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PubMedDate not supplied

Extinction training regulates neuroadaptive responses to withdrawal from chronic cocaine self-administration.

Cocaine produces multiple neuroadaptations with chronic repeated use. Many of these neuroadaptations can be reversed or normalized by extinction training during withdrawal from chronic cocaine self-administration in rats. This article reviews our past and present studies on extinction-induced modulation of the neuroadaptive response to chronic cocaine in the mesolimbic dopamine system, and the role of this modulation in addictive behavior in rats. Extinction training normalizes tyrosine hydroxylase levels in the nucleus accumbens (NAc) shell, an effect that could help ameliorate dysphoria and depression associated with withdrawal from chronic cocaine use. Extinction training also increases levels of GluR1 and GluR2/3 AMPA receptor subunits, while normalizing deficits in NR1 NMDA receptor subunits, in a manner consistent with long-term potentiation of excitatory synapses in the NAc shell. Our results suggest that extinction-induced increases in AMPA and NMDA receptors may restore deficits in cortico-accumbal neurotransmission in the NAc shell and facilitate inhibitory control over cocaine-seeking behavior. Other changes identified by gene expression profiling, including up-regulation in the AMPA receptor aggregating protein Narp, suggest that extinction training induces extensive synaptic reorganization. These studies highlight potential benefits for extinction training procedures in the treatment of drug addiction.

Adaptation, Physiological↗
PubMedDate not supplied

Electrolytic lesions of the dorsal hippocampus disrupt renewal of conditional fear after extinction.

There is a growing body of evidence that the hippocampus is critical for context-dependent memory retrieval. In the present study, we used Pavlovian fear conditioning in rats to examine the role of the dorsal hippocampus (DH) in the context-specific expression of fear memory after extinction (i.e., renewal). Pre-training electrolytic lesions of the DH blunted the expression of conditional freezing to an auditory conditional stimulus (CS), but did not affect the acquisition of extinction to that CS. In contrast, DH lesions impaired the context-specific expression of extinction, eliminating the renewal of fear normally observed to a CS presented outside of the extinction context. Post-extinction DH lesions also eliminated the context dependence of fear extinction. These results are consistent with those using pharmacological inactivation of the DH and suggest that the DH is required for using contextual stimuli to regulate the expression of fear to a Pavlovian CS after extinction.

Animals↗
PubMed2006

Extinction is not a sufficient condition to prevent fear memories from undergoing reconsolidation in the basolateral amygdala.

Consolidated memories when reactivated may return to a state that requires protein synthesis in order to be restabilized (reconsolidation). It has been shown in a variety of systems that if reactivation induces significant extinction then extinction is the protein synthesis dependent memory state, rather than reconsolidation. Thus, extinction consolidation may prevent the memory from undergoing reconsolidation. We investigated whether such an interaction also exists between extinction and reconsolidation of fear memories within the amygdala, by using a within subjects experimental design. We found that inhibition of protein synthesis in the basolateral amygdala (BLA) impaired reconsolidation for both the briefly reactivated and extinguished fear memories suggesting that extinction is not a sufficient condition to prevent induction of reconsolidation in the amygdala. These findings demonstrate that extinction consolidation does not always interact with reconsolidation. Therefore, under these conditions, extinction is not a boundary condition on reconsolidation of fear memories in the basolateral amygdala.

Acoustic Stimulation↗
PubMed2005

Context modulation of memory for fear extinction in humans.

Distinct memories are formed during fear conditioning and subsequent extinction. In animals, the expression of the latter is gated by the context. The recall of extinction memory after a long delay, and the contextual modulation thereof, has not been directly tested in humans. Mentally healthy volunteers underwent a 2-day fear conditioning and extinction protocol that examined the recall of extinction memory and its relationship to context. Conditioned stimuli were paired with an aversive electric shock in one visual context and extinguished in a different context. Extinction recall and renewal were examined 24 h after training. We found that skin conductance responses were small when the conditioned stimulus was presented in the extinction context, but responses were renewed when the conditioned stimulus was presented in the conditioning context. This finding demonstrates context dependency of extinction recall in humans.

Adolescent↗
PubMed1994

Anatomical correlates of visual and tactile extinction in humans: a clinical CT scan study.

