Extinction Of Conditioned Taste Aversion Research Articles

Brief environmental enrichment elicits metaplasticity on the insular cortex in vivo and reduces the strength of conditioned taste aversion

Environmental enrichment (EE) is known to improve memory and cognition and modulate the impact of aversive stimuli in animals, promoting the development of resilience to stressful situations. Likewise, it is known that EE can modulate synaptic plasticity as is the case of long-term potentiation (LTP). These findings have been described initially in ex vivo preparations, suggesting that the effects of EE are the result of an early modification of the synaptic excitability and transmission. In this regard, it is known that metaplasticity refers to the persistent modification, by previous activity, in the ability to induce synaptic plasticity. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of LTP in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. In addition, we have shown that CTA extinction allows the induction but not the maintenance of IC-LTP of the Bla-IC pathway. Recently, we also showed that prior exposure to environmental enrichment for three weeks reduces the strength of CTA, restoring the brain-derived neurotrophic factor (BDNF) levels in the IC. The present study aimed to analyze the effects of brief exposure to an enriched environment on the strength of aversive memory, as well as on the in vivo IC-LTP. To do so, adult rats were exposed for seven days to an EE, either before CTA training or LTP induction in the Bla-IC pathway. Our results demonstrate that a seven-day exposure to an enriched environment attenuates the aversive response to a strong CTA and allows the induction but not the maintenance of LTP in the insular cortex. These findings provide evidence that metaplastic regulation in a neocortical region takes part in the mechanisms through which brief exposure to enriched environments attenuates an aversive response.

Switching from sucrose to saccharin: Extended successive negative contrast is not maintained by hedonic changes.

Previous experiments found that acceptance of saccharin by rats was reduced if they had prior experience of sucrose or some other highly palatable solution. This reduction in saccharin consumption was particularly extended after a switch from sucrose. On the surface, this seems to correspond to a successive negative contrast (SNC) effect. This term was coined by C. F. Flaherty to describe the situation where consumption of a target solution is reduced by prior experience of a more valuable solution, typically a more concentrated version of the target solution. However, SNC effects are normally transient and assessed relative to a nonshifted control. Here, we confirm that the reduction in consumption seen when shifting from sucrose to saccharin is persistent and is seen relative to the traditional unshifted control. In addition, an analysis of licking microstructure showed that the shift from sucrose to saccharin suppressed the hedonic value of saccharin relative to controls, but this effect was less persistent than consumption suppression. Interestingly, a similar dissociation is observed in extinction of conditioned taste aversion (CTA): suppression of consumption produced by CTA is far more persistent than suppression of hedonic value. The comparison of results across procedures suggests that persistent SNC produced by a qualitative downshift from sucrose to saccharin appears different from quantitative downshifts in the concentration of a single solution, and qualitative downshift effects may involve CTA. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Differential effects of thirst and satiety on conditioned taste aversion acquisition, retrieval, and memory extinction

Thirst is an essential motivational component that could modulate the strength of conditioning; pioneer studies show that the rats' sexual dimorphism observed in the rate of aversive memory extinction of conditioned taste aversion (CTA) is affected by the state of fluid deprivation. On the other hand, previous evidence suggests that fluid intake volume and temporal context before and during conditioning may influence CTA. Furthermore, although CTA has been demonstrated using various types of stimuli, neural processing and homeostatic regulation of water and nutritional balance may differ depending on the stimulus used and the conditioning stages. Therefore, this study explored the effects of state motivated by thirst and satiation, using saccharin, as a non-caloric sweet stimulus, during CTA and the aversive memory extinction process under similar contextual and temporal conditions. First, we implemented an ad libitum water protocol in male and female adult rats to evaluate saccharin aversive memory formation; we compared this with a traditional CTA with liquid deprivation in the same context and temporal consumption conditions. Furthermore, we evaluated whether liquid satiety affects the acquisition or the aversive memory retrieval differentially. Our results show that the ad libitum liquid regimen allows reliable quantifications of basal water consumption, monitored every hour for more than five days. We observed a reliable CTA, where the magnitude of aversive memory and its extinction is significantly higher in both male and female rats; the strong CTA observed is substantially due to the satiety state during taste aversion memory retrieval. Our data show that although liquid deprivation does not affect CTA acquisition, it does induce weakness in the magnitude of aversive retrieval expression and fast aversive memory extinction, similarly in male and females. Overall, the results indicate that the need to satiate the demand for liquids during retrieval prevails over the conditioned aversion learned, suggesting, that thirst is a source of temporary variables dominating the aversive responses during CTA retrieval.

