling fear extinction acquired the previous day. Several electrophysiological studies have also supported this observation by demonstrating that extinction-related increases in neuronal activity in the mPFC participate in expression of fear extinction. However, a more recent study has shown that fear extinction can be recalled, in certain circumstances, without mPFC potentiation, suggesting contribution of other circuits. Here, we examined this possibility in rats that were subjected to auditory fear conditioning, extinction training, and extinction retention test 7 d later. Electrolytic lesions were made in the mPFC, the motor cortex (MO), the dorsal septum (SEP), or the mediodorsal thalamus (MD), because of their potential participation in conditioned fear inhibition; combined lesions including the mPFC with the MO, SEP, or MD were also made. The lesions were made either 1 wk before conditioning or 1 d after extinction training. All rats normally extinguished their conditioned freezing behavior during extinction training and did not display any return of this behavior during the retention test. These data reveal that the mPFC is not required for the acquisition, the expression, or the retrieval of extinction memories but do not exclude the possibility that the mPFC normally participates in these processes.

Acoustic Stimulation↗
PubMedDate not supplied

Extinction as new learning versus unlearning: considerations from a computer simulation of the cerebellum.

Like many forms of Pavlovian conditioning, eyelid conditioning displays robust extinction. We used a computer simulation of the cerebellum as a tool to consider the widely accepted view that extinction involves new, inhibitory learning rather than unlearning of acquisition. Previously, this simulation suggested basic mechanistic features of extinction and savings in eyelid conditioning, with predictions born out by experiments. We review previous work showing that the simulation reproduces behavioral phenomena and lesion effects generally taken as evidence that extinction does not reverse acquisition, even though its plasticity is bidirectional with no site dedicated to inhibitory learning per se. In contrast, we show that even though the sites of plasticity are, in general, affected in opposite directions by acquisition and extinction training, most synapses do not return to their naive state after acquisition followed by extinction. These results suggest caution in interpreting a range of observations as necessarily supporting extinction as unlearning or extinction as new inhibitory learning. We argue that the question "is extinction reversal of acquisition or new inhibitory learning?" is therefore not well posed because the answer may depend on factors such as the brain system in question or the level of analysis considered.

Association Learning↗
PubMed2006

Extinction of auditory fear conditioning requires MAPK/ERK activation in the basolateral amygdala.

Whereas the neuronal substrates underlying the acquisition of auditory fear conditioning have been widely studied, the substrates and mechanisms mediating the acquisition of fear extinction remain largely elusive. Previous reports indicate that consolidation of fear extinction depends on the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) signalling pathway and on protein synthesis in the medial prefrontal cortex (mPFC). Based on experiments using the fear-potentiated startle paradigm suggesting a role for neuronal plasticity in the basolateral amygdala (BLA) during fear extinction, we directly addressed whether MAPK/ERK signalling in the basolateral amygdala is necessary for the acquisition of fear extinction using conditioned freezing as a read-out. First, we investigated the regional and temporal pattern of MAPK/ERK activation in the BLA following extinction learning in C57Bl/6J mice. Our results indicate that acquisition of extinction is associated with an increase of phosphorylated MAPK/ERK in the BLA. Moreover, we found that inhibition of the MAPK/ERK signalling pathway by intrabasolateral amygdala infusion of the MEK inhibitor, U0126, completely blocks acquisition of extinction. Thus, our results indicate that the MAPK/ERK signalling pathway is required for extinction of auditory fear conditioning in the BLA, and support a role for neuronal plasticity in the BLA during the acquisition of fear extinction.

Acoustic Stimulation↗
PubMed2001

Relationship of extinction to perceptual thresholds for single stimuli.

OBJECTIVE: To demonstrate the effects of target stimulus intensity on extinction to double simultaneous stimuli. BACKGROUND: Attentional deficits contribute to extinction in patients with brain lesions, but extinction (i.e., masking) can also be produced in healthy subjects. The relationship of extinction to perceptual thresholds for single stimuli remains uncertain. METHODS: Brief electrical pulses were applied simultaneously to the left and right index fingers of 16 healthy volunteers (8 young and 8 elderly adults) and 4 patients with right brain stroke (RBS). The stimulus to be perceived (i.e., target stimulus) was given at the lowest perceptual threshold to perceive any single stimulus (i.e., Minimal) and at the threshold to perceive 100% of single stimuli. The mask stimulus (i.e., stimulus given to block the target) was applied to the contralateral hand at intensities just below discomfort. RESULTS: Extinction was less for target stimuli at 100% than Minimal threshold for healthy subjects. Extinction of left targets was greater in patients with RBS than elderly control subjects. Left targets were extinguished less than right in healthy subjects. In contrast, the majority of left targets were extinguished in patients with RBS even when right mask intensity was reduced below right 100% threshold for single stimuli. RBS patients had less extinction for right targets despite having greater left mask - threshold difference than control subjects. In patients with RBS, right "targets" at 100% threshold extinguished left "masks" (20%) almost as frequently as left masks extinguished right targets (32%). CONCLUSIONS: Subtle changes in target intensity affect extinction in healthy adults. Asymmetries in mask and target intensities (relative to single-stimulus perceptual thresholds) affect extinction in RBS patients less for left targets but more for right targets as compared with control subjects.

Adult↗