The anatomical correlates of tactile and visual extinction with double simultaneous stimulation were investigated in a series of 159 patients with right brain damage caused by stroke. Forty six patients showed extinction (22 tactile, 14 visual, 10 tactile and visual). Over 50% of the patients with extinction had deep lesions, which were found in about 25% of the patients with visuospatial neglect not associated with extinction. In the patients with extinction and cortico-subcortical damage the paraventricular occipital white matter and the dorsolateral frontal cortex were most often involved. By contrast, when neglect was also present, the lesions clustered in the inferior parietal lobule. These data suggest, from an anatomical perspective, that partly different neural mechanisms may underlie neglect and extinction. The comparatively high frequency of subcortical lesions involving the ascending pathways may be a neural correlate of a sensory component of extinction.

Adolescent↗
PubMed1994

Tactile extinction and functional status after stroke. A preliminary investigation.

BACKGROUND AND PURPOSE: Research has identified a number of factors associated with poststroke recovery, but the prediction of long-term functional outcome remains an uncertain endeavor. In previous work, extinction to tactile, double-simultaneous stimulation has been shown to have short-term predictive utility. The present study was designed to examine its long-term prognostic value and to determine the relative importance of tactile extinction, cognitive functioning, and visual neglect as predictors of poststroke functional status. METHODS: Successive admissions to an acute-care facility (n = 26) were assessed three times: 1 month, 3.5 months, and 6 months after stroke. Hierarchical multiple regression, a procedure that maximizes the effect of the variables first entered, was used to predict functional status. Cognitive functioning and visual neglect were forced into the equation on the first step; tactile extinction was entered on the second step. Multivariate analysis of variance was used to compare the functional status of subjects with no extinction versus those who demonstrated extinction at the first assessment and later improved and those who continued to manifest the deficit. RESULTS: Tactile extinction on the left-hand side of the body was the most important predictor of functional outcome. A significant group-by-time interaction implied that the course of improvement in functional status differed between the groups. CONCLUSIONS: Tactile extinction shows promise as a predictor of poststroke functional status, but further work is required to substantiate the present findings.

Activities of Daily Living↗
PubMed1999

Somatosensory cortical activations are suppressed in patients with tactile extinction: a PET study.

OBJECTIVE: To investigate whether tactile extinction alters the cortical somatosensory activations induced by hand vibration. BACKGROUND: Tactile extinction occurs mainly after right-brain lesions and consists of the inability to perceive a contralesional cutaneous stimulation when a similar stimulus is applied to the mirror region of the ipsilesional hemibody. The pathophysiology of tactile extinction is poorly understood, but it is considered to be a deficit of selective attention of somatosensory stimuli. Although other theories have been proposed, our understanding of the pathophysiology of tactile extinction may benefit from functional imaging studies. METHODS: We selected three patients with pure tactile extinction and a mainly subcortical right-brain lesion that spared the primary sensorimotor cortex (SM1). We used PET to investigate the responses to unilateral and bilateral hand vibration in SM1 and the secondary somatosensory cortical area (SII). RESULTS: During bilateral hand vibration, activation was normal in the left SM1, suppressed in the right SM1, and markedly decreased in both SII, which was consistent with the extinction of the left-hand stimulus. During unilateral left-hand vibration, the activation of the right SM1 was still markedly impaired, but the activation of both SII was normal. CONCLUSIONS: We found marked changes in the activation of cortical somatosensory areas induced by hand vibration in patients with tactile extinction. The role of selective attention in cortical activation is also examined.

Aged↗
PubMed2006

Extinction training in conjunction with a partial agonist of the glycine site on the NMDA receptor erases memory trace.

Much evidence indicates that extinction training does not erase memory traces but instead forms inhibitory learning that prevents the expression of original memory. Fear conditioning induces long-term potentiation and drives synaptic insertion of AMPA receptors into the amygdala. Here we show that extinction training applied 1 h after training reversed the conditioning-induced increase in surface glutamate receptor subunit 1 (GluR1) in parallel with the inhibition of startle potentiation. However, if applied 24 h after training, extinction training reduced startle potentiation without influencing the GluR1 increase. We infused D-cycloserine (DCS), a partial agonist of the glycine site on the NMDA receptor, bilaterally into the amygdala 30 min before extinction training. This augmented the extinction training-elicited reduction in startle and reversed the conditioning-induced increase in GluR1. Delivery of five sets of tetanic stimulation (TS) to the external capsule produced a robust enhancement of synaptic responses in the lateral amygdala neurons that persisted for >2 h. Low-frequency stimulation applied 1 h after TS had no long-lasting effect on synaptic responses. The same treatments, however, induced depotentiation in the presence of DCS and reversed TS-induced increase in surface GluR1. Together, this study has two important findings: (1) whether a memory trace remains intact or is erased depends on the interval between conditioning and extinction training and (2) DCS facilitates the reversal of memory trace. DCS-induced augmentation of extinction and reversal of GluR1 surface expression are likely mediated by DCS-facilitated endocytosis of AMPA receptors.