Effect of early-life stress or fluoxetine exposure on later-life conditioned taste aversion learning in Sprague-Dawley rats

In rodents, early-life exposure to environmental stress or antidepressant medication treatment has been shown to induce similar long-term consequences on memory- and depression-related behavior in adulthood. To expand on this line of work, we evaluated how juvenile exposure to chronic variable stress (CVS) or the selective serotonin reuptake inhibitor fluoxetine (FLX) influences conditioned taste aversion (CTA) learning in adulthood. To do this, in Experiment 1, we examined how adolescent CVS alone (postnatal day [PND] 35–48), or with prenatal stress (PNS) history (PNS + CVS), influenced the acquisition and extinction of CTA in adult male Sprague Dawley rats. Specifically, at PND70+ (adulthood), rats were presented with 0.15 % saccharin followed by an intraperitoneal (i.p.) injection of lithium chloride (LiCl) to induce visceral malaise. A total of four saccharin (conditioned stimulus) and LiCl (unconditioned stimulus) pairings occurred across the CTA acquisition phase. Next, saccharin was presented without aversive consequences, and intake was measured across consecutive days of the extinction phase. No differences in body weight gain across the experimental days, rate of CTA acquisition, or extinction of CTA, were observed among the experimental groups (control, n = 7; CVS, n = 12; PNS + CVS, n = 9). In Experiment 2, we evaluated if early-life FLX exposure alters CTA learning in adulthood. Specifically, adolescent stress naïve male and female rats received FLX (0 or 20 mg/kg/i.p) once daily for 15 consecutive days (PND35-49). During antidepressant exposure, FLX decreased body weight gain in both male (n = 7) and female rats (n = 7), when compared to respective controls (male control, n = 8; female control, n = 8). However, juvenile FLX exposure decreased body weight-gain in adult male, but not female, rats. Lastly, adolescent FLX history had no effect on CTA acquisition or extinction in adulthood (PND70), in neither male nor female rats. Together, the data indicate that juvenile FLX exposure results in a long-term decrease of body weight-gain in a male-specific manner. Yet, independent of sex, neither early-life stress nor FLX exposure alters CTA learning in adulthood.

Calcineurin requirement for in vivo insular cortex LTD and CTA-extinction

Currently, it is widely accepted that memory extinction involves the formation of a new associative memory rather than unlearning of the information previously acquired. Nonetheless, the cellular and molecular mechanisms underlying this process are still unclear. In this regard, it has been suggested that while kinases modulate conditioning and LTP, phosphatases are relevant for extinction and LTD. In particular, the protein phosphatase calcineurin (CaN) has been involved in the extinction of some behavioral tasks along with LTD. Indeed, studies of our research group have demonstrated that induction of LTD in the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) pathway facilitates the extinction of conditioned taste aversion (CTA), while the induction of LTP in this pathway slows it down. In addition, we have shown that the extinction of CTA elicits an increase of CaN. The aim of the present study was to evaluate the participation of calcineurin in the extinction of CTA and in the expression of in vivo LTD in the Bla-IC pathway. For this purpose, we chemically inhibited calcineurin in the IC of adult male Wistar rats, either during CTA-extinction or thirty minutes after LTD induction in the Bla-IC pathway. Our results show that calcineurin inhibition slows down the CTA-extinction and blocks the maintenance of LTD. Furthermore, we show that CaN levels increase after LTD induction. These findings support the idea that calcineurin is a key molecular actor for both CTA extinction and LTD expression in the IC, a highly relevant neocortical area for the processing of aversively motivated learning tasks, suggesting that both processes are associated at a molecular level.

