Extinction Of Taste Aversion Research Articles

Bidirectional modulation of taste aversion extinction by insular cortex LTP and LTD

The history of activity of a given neuron has been proposed to bidirectionally influence its future response to synaptic inputs. In particular, induction of synaptic plasticity expressions such as long-term potentiation (LTP) and long-term depression (LTD) modifies the performance of several behavioral tasks. Our previous studies in the insular cortex (IC), a neocortical region that has been related to acquisition and retention of conditioned taste aversion (CTA), have demonstrated that induction of LTP in the basolateral amygdaloid nucleus (Bla)-IC pathway before CTA training enhances the retention of this task. In addition, we reported that CTA training triggers a persistent impairment in the ability to induce in vivo LTP in the IC. The aim of the present study was to investigate whether LTD can be induced in the Bla-IC projection in vivo, as well as, whether the extinction of CTA is bidirectionally modified by previous synaptic plasticity induction in this pathway. Thus, rats received 900 train pulses (five 250μs pulses at 250Hz) delivered at 1Hz in the Bla-IC projection in order to induce LTD or 10 trains of 100Hz/1s with an intertrain interval of 20s in order to induce LTP. Seven days after surgery, rats were trained in the CTA task including the extinction trials. Our results show that the Bla-IC pathway is able to express in vivo LTD in an N-Methyl-D-aspartate (NMDA) receptor-dependent manner. Induction of LTD in the Bla-IC projection previous to CTA training facilitates the extinction of this task. Conversely, LTP induction enhances CTA retention. The present results show the bidirectional modulation of CTA extinction in response to IC-LTP and LTD, providing evidence of the homeostatic adaptation of taste learning.

ASIC1a regulates insular long-term depression and is required for the extinction of conditioned taste aversion.

Acid-sensing ion channel 1a (ASIC1a) has been shown to play important roles in synaptic plasticity, learning and memory. Here we identify a crucial role for ASIC1a in long-term depression (LTD) at mouse insular synapses. Genetic ablation and pharmacological inhibition of ASIC1a reduced the induction probability of LTD without affecting that of long-term potentiation in the insular cortex. The disruption of ASIC1a also attenuated the extinction of established taste aversion memory without altering the initial associative taste learning or its long-term retention. Extinction of taste aversive memory led to the reduced insular synaptic efficacy, which precluded further LTD induction. The impaired LTD and extinction learning in ASIC1a null mice were restored by virus-mediated expression of wild-type ASIC1a, but not its ion-impermeable mutant, in the insular cortices. Our data demonstrate the involvement of an ASIC1a-mediated insular synaptic depression mechanism in extinction learning, which raises the possibility of targeting ASIC1a to manage adaptive behaviours.

Acute infusion of brain-derived neurotrophic factor in the insular cortex promotes conditioned taste aversion extinction

Brain-derived neurotrophic factor (BDNF) has emerged as one of the most potent molecular mediators not only for synaptic plasticity, but also for the behavioral organism–environment interactions. Our previous studies in the insular cortex (IC), a neocortical region that has been related with acquisition and retention of conditioned taste aversion (CTA), have demonstrated that intracortical microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the basolateral amygdaloid nucleus (Bla)-IC projection and enhances the retention of CTA memory of adult rats in vivo. The aim of the present study was to analyze whether acute BDNF-infusion in the IC modifies the extinction of CTA. Accordingly, animals were trained in the CTA task and received bilateral IC microinfusions of BDNF before extinction training. Our results showed that taste aversion was significantly reduced in BDNF rats from the first extinction trial. Additionally, we found that the effect of BDNF on taste aversion did not require extinction training. Finally we showed that the BDNF effect does not degrade the original taste aversion memory trace. These results emphasize that BDNF activity underlies memory extinction in neocortical areas and support the idea that BDNF is a key regulator and mediator of long-term synaptic modifications.

BDNF signaling potentiates transmission of information from the basolateral amygdala to infralimbic prefrontal cortex during conditioned taste aversion extinction.