Amygdala↗
PubMed1986

Behavioral contrast in fixed-interval components: effects of extinction-component duration.

Seven albino rats were exposed to a multiple schedule of reinforcement in which the two components (fixed interval and extinction) alternated such that a presentation of the extinction component followed each fixed-interval reinforcement. In baseline sessions, the duration of the extinction component was constant and always one-third of the fixed-interval value. Probe sessions contained a probe segment in which the duration of the extinction component was increased; the response rate in fixed-interval components during the probe segment was compared with the response rate in the segments preceding and following the probe. The effect of increasing the duration of the extinction component was studied under three values of fixed interval: 30 s, 120 s, and 18 s, in three successive conditions. Response rate within fixed intervals was a direct function of duration of the extinction component. Pausing at the beginning of the fixed interval decreased as extinction duration increased. These effects were larger and more consistent for the shorter fixed-interval values (18 s and 30 s). These results indicate a functional relation between relative component duration and responding. For the component providing more frequent reinforcement, this could be stated as an inverse relationship between relative component duration and response rate. This relation is similar to findings regarding the ratio of trial and intertrial duration in Pavlovian conditioning procedures, and suggests that behavioral contrast may be related to Pavlovian contingencies underlying the multiple schedule.

Animals↗
PubMed2003

The similarities and diversities of signal pathways leading to consolidation of conditioning and consolidation of extinction of fear memory.

It is generally believed that consolidation of long-term memory requires activation of protein kinases, transcription of genes, and new protein synthesis. However, little is known about the signal cascades involved in the extinction of memory, which occurs when the conditioned stimulus is no longer followed by the unconditioned stimulus. Here, we show for the first time that an intra-amygdala injection of transcription inhibitor actinomycin D at the dose that blocked acquisition failed to affect extinction of a learned response. Conversely, protein synthesis inhibitor anisomycin blocked both acquisition and extinction. Extinction training-induced expression of calcineurin was blocked by anisomycin but not by actinomycin D. NMDA receptor antagonist, phosphatidylinositol 3-kinase (PI-3 kinase), and MAP kinase inhibitors that blocked the acquisition also blocked the extinction of conditioned fear. Likewise, PI-3 kinase inhibitor blocked fear training-induced cAMP response element-binding protein (CREB) phosphorylation as well as extinction training-induced decrease in CREB phosphorylation, the latter of which was associated with calcineurin expression and could be reversed by a specific calcineurin inhibitor. Thus, molecular processes that underlie long-term behavioral changes after acquisition and extinction share some common mechanisms and also display different characteristics.

Acoustic Stimulation↗
PubMed2003

Context-dependent neuronal activity in the lateral amygdala represents fear memories after extinction.

The context in which fear memories are extinguished has important implications for treating human fear and anxiety disorders. Extinction of Pavlovian fear conditioning is context specific; after extinction, fear responses are reduced only in the extinction context and remain elevated in every other context. Contextual modulation of spike firing in the amygdala is a putative mechanism for the context-specific expression of extinguished fear. To test this possibility, we conditioned rats to fear two auditory conditional stimuli (CSs) and then extinguished each CS in separate and distinct contexts. Thereafter, single-unit activity in the lateral nucleus of the amygdala (LA) and freezing behavior were recorded during tests in which each CS was presented in each extinction context. Hence, each CS was tested in its own extinction context and in the context of the other CS. Conditional freezing was context dependent; fear to an extinguished CS was low in its own extinction context and high in the other test context. Similarly, the majority of LA neurons exhibited context-dependent spike firing; short-latency spike firing was greater to both CSs when they were presented outside of their own extinction context. In contrast, behavioral and neuronal responses to either non-extinguished CSs or habituated auditory stimuli were not contextually modulated. Context-dependent neuronal activity in the LA may be an important mechanism for disambiguating the meaning of fear signals, thereby enabling appropriate behavioral responses to such stimuli.

