Cortical substrates of taste aversion learning: dorsal prepiriform (insular) lesions disrupt taste aversion learning

The functional relation between restricted damage to ventral primary somatosensory neocortex and the ability of rats to acquire conditioned taste aversion (CTA( was examined by a combination of behavioral and neurohistological techniques. Lesions confined exclusively to the established gustatory neocortex (GN) did not disrupt CTA acquisition, nor did lesions confined to suprarhinal cortical areas ventral to the GN. Lesions that encroached on dorsal prepiriform and insular cortices produced CTA acquisition deficits and damaged a large proportion of efferent projections to the prefrontal and precentral neocortex. In a second experiment, lesions of dorsal prepiriform and insular cortices did not modify taste preference-aversion threshold to any of the four taste modalities. It is concluded tha ventral somatosensory neocortical fields, including the established GN, do not mediate CTA acquisition and that rhinal cortices ventral and posterior to the GN are preferentially involved in associative learning for tastes and illness.     

Relationship between vomiting and taste aversion learning in the ferret: studies with ionizing radiation, lithium chloride, and amphetamine.

The relationship between emesis and taste aversion learning was studied in ferrets (Mustela putorius furo) following exposure to ionizing radiation (50-200 cGy) or injection of lithium chloride (1.5-3.0 mEq/kg, ip). When 10% sucrose or 0.1% saccharin was used as the conditioned stimulus, neither unconditioned stimulus produced a taste aversion, even when vomiting was produced by the stimulus (Experiments 1 and 2). When a canned cat food was used as the conditioned stimulus, lithium chloride, but not ionizing radiation, produced a taste aversion (Experiment 3). Lithium chloride was effective in producing a conditioned taste aversion when administration of the toxin was delayed by up to 90 min following the ingestion of the canned cat food, indicating that the ferrets are capable of showing long-delay learning (Experiment 4). Experiment 5 examined the capacity of amphetamine, which is a qualitatively different stimulus than lithium chloride or ionizing radiation, to produce taste aversion learning in rats and cats as well as in ferrets. Injection of amphetamine (3 mg/kg, ip) produced a taste aversion in rats and cats but not in ferrets which required a higher dose (> 5 mg/kg). The results of these experiments are interpreted as indicating that, at least for the ferret, there is no necessary relationship between toxin-induced illness and the acquisition of a CTA and that gastrointestinal distress is not a sufficient condition for CTA learning.     

The role of the insular cortex in taste function

In spite of over 30 years of research, the role of the Insular Cortex (IC) in taste memory still remains elusive. To study the role of the IC in taste memory, we used conditioned taste aversion (CTA) for two different concentrations of saccharin; 0.1% which is highly preferred, and 0.5% which is non-preferred. Rats that had been IC lesioned bilaterally with ibotenic acid (15 mg/ml) before CTA showed significant learning impairments for saccharin 0.1% but not for saccharin 0.5%. To test CTA memory retention, rats lesioned a week after CTA training became completely amnesic for saccharin 0.1% yet only mildly impaired for saccharin 0.5%. Interestingly, the resulting preference for either concentration matched that of IC lesioned animals when exposed to either saccharin solution for the first time, but not those of sham animals, implying that IC lesions after CTA for either saccharin solution rendered complete amnesia, irrespective of the original preference. Our data indicate that an intact IC is essential for CTA learning and retention, as well as for an early neophobic response, but not for taste preference itself. Our data supports a model where the IC is involved in general taste rejection.     

Intragastric copper sulfate produces a more reliable conditioned taste aversion in vagotomized rats than in intact rats

Although copper sulfate is an emetic stimulus, preliminary experiments failed to obtain a taste aversion in intact rats following intragastric administration as had been previously reported in the literature. Several experiments were therefore run to further investigate the capacity of intragastric copper sulfate to function as an unconditioned stimulus for taste aversion learning and the role of the vagus in mediating that learning. The results of the first series of experiments showed that intragastric administration of copper sulfate (5 mg/kg X 5H2O) was more effective in reliably producing a taste aversion in vagotomized rats than in sham-operated control rats. The second experiment examined the effects of area postrema lesions on the acquisition of a taste aversion produced by intragastrically administered copper sulfate in vagotomized rats. The results indicated that the taste aversion observed following treatment with intragastric copper sulfate in vagotomized rats could be prevented by lesions of the area postrema. The present results indicate that intragastric administration of copper sulfate is a more reliable unconditioned stimulus for taste aversion learning in vagotomized rats than in intact rats. It is not certain what factors might account for the discrepant results between the present experiments and previously published research.     

Cholinergic dependence of taste memory formation: evidence of two distinct processes

Learning the aversive or positive consequences associated with novel taste solutions has a strong significance for an animal's survival. A lack of recognition of a taste's consequences could prevent ingestion of potential edibles or encounter death. We used conditioned taste aversion (CTA) and attenuation of neophobia (AN) to study aversive and safe taste memory formation. To determine if muscarinic receptors in the insular cortex participate differentially in both tasks, we infused the muscarinic antagonists scopolamine at distinct times before or after the presentation of a strong concentration of saccharin, followed by either an i.p. injection of a malaise-inducing agent or no injection. Our results showed that blockade of muscarinic receptors before taste presentation disrupts both learning tasks. However, the same treatment after the taste prevents AN but not CTA. These results clearly demonstrate that cortical cholinergic activity participates in the acquisition of both safe and aversive memory formation, and that cortical muscarinic receptors seem to be necessary for safe but not for aversive taste memory consolidation. These results suggest that the taste memory trace is processed in the insular cortex simultaneously by at least two independent mechanisms, and that their interaction would determine the degree of aversion or preference learned to a novel taste.     

Time-dependent recovery of taste aversion learning by fetal brain transplants in gustatory neocortex-lesioned rats.

We recently showed that fetal brain transplants produced a significant recovery in the ability of gustatory neocortex-lesioned rats to learn a conditioned taste aversion. In this report we assessed the capability of gustatory neocortex fetal brain transplants to produce behavioral recovery at different times. Four groups of male Wistar rats showing disrupted taste aversions due