Conditioned taste aversion (CTA) is a form of associative learning in which a palatable taste [e.g., saccharin; conditioned stimulus (CS)] is paired with a toxic unconditioned stimulus (e.g., injection of lithium chloride), resulting in a reduced preference for the CS. Extinction is a form learning

Involvement of BDNF signaling transmission from basolateral amygdala to infralimbic prefrontal cortex in conditioned taste aversion extinction.

Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB), play a critical role in memory extinction. However, the detailed role of BDNF in memory extinction on the basis of neural circuit has not been fully understood. Here, we aim to investigate the role of BDNF signaling circuit in mediating conditioned taste aversion (CTA) memory extinction of the rats. We found region-specific changes in BDNF gene expression during CTA extinction. CTA extinction led to increased BDNF gene expression in the basolateral amygdala (BLA) and infralimbic prefrontal cortex (IL) but not in the central amygdaloid nucleus (CeA) and hippocampus (HIP). Moreover, blocking BDNF signaling or exogenous microinjection of BDNF into the BLA or IL could disrupt or enhance CTA extinction, which suggested that BDNF signaling in the BLA and IL is necessary and sufficient for CTA extinction. Interestingly, we found that microinjection of BDNF-neutralizing antibody into the BLA could abolish the extinction training-induced BDNF mRNA level increase in the IL, but not vice versa, demonstrating that BDNF signaling is transmitted from the BLA to IL during extinction. Finally, the accelerated extinction learning by infusion of exogenous BDNF in the BLA could also be blocked by IL infusion of BDNF-neutralizing antibody rather than vice versa, indicating that the IL, but not BLA, is the primary action site of BDNF in CTA extinction. Together, these data suggest that BLA-IL circuit regulates CTA memory extinction by identifying BDNF as a key regulator.

Reacquisition, reinstatement, and renewal of a conditioned taste aversion in preweanling rats

Pavlovian extinction is defined as a reduction of the conditioned response (CR) as a consequence of repeated and nonreinforced presentations of the conditioned stimulus (CS). This phenomenon has been explained through two nonexclusive associative hypotheses. One of them proposes that the CS-unconditioned stimulus (US) association is weakened during extinction, while the second one explains extinction by the formation of a new inhibitory association between the CS, and the US (CS-noUS) which competes with the excitatory one acquired at conditioning (CS-US). Research supporting this second hypothesis is based on the demonstration that the CR can be recovered after extinction. However, in preweanling rats, renewal, and reinstatement treatments have failed to recover a conditioned fear response, suggesting that extinction during this ontogenetic period may involve erasure of the CS-US association. The goal of the present study was to explore whether this conclusion can be extended to the extinction of a conditioned taste aversion by evaluating infant rats in three different procedures (reacquisition, ABA renewal, and reinstatement). The results are consistent with the idea that extinction of a taste aversive memory during infancy involves relearning about the relationship between the CS and the US, with the initial CS-US association remaining relatively intact. Extinction of a taste aversive memory and a fear memory may involve different biological mechanisms during infancy. The conclusion that the only psychological mechanism for extinction during infancy is unlearning should be confined to a particular type of memory.

Periaqueductal gray c-Fos expression varies relative to the method of conditioned taste aversion extinction employed

A conditioned taste aversion (CTA) is acquired when an animal consumes a novel taste (CS) and then experiences the symptoms of poisoning (US). Following CTA training, animals will avoid the taste that was previously associated with malaise. This defensive reaction to a learned fear can be extinguished by repeated exposure to the CS alone (CS-only; CSO-EXT). However, following a latency period in which the CS is not presented, the CTA will spontaneously recover (SR). Through the use of an explicitly unpaired extinction procedure (EU-EXT) we have shown that we can speed up extinction and attenuate SR of the CTA. Here we compared and contrasted the ability of CSO and EU extinction procedures to affect c-Fos expression in the periaqueductal gray (PAG). Fluid-deprived Sprague–Dawley rats acquired a strong CTA [via 3 pairings of 0.3% oral saccharin (SAC; the CS) and 81 mg/kg i.p. lithium chloride (LiCl; the US)] followed by extinction trials consisting of multiple exposures to either, (a) the CS every-other day (CSO-EXT), or (b) CS and US on alternate days (EU-EXT). A different group of rats did not receive multiple CS exposures and served as a “no extinction” (NE) control. Both extinction procedures resulted in ≥ 90% reacceptance of SAC (achieving asymptotic extinction). Some of the animals were sacrificed for c-Fos immunohistochemical analysis following asymptotic extinction. Other rats entered a 30-day latency period where they drank water only. These remaining animals were then tested for SR with a final exposure to SAC before being sacrificed for c-Fos immunohistochemistry. As reported previously, rats in the CS-only group exhibited a significant SR of the CTA. However, animals in the EU extinction group reached asymptotic extinction more rapidly than did CSO rats and they did not show SR of the CTA. As compared to rats that retained their CTA, both groups of extinguished rats showed suppression in the number of c-Fos-labeled neurons in all 4 longitudinal columns of the PAG. The number of c-Fos-labeled cells in the PAG was generally low but there was a reliable increase in c-Fos expression in dorsolateral PAG (dlPAG) following the SR test in the brains of rats that went through the EU-EXT procedure as compared with those that either went through the more-traditional CSO extinction procedure or experienced no extinction at all. The number of c-Fos-labeled neurons in the dlPAG was significantly correlated with the amount of SAC consumed at the SR test. Surprisingly, the brains of EU-extinguished rats and CSO extinguished rats did not differ in the number of c-Fos-labeled neurons in gustatory neocortex, medial prefrontal cortex, basolateral amygdala, or the central nucleus of the amygdala. Thus, behavioral differences in SR between the EU and CSO extinction animals were not represented by corresponding changes in the neural activity of several brain nuclei classically associated with extinction learning. However a detailed analysis of PAG c-Fos expression provided hints about some of the physiological changes evoked by these 2 extinction paradigms that produce very different behavioral outcomes. The findings are clinically relevant as we seek the development of treatments for deficits in fear extinction (e.g. PTSD, phobias).

Differential participation of temporal structures in the consolidation and reconsolidation of taste aversion extinction

The extinction process has been described as the decline in the frequency or intensity of the conditioned response following the withdrawal of reinforcement. Hence, experimental extinction does not reflect loss of the original memory, but rather reflects new learning, which in turn requires consolidation in order to be maintained in the long term. During extinction of conditioned taste aversion (CTA), a taste previously associated with aversive consequences acquires a safe status through continuous presentations of the flavor with no aversive consequence. In addition, reconsolidation has been defined as the labile state of a consolidated memory after its reactivation by the presentation of relevant information. In this study, we analyzed structures from the temporal lobe that could be involved in consolidation and reconsolidation of extinction of CTA by means of new protein synthesis. Our results showed that protein synthesis in the hippocampus (HC), the perirhinal cortex (PR) and the insular cortex (IC) of rats participate in extinction consolidation, whereas the basolateral amygdala plays no part in this phenomenon. Furthermore, we found that inhibition of protein synthesis in the IC in a third extinction trial had an effect on reconsolidation of extinction. The participation of the HC in taste memory has been described as a downmodulator for CTA consolidation, and has been related to a context-taste association. Altogether, these data suggest that extinction of aversive taste memories are subserved by the IC, HC and PR, and that extinction can undergo reconsolidation, a process depending only on the IC.

Time-dependent retrograde amnesic effects of muscimol on conditioned taste aversion extinction

We explored how stimulation of GABA A receptors at different times during conditioned taste aversion (CTA) acquisition or extinction influenced extinction. In Experiment 1, rats acquired a CTA to 0.3% saccharin-flavored water (SAC) when it followed an injection of lithium chloride (LiCl; 81.0 mg/kg, i.p.). Following conditioning, rats received extinction training in which the GABA A agonist muscimol (1.0 mg/kg, i.p.), or control (saline) injections, were administered either before or after each extinction trial. Muscimol hindered extinction when administered after extinction trials. Muscimol's inhibitory effects may have impeded extinction learning by disrupting synaptic mechanisms required to consolidate information experienced during extinction training. In Experiment 2, we studied the effects of muscimol on CTA acquisition and subsequent extinction. Rats received muscimol (1.0 mg/kg, i.p.) either before or after CTA conditioning trials. Following CTA acquisition, all rats were given CTA extinction training without muscimol administration. All groups developed CTA, but the group that received muscimol before CTA conditioning trials extinguished rapidly in comparison to other treatment groups. Differences between muscimol's effects on CTA conditioning and CTA extinction indicate that fear conditioning and extinction involve, to some degree, different neuronal mechanisms.

Short Article: Microstructural Analysis of Ingestive Behaviour Reveals no Contribution of Palatability to the Incomplete Extinction of a Conditioned Taste Aversion

An analysis of the microstructure of licking responses was used to investigate the effects of conditioning and extinguishing a taste aversion. Rats received a single pairing of 8% fructose with lithium chloride (LiCl) while controls received unpaired exposure to fructose and LiCl. Pairing fructose with LiCl produced a reduction both in consumption and in the size of licking clusters. Subsequent exposure to fructose in the absence of LiCl produced some extinction of the taste aversion although at asymptote there was a residual difference in consumption between the taste aversion group and unpaired controls. In contrast the reduction in lick cluster size did completely extinguish. Previous analyses of licking microstructure indicate that lick cluster size is related to the palatability of the ingested solution. Thus these results indicate that although taste aversion learning initially reduces the palatability of the cue solution this reduction is not permanent. These results are discussed with reference to the possibility that preparatory behaviours are more resistant to extinction than are consummatory behaviours.

Dynamic processing of taste aversion extinction in the brain

While substantial advances have been made in discovering how the brain learns and remembers, less is known about how the brain discards information, reorganizes information, or both. These topics are not only relevant to normal brain functioning but also speak to pathologies in which painful memories do not wane but are evoked time and again (e.g., post-traumatic stress disorder; PTSD). Here, we measured brain activity (as indicated by the regional expression of c-Fos protein) in rats during acquisition and throughout extinction of a conditioned taste aversion (CTA). We compared that brain activity with animals that had intact CTA memories or those that experienced an explicitly unpaired (EU) conditioned stimulus (CS; saccharin, SAC) and unconditioned stimulus (US; lithium chloride, LiCl). The data show a dynamic and nonuniform pattern of c-Fos protein expression in brain nuclei known to mediate gustation and CTAs. In particular, brainstem nuclei (e.g., nucleus of the solitary tract; NTS) and the basolateral nucleus of the amygdala (BLA) are active early as CTAs are formed and as extinction of the learned response begins. Later in the extinction process, the BLA reduces c-Fos expression relative to nonextinguished controls. Finally, as almost full reacceptance of the taste is achieved, the gustatory neocortex (GNC) expresses enhanced levels of c-Fos protein. Thus, extinction of a CTA is not represented by a simple reversal of the c-Fos activity evoked by CTA conditioning. Rather, the data demonstrate that extinction of conditioned responses is a dynamic process in which the activity levels of particular nuclei along the brain's taste pathway change depending on the extent to which the conditioned response has been extinguished.

Context change and retention interval can have additive, rather than interactive, effects after taste aversion extinction

Spontaneous forgetting is often attributed to retrieval failure caused by natural changes in the background context that occur over time. However, some investigators have argued that the context-change account of forgetting is paradoxical, because context-change effects themselves decrease over time. To resolve the paradox, we have suggested that organisms may merely forget the physical context as the temporal context in which it is embedded changes; this explanation accepts a fundamental similarity between time and physical context. The present experiment tested an implication of this analysis by examining the interaction between retention interval and context change in rats after a taste aversion was conditioned and then extinguished. Importantly, subjects tested at the longer (24-day) retention interval received reminder exposure to the physical contexts before testing. Under these conditions, retention interval and context change both caused relapse of the extinguished aversion (spontaneous recovery and renewal, respectively), and the strongest overall relapse was observed when the two treatments were combined. Such additivity (rather than interactivity) is consistent with a context-change account of forgetting and sets the stage for resolution of the context-forgetting paradox.

Extinction of taste aversion does not eliminate taste-mediated aversion to visual cues: Replicating Lett (1984)

In this experiment, we evaluated whether extinction of taste aversion following conditioning with a compound CS of visual and taste cues would attenuate taste-mediated aversion to visual cues. Sixty chicks (Gallus domesticus) received a pairing of a compound CS, red-colored water or red-colored vinegar, with a toxin and then extinction procedures with clear vinegar. Testing with red water showed reliable evidence of potentiation to visual cues in the red vinegar conditioning groups, as measured by latency to start drinking and intake performance. Taste-aversion extinction groups (n = 30), tested with clear vinegar, showed no reliable evidence of taste aversion. The results contradicted the within-compound hypothesis of taste-mediated potentiation and replicated Lett (1984).

Anorexia treatment based on extinction of a taste aversion: an addendum to Bernstein and Borson (1986).

The speculative theorizing of Bernstein and Borson, that anorexia in man can be due to conditioned taste aversions, is reviewed. Animal studies demonstrating hastened extinction of taste aversions by behavioral procedures are discussed, suggesting an analogous treatment in man.

Extinction of taste aversion does not eliminate taste potentiation of odor aversion in rats or color aversion in pigeons

Rats were exposed to an odor-taste compound prior to being poisoned with lithium chloride on two occasions in Experiment 1 but only once in Experiment 2. Then, in each experiment, one group was given unreinforced exposures to the taste cue until extinction of the conditioned taste aversion occurred. During a later test, taste potentiation of odor aversion was obtained to a similar extent whether or not the taste aversion had been extinguished. An analogous finding was obtained with pigeons in Experiment 3. The present results indicate that taste potentiation does not depend on an underlying conditioned taste aversion, and, therefore, they support the notion that taste strengthened the odor-sickness (or color-sickness) association during the conditioning process.

Analysis of behavioural responses to an ACTH analog in CXB/By recombinant inbred mice

Male mice of the C57BL/6By and BALB/cBy inbred strains, their reciprocal F 1 hybrids, and 7 recombinant inbred strains, were tested for open-field activity, a shock-motivated successive reversal position discrimination problem in a T-maze, and a toggle box exploration task. The test battery was repeated one month later. Finally, mice were tested for the acquisition and extinction of a taste aversion conditioned by ethanol injection. Mice of each strain were tested after injection with saline or one of 3 doses of an ACTH analogue. Highly significant genotypic differences were found for all measures, an expected result. The strain distribution pattern seen in the toggle box suggested single gene mediation of exploratory activity after habituation. One aspect of avoidance responding and extinction of conditioned taste aversion also yielded strain distribution pattern consistent with single gene control. Peptide treatment reduced internal field crossings in the open field. This effect was not strain dependent. Peptide treatment had no effect on T-maze learning, conditioned taste aversion, or toggle-box exploration.

Associative and nonassociative effects of exteroceptive context in taste-aversion conditioning with rats

Two experiments were performed to assess the role of exteroceptive context novelty in producing context-dependent taste-aversion learning. In Experiment 1, saccharin—lithium chloride pairings were given to four groups of rats, two of which were placed in a completely novel conditioning context (compartments and bottles), and two in a familiar context. Extinction tests showed that the exteroceptive control of saccharin intake was significantly stronger in the “novel context” groups than in the “familiar context” groups. However, postextinction preference tests indicated context-dependent taste-aversion extinction irrespective of conditioning context novelty. Experiment 2 varied the novelty of the extinction context and demonstrated that groups placed in the same exteroceptive context during extinction as during conditioning drank significantly less saccharin compared to groups placed in a different context, irrespective of the relative novelty of the extinction context. Thus, differential neophobic reactions to the extinction context can be excluded as an account of context dependence. The results lend credibility to an associative interpretation of context-dependent taste-aversion learning.

Environment-dependent taste-aversion extinction: A question of stimulus novelty at conditioning

In Experiment 1, four groups of rats were exposed to two saccharin(Sac)-lithium chloride(LiCl) pairings in a novel animal compartment. In subsequent daily extinction trials, Sac (two groups) or water (H2O) (two groups) was presented either in the same (as conditioning) or a different compartment. There was no evidence that the presence or absence of the conditioning compartment influenced the amounts of Sac or H2O drunk. Postextinction preference tests (Sac vs. H2O), performed in the conditioning compartment, showed a compartment-dependent extinction effect: There was a significantly stronger aversion in the group drinking Sac during extinction in a different (from conditioning) compartment than in the group drinking Sac in the conditioning compartment. In Experiment 2, four groups were given two Sac-LiCl trials in a novel (2 groups) or a familiar (2 groups) compartment. One “novel compartment” group and one “familiar” group were offered Sac during daily Sac-aversion extinction trials in the conditioning compartment, and the remaining groups drank Sac in a different compartment. Again, intercompartment generalization of the Sac aversion was demonstrated: There was no evidence that the particular compartment present influenced the strength of aversion during extinction. Postextinction preference tests showed the previously observed compartment-dependent extinction effect only in the case of the “novel compartment” groups. Thus, in view of previously reported data, the number of conditioning trials and the novelty of the conditioning compartment were shown to be critical to compartment-dependent taste-aversion extinction.

Hippocampal lesions slow extinction of a conditioned taste aversion in rats

Rats were subjected to either a bilateral removal of the superior cervical ganglia or to a sham operation of the neck. In subsequent operations, these animals underwent either bilateral dorsal hippocampal lesions, bilateral neopallial lesions or no further operation. Removal of the superior cervical ganglia prevented the anomalous innervation of the remaining hippocampal tissue. All animals then learned a conditioned taste aversion to a sweetened milk solution (CS) following LiCl-induced gastrointestinal illness (UCS). The rats with hippocampal lesions were significantly slower to extinguish the aversion conditioning across the 14 day recovery period than were controls. There was no effect of any manipulation on the acquisition of the conditioned taste aversion, and there were no behavioral consequences of the presence or absence of the anomalous innervation. The slower extinction of the taste aversion shown by the hippocampal lesioned rats was discussed in terms of a lessened impact of the pre-illness exposure to the CS in these animals.

The effect of flavor preexposure upon the acquisition and retention of poison-based taste aversions in deer mice: latent inhibition or partial reinforcement?

An investigation was made of the effects of prior familiarization with sucrose on the acquisition and extinction of LiCl-induced aversions to sucrose by mice of the genus Peromyscus . As in previous studies on other species, it was found that flavor familiarization inhibits the formation of learned taste aversions. However, in contrast to some reports on other species, it was demonstrated that for Peromyscus familiarization does not accelerate, but instead retards, the extinction of taste aversions. It was noted that (a) the contrasting extinction results reported for other species may be confounded with masked acquisition effects, (b) the latent inhibition effect is often not obtained with fewer than 20 preexposures, yet the flavor-preexposure effect has been demonstrated with as few as one preexposure, (c) the flavor-preexposure schedule is logically and operationally equivalent to a short partial-reinforcement schedule, and (d) both the acquisition and extinction effects shown by Peromyscus are consistent with a partial-reinforcement interpretation. Therefore, it was suggested that future analysis of the phenomenon might profitably consider the possibility that the flavor-preexposure effect upon taste-aversion learning may be a case of partial reinforcement.