Action Potentials↗
PubMed1989

["My hand" sign associated with tactile extinction in two patients with callosal lesion].

Two patients with "my hand" sign in association with tactile extinction from callosal lesion, one due to left anterior cerebral artery occlusion, the other due to right anterior cerebral artery aneurysm rupture, were reported. The examination of "my hand" sign was performed with the methods proposed by Brion et al. Our patients correctly responded when they grasped their own or the examiner's thumb with their left hand. But they replied "my finger"when they grasped not only their own but also the examiner's thumb with their right hand. Left tactile extinction was observed after a routine extinction test in one patient, and it was observed in the other after the following method: both patient's index fingers were disposed in his midline position. In these methods of extinction test, they made errors in saying "right" when both fingers were touched simultaneously. However, they said "both" when their right index finger alone was touched (synchiria) during an extinction test using the following method: both index fingers of patients were approached by examiner to touch each other or for one of them to touch the examiner's finger. When they were asked whose finger they touched in this method (whose finger test), they made the same errors as seen in "my hand" sign test. These test results suggest that there is a common underlying mechanism in the "my hand" sign and extinction, because the sense of double stimulations felt when only one stimulation is given (synchiria), is a possible explanation for the "my hand" sign and the pathogenesis of synchiria appears to be related to extinction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1983

Simultaneous modulation of hippocampal cholinergic activity and extinction by intraseptal muscimol.

The relationship between regulation of acetylcholine metabolism in the septal-hippocampal pathway and extinction of a food reinforced lever press response was investigated by comparing the turnover rate of acetylcholine (TRACh) in the rat hippocampus with the amount of responding during extinction after intraseptal injection of the gamma-aminobutyric acid receptor agonist muscimol. Doses (0.3-3.0 nmol) which decreased the TRACh in the hippocampus also increased the responding during extinction over that of saline controls. Responding during the continuous reinforcement schedule before extinction was also increased, but to a lesser extent. Higher doses (10-30 nmol) further decreased the TRACh in the hippocampus, decreased it in the cortex and were accompanied by irregular responding and sedation. The TRACh in the hippocampus was also measured in drug-free rats undergoing extinction after training on a continuous reinforcement or variable interval 60 sec reinforcement schedule. Although the variable interval 60 sec reinforcement schedule rats responded more than the continuous reinforcement rats during extinction, there were no differences between the TRACh in the hippocampus. The present results indicate that the decrease in the hippocampal TRACh which is produced by intraseptal muscimol is accompanied by an increase in the response rate during extinction, but that operantly induced differences in this behavior are not accompanied by detectable changes in hippocampal TRACh.

Acetylcholine↗
PubMed1980

Factors of extinction of alimentary instrumental conditioned reflex.

Observations were made on the animal's behavior and dynamics of electrical activity in the neo- and archipaleocortex during acquisition of sound discrimination under different experimental conditions and subsequent extinction. On the basis of analysis of the data obtained the following conclusions were drawn: (1) In pre-satiated cats even hundreds of applications of conditioned stimuli without food reinforcement do not lead to extinction of the conditioned reflex. Sound discrimination is not disturbed either. (2) Conditioned reflex and discrimination are not disturbed at repeated (over 300) application of conditioned sounds without food reinforcement provided the animal is hungry and is not allowed to approach the feeders. (3) Extinction of the conditioned reflex is achieved only when the animal is allowed, in response to conditioned stimuli, to approach the feeders where there is no reinforcing portion of food. (4) Stimulation of some mesodiencephalic structures results in the restoration of the extinguished alimentary instrumental reflexes and discrimination. (5) Functional inactivation of the hippocampus by way of induction of epileptiform discharges does not prevent the acquisition and extinction of conditioned feeding behavior. (6) Septal lesions do not prevent the acquisition, but extinction is tangibly delayed (7). It is concluded that the factor of extinction is the recognition that feeders contain no food rather than non-reinforcement, i.e. no food intake. On the basis of analysis of the dynamics of electrical activity in the neo- and archipaleocortex, as well as the mesodiencepalic electrical stimulation effects, some aspects of neurophysiological mechanisms of extinction are discussed.

Animals↗
PubMed1980

Progesterone, estradiol, testosterone and dihydrotestosterone: effects on rate of extinction of a conditioned taste aversion in rats.

An investigation was made to determine why the prolonged rate of extinction of a conditioned taste aversion induced by testosterone is diminished when the ovarian system is intact. In the first experiment, 36 gonadectomized female rats received injections of progesterone, testosterone propionate (TP), progesterone plus TP, or sesame oil. Progesterone did not reduce the slow extinction rate induced by TP. In a second experiment, 36 gonadectomized female rats received injections of estradiol dipropionate (EP), TP, EP plus TP, or sesame oil. Estradiol dipropionate reduced the effectiveness of TP in prolonging the extinction rate. These same results (the ineffectiveness of progesterone and the effectiveness of EP in blocking TP-induced slow extinction) were also observed in male rats in a third experiment. Dihydrotestosterone, as well as testosterone, has been shown to prolong extinction: hence, in a fourth experiment 30 gonadectomized female rats received injections of EP, TP, dihydrotestosterone propionate (DHTP), EP plus DHTP, or sesame oil. Estradiol dipropionate reduced the DHTP-induced slow extinction. All the above data are consistent with the hypothesis that it is estradiol from the ovaries that diminishes the effect of testosterone on the rate of extinction of a conditioned taste aversion in intact females.

Animals↗
PubMed2003

Assessing the impact of the Japanese 2005 World Exposition Project on vascular plants' risk of extinction.

The Red Data Book of Japanese Vascular Plants is based on their risk of extinction. In order to construct the list, 2000 taxa were evaluated using population data and rates of decline for approximately 4400 grids, each of approximately 100 km(2). This database can be used to estimate the impact of human activity on a threatened plant's risk of extinction. In order to evaluate extinction risks and apply the evaluation to conservation actions, the discount mean time to extinction is defined as a measure of extinction risk, where the present value of a species' persistence in the future decreases exponentially. The rate of decrease has to be much less than the rate of economic discounting, in order to realize intergenerational sustainability. Increases of the inverse, and logarithm, of the discount mean time to extinction are considered measures of the extinction risk. We applied these measures to an environmental impact assessment for the Japanese World Exposition that is to be held in 2005. Development will have a greater impact on threatened Salvia species than it will on star magnolia, Magnolia tomentosa, which has been conserved by changing the site plan.

Conservation of Natural Resources↗
PubMed1992

Large-body impact and extinction in the Phanerozoic.

The kill curve for Phanerozoic marine species is used to investigate large-body impact as a cause of species extinction. Current estimates of Phanerozoic impact rates are combined with the kill curve to produce an impact-kill curve, which predicts extinction levels from crater diameter, on the working assumption that impacts are responsible for all "pulsed" extinctions. By definition, pulsed extinction includes the approximately 60% of Phanerozoic extinctions that occurred in short-lived events having extinction rates greater than 5%. The resulting impact-kill curve is credible, thus justifying more thorough testing of the impact-extinction hypothesis. Such testing is possible but requires an exhaustive analysis of radiometric dating of Phanerozoic impact events.

Biological Evolution↗
PubMed2003

Sexual selection affects local extinction and turnover in bird communities.

Predicting extinction risks has become a central goal for conservation and evolutionary biologists interested in population and community dynamics. Several factors have been put forward to explain risks of extinction, including ecological and life history characteristics of individuals. For instance, factors that affect the balance between natality and mortality can have profound effects on population persistence. Sexual selection has been identified as one such factor. Populations under strong sexual selection experience a number of costs ranging from increased predation and parasitism to enhanced sensitivity to environmental and demographic stochasticity. These findings have led to the prediction that local extinction rates should be higher for speciespopulations with intense sexual selection. We tested this prediction by analyzing the dynamics of natural bird communities at a continental scale over a period of 21 years (1975-1996), using relevant statistical tools. In agreement with the theoretical prediction, we found that sexual selection increased risks of local extinction (dichromatic birds had on average a 23% higher local extinction rate than monochromatic species). However, despite higher local extinction probabilities, the number of dichromatic species did not decrease over the period considered in this study. This pattern was caused by higher local turnover rates of dichromatic species, resulting in relatively stable communities for both groups of species. Our results suggest that these communities function as metacommunities, with frequent local extinctions followed by colonization. Anthropogenic factors impeding dispersal might therefore have a significant impact on the global persistence of sexually selected species.

Animals↗