Virus-mediated GHS-R1a expression in the basolateral amygdala blocks extinction of conditioned taste aversion memory in rats

Ghrelin is an orexigenic gastric hormone that promotes feeding behaviors and regulating energy homeostasis in both humans and rodents. Our previous studies have shown that ghrelin, when locally infused into the basolateral amygdala (BLA), blocks both acquisition and extinction of conditioned taste aversion (CTA) memory in rats. In this study, we further investigated the effect of virus-mediated overexpression of ghrelin receptor growth hormone secretagogue receptor 1a (GHS-R1a) in BLA pyramidal neurons on CTA memory processes. We found that upregulation of GHS-R1a expression in BLA pyramidal neurons repressed CTA extinction while it had no effect on CTA acquisition. In addition, we reported that local infusion of the endogenous GHS-R1a antagonist, liver-expressed antimicrobial peptide 2 (LEAP2), in the BLA abolished the inhibitory effect of increased GHS-R1a on CTA memory extinction. Those findings provide new supportive evidence that ghrelin/GHS-R1a signaling in the BLA circuit shapes emotional memory processes.

Metaplastic regulation of neocortical long-term depression in vivo is sensitive to distinct phases of conditioned taste aversion

Metaplasticity refers to the persistent modification, by previous activity, in the ability to induce synaptic plasticity. Accumulated evidence has proposed that metaplasticity contributes to network function and cognitive processes such as learning and memory. In this regard, it has been observed that training in several behavioral tasks modifies the possibility to induce subsequent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). For instance, our previous studies have shown that conditioned taste aversion (CTA) training prevents the induction of in vivo LTP in the projection from the basolateral nucleus of the amygdala to the insular cortex (BLA-IC). Likewise, we reported that extinction of CTA allows induction but not maintenance of LTP in the same pathway. Besides, we showed that it is possible to express in vivo low-frequency stimulation LTD in the BLA-IC projection and that its induction prior to CTA training facilitates the extinction of this task. However, until now, little is known about the participation of LTD on metaplastic processes. The present study aimed to analyze whether CTA training modifies the expression of in vivo LTD in the BLA-IC projection. To do so, animals received low-frequency stimulation to induce IC-LTD 48 h after CTA training. Our results show that CTA training occludes the subsequent induction of LTD in the BLA-IC pathway in a retrieval-dependent manner. These findings reveal that CTA elicits a metaplastic regulation of long-lasting changes in the IC synaptic strength, as well as that specific phases of learning differentially take part in adjusting the expression of synaptic plasticity in neocortical regions.

Interactions between prelimbic cortex and basolateral amygdala contribute to morphine-induced conditioned taste aversion in conditioning and extinction

The consequences of exciting or destroying the prelimbic cortex (PrL) or the basolateral amygdala (BLA) remain unclear, including the effects on morphine-induced conditioned taste aversion (CTA) in the conditioning and extinction phases, plasma corticosterone (CORT) levels, and c-Fos/p-ERK expressions in the subareas of the medial prefrontal cortex (i.e., PrL, infralimbic cortex [IL], cingulate cortex 1 [Cg1]), basolateral amygdala (BLA), central amygdala (CeA), hippocampus (i.e., CA1, CA2, CA3, and dentate gyrus [DG]), nucleus accumbens (NAc), lateral hypothalamus (LH), and piriform cortex (PC). During conditioning, excitation of the PrL glutamate neurons via NMDA injections disrupted morphine-induced CTA and decreased plasma CORT levels; moreover, c-Fos and p-ERK expression was hyperactive in the PrL and IL but hypoactive in the Cg1 and BLA. In conditioning, excitation of the BLA glutamate neurons via NMDA injections facilitated morphine-induced CTA and increased plasma CORT levels. The expression of c-Fos and p-ERK was hypoactive in the PrL and IL but hyperactive in the BLA. During extinction, lesion of the PrL glutamate neurons via NMDA injections impaired morphine-induced CTA extinction and enhanced plasma CORT levels. The expression of c-Fos and p-ERK was hypoactive in the PrL and IL but hyperactive in the BLA. In extinction, excitation of the PrL glutamatergic neurons via NMDA injections facilitated morphine-induced CTA extinction and did not affect plasma CORT levels; moreover, the expression of c-Fos and p-ERK was hypoactive in the Cg1, PrL, and IL but hyperactive in the BLA. Altogether, the interaction between the PrL and BLA plays a balancing role in morphine-induced CTA conditioning and extinction. During conditioning, the activity of the PrL correlated negatively with plasma CORT secretions, whereas the activity of the BLA correlated positively with the plasma CORT levels. During extinction, the activity of the PrL correlated negatively with plasma CORT secretions; however, the activity of the BLA may be negatively associated with the plasma CORT levels. The data presented here provide some implications for morphine addiction and dependence.

Extra-Hippocampal Learning Deficits in Young Apolipoprotein E4 Mice and Their Synaptic Underpinning.

The E4 allele of apolipoprotein (apoE4) is the primary genetic risk factor for late onset Alzheimer's disease (AD), yet the exact manner in which apoE4 leads to the development of AD is undetermined. Human and animal studies report that apoE4-related memory deficits appear earlier than the AD clinical manifestation, thus suggesting the existence of early, pre-pathological, apoE4 impairments that may later lead to AD onset. While current research regards the hippocampus as the initial and primary effected locus by apoE4, we presently investigate the possibility that apoE4 innately impairs any brain area that requires synaptic plasticity. To test this hypothesis, we trained young (3-4-month-old) target-replacement apoE3 and apoE4 mice in conditioned taste aversion (CTA) acquisition and extinction learnings- hippocampus-independent learnings that are easily performed at a young age. Synaptic vesicular markers analysis was conducted in the gustatory cortex (GC), basolateral amygdala (BLA), medial prefrontal cortex (mPFC), and hippocampal CA3 to reveal underlying apoE4-related impairments. We have found that young apoE4 mice are severely impaired in CTA acquisition and extinction learning. CTA acquisition impairments were correlated with reduced vGat and vGlut levels in the BLA and GC, but not in the CA3. CTA extinction was correlated with lower synaptophysin and vGlut levels in the mPFC, a central region in CTA extinction. Our results support apoE4-related early-life plasticity impairments that precede the AD clinical manifestations and affect any brain area that depends on extensive plasticity; early impairments that may promote the development of AD pathologies later in life.

Conditioned taste aversion memory extinction temporally induces insular cortical BDNF release and inhibits neuronal apoptosis.

BackgroundMemory extinction has been reported to be related to psychiatric disorders, such as post-traumatic stress disorder (PTSD). Secretion and synthesis of brain-derived neurotrophic factor (BDNF) have been shown to temporally regulate various memory processes via activation of tropomyosin-related kinase B (TrkB) receptors. However, whether memory extinction induces the synthesis and secretion of BDNF on the basis of its localization is not understood. In this study, we aim to investigate activity-dependent BDNF secretion and synthesis in the insular cortex (IC) in the setting of conditioned taste aversion (CTA) memory extinction.Materials and methodsRats were subjected to CTA memory extinction and BDNF antibody (or the equal volume of vehicle) was microinjected into the IC immediately after the extinction testing. Real-time polymerase chain reaction and in situ hybridization were used to detect the gene expression of BDNF, NGF and NT4. The protein levels of BDNF were determined through the enzyme-linked immunosorbent assay. In addition, the levels of phosphorylated TrkB normalized to total TrkB were evaluated using immunoprecipitation and immunoblotting. c-Fos, total extracellular signal-regulated kinase (Erk), phosphorylated Erk, and apoptosis-related protein (caspase-3), were detected by Western blotting.ResultsWe found that blocking BDNF signaling within the IC disrupts CTA extinction, suggesting that BDNF signaling in the IC is necessary for CTA extinction. Increased expression levels of c-Fos indicate the induced neuronal activity in the IC during CTA extinction. In addition, temporal changes in the gene expression and protein levels of BDNF in the IC were noted during extinction. Moreover, we found that phosphorylation of TrkB increased prior to the enhanced BDNF expression, suggesting that CTA extinction induces rapid activity-dependent BDNF secretion in the IC. Finally, we found decreased expression of caspase-3 in the IC after CTA extinction.ConclusionThese results demonstrate that CTA memory extinction temporally induces the release and synthesis of BDNF in the IC and inhibits neuronal apoptosis.

APOE4 EXPRESSING ANIMALS SHOW IMPAIRMENTS IN CONDITIONED TASTE AVERSION ACQUISITION AND EXTINCTION

ApoE4, the strongest genetic risk to Alzheimer's disease (AD), was so far mainly investigated in the hippocampus. ApoE4 carriers already show early-life hippocampal anomalies which may prevent the accurate characterization of the effect of ApoE4 on normal brain functioning. Conditioned taste aversion (CTA) acquisition and extinction, a processes that does not require an intact hippocampus, was tested on ApoE4 expressing mice and rats. Additionally, electrophysiological and immunohistochemical procedures were preformed to identify extra hippocampal anomalies in young ApoE4 animals. Both ApoE4 expressing mice and rats showed severe CTA acquisition and extinction abnormalities that correlated with plasticity related cellular aberrations. Robust ApoE4 taste learning deficits were detected despite lack of evident tissue damage in the tested regions. Therefore, the system developed in this research may provide a sensitive tool for testing the basal effect of ApoE4.

Extinction of aversive taste memory homeostatically prevents the maintenance of in vivo insular cortex LTP: Calcineurin participation.

Accumulating evidence indicates that homeostatic plasticity mechanisms dynamically adjust synaptic strength to promote stability that is crucial for memory storage. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of long-term potentiation (LTP) in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. We have also reported that induction of LTP in the Bla-IC pathway modifies the CTA extinction. Memoryextinction involves the formation of a new associativememorythat inhibits a previously conditioned association. The aim of the present study was to analyze the effect of CTA extinction on the ability to induce subsequent LTP in the Bla-IC projection in vivo. Thus, 48 h after CTA extinction animals received high frequency stimulation in order to induce IC-LTP. Our results show that extinction training allows the induction but not the maintenance of IC-LTP. In addition, with the purpose of exploring part of the mechanisms involved in this process and since a body of evidence suggests that protein phosphatase calcineurin (CaN) is involved in the extinction of some behavioral tasks, we analyzed the participation of this phosphatase. The present results show that extinction training increases the CaN expression in the IC, as well as that the inhibition of this phosphatase reverts the effects of the CTA-extinction on the IC-LTP. These findings reveal that CTA extinction promotes a homeostatic regulation of subsequent IC synaptic plasticity maintenance through increases in CaN levels.

Local infusion of ghrelin into the lateral amygdala blocks extinction of conditioned taste aversion in rats.

Ghrelin is an orexigenic brain-gut hormone promoting feeding and regulating energy metabolism in human and rodents. Our previous study showed that ghrelin locally infused into the lateral amygdala (LA) activates its receptor GHS-R1a and blocks acquisition of conditioned taste aversion (CTA) in rats. In this study, we further investigated the effect of ghrelin/GHS-R1a signaling on extinction of CTA. We found that local infusion of ghrelin (5μM, 0.5μl/side) into the LA not only interfered with CTA memory formation, but also the extinction of CTA memory. Pre-administration of GHS-R1a antagonist blocked ghrelin's effect on both CTA acquisition and extinction. However, pre-treatment with PI3K inhibitor only abolished the inhibitory effect of ghrelin on acquisition, but not on extinction. Altogether, our data indicated that ghrelin/GHS-R1a signaling in the LA circuit modulates both acquisition and extinction of CTA, the two forms of taste aversion processes with distinct mechanisms may also share certain molecular and circuit components in common.

Molecular mechanisms involved in taste learning and memory

Taste learning, and particularly conditioned taste aversion (CTA), is an adaptive learning involving complex brain mechanisms and molecular pathways. Taste learning and CTA are critical behaviors for survival, and the knowledge of the molecular bases involved in the acquisition, retention and extinction of CTA can help to understand the brain mechanisms of normal and altered taste learning. The aim of this review is to describe recent findings on the molecular mechanisms of taste learning, from the genetic, receptors, and intracellular and extracellular signaling biological levels. We can conclude that some molecular pathways and processes for the acquisition of taste learning and the formation of taste memories are well identified. However, new molecular, neurobiological and behavioral studies are needed to thoroughly elucidate the complexity of the taste system and the neural mechanisms of CTA.

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.

Rats taste-aversive learning with cyclosporine a is not affected by contextual changes

In conditioned taste aversion (CTA) rats associate a novel taste (conditioned stimulus; CS) with a treatment (unconditioned stimulus; US) that induces symptoms of malaise. During retrieval, animals learn that the CS no longer predicts the US, with the consequence that the behavior elicited by the CS extinguishes. Importantly, CTA data with lithium chloride (LiCl) as US indicate that extinction learning is affected by changing the physical context. However, if this is also the case in different taste-aversion paradigms employing compounds other than LiCL as US is unknown. Against this background the present study investigated in a CTA paradigm with saccharin as CS and the immunosuppressant cyclosporine A (CsA) as US the influence of contextual changes on CTA extinction. Our results show, that extinction of a learned CS-US association with CsA is not prone to contextual changes. Due to the direct effects of CsA on CNS functioning, CTA with this immunosuppressant apparently operates under different mechanisms compared to other drugs, such as LiCl. These data indicate that taste aversive learning and its extinction are not necessarily specific to the context in which it is learned but also depends, at least in part, on the physiological and neuropharmacological effects of the drug employed as US.

Transient inhibition of protein synthesis in the rat insular cortex delays extinction of conditioned taste aversion with cyclosporine A

Conditioned responses gradually weaken and eventually disappear when subjects are repeatedly exposed to the conditioned stimulus (CS) in the absence of the unconditioned stimulus (US), a process called extinction. Studies have demonstrated that extinction of conditioned taste aversion (CTA) can be prevented by interfering with protein synthesis in the insular cortex (IC). However, it remained unknown whether it is possible to pharmacologically stabilize the taste aversive memory trace over longer periods of time. Thus, the present study aimed at investigating the time frame during which extinction of CTA can be efficiently prevented by blocking protein synthesis in the IC. Employing an established conditioning paradigm in rats with saccharin as CS, and the immunosuppressant cyclosporine A (CsA) as US, we show here that daily bilateral intra-insular injections of the protein synthesis inhibitor anisomycin (120μg/μl) immediately after retrieval significantly diminished CTA extinction over a period of five retrieval days and subsequently reached levels of saline-infused controls. These findings demonstrate that it is possible to efficiently delay but not to fully prevent CTA extinction during repeated retrieval trials by blocking protein translation with daily bilateral infusions of anisomycin in the IC. These data confirm and extent earlier reports indicating that the role of protein synthesis in CTA extinction learning is not limited to gastrointestinal malaise-inducing drugs such as lithium chloride (LiCl).

Temporal and qualitative dynamics of conditioned taste aversions in C57BL/6J and DBA/2J mice self-administering LiCl

Self-administration of LiCl solution has been shown to result in the formation of a conditioned taste aversion (CTA) that generalizes to NaCl in rats. This paradigm may have considerable ecological validity as it models CTA learning in natural settings, and also allows for the investigation of drinking microstructure as an assay of potential shifts in stimulus palatability. We used this paradigm to examine possible mouse strain differences in CTA acquisition, generalization, and extinction. In the first experiment, C57BL/6J (B6) and DBA/2J (D2) mice self-administered LiCl (or control NaCl) over a 20-minute free access acquisition period and were tested on the following day with a panel of taste solutions available in brief (5-s) trials delivered in random order. In the second experiment, mice again self-administered LiCl or NaCl (at low, 0.12M, or high, 0.24M concentrations) in a 20-minute session, and on the following day received a 20-minute free access period to equimolar NaCl. Strain differences were found for aspects of ingestive behavior, with B6 mice showing greater consumption of all stimuli, including water, while D2 mice lick faster, in less frequent but longer bursts. We did not, however, find evidence of a robust strain difference in taste aversion learning. Both strains demonstrated profound alterations in licking microstructure in the generalization session relative to controls. We suggest that a decrease in “lick efficiency” (the percentage of inter-lick intervals within a burst of short duration vs. longer duration) reflects avoidance behavior, and signals a shift in palatability of a stimulus following CTA.

Memory-updating abrogates extinction of learned immunosuppression

When memories are recalled, they enter a transient labile phase in which they can be impaired or enhanced followed by a new stabilization process termed reconsolidation. It is unknown, however, whether reconsolidation is restricted to neurocognitive processes such as fear memories or can be extended to peripheral physiological functions as well. Here, we show in a paradigm of behaviorally conditioned taste aversion in rats memory-updating in learned immunosuppression. The administration of sub-therapeutic doses of the immunosuppressant cyclosporin A together with the conditioned stimulus (CS/saccharin) during retrieval blocked extinction of conditioned taste aversion and learned suppression of T cell cytokine (interleukin-2; interferon-γ) production. This conditioned immunosuppression is of clinical relevance since it significantly prolonged the survival time of heterotopically transplanted heart allografts in rats. Collectively, these findings demonstrate that memories can be updated on both neural and behavioral levels as well as on the level of peripheral physiological systems such as immune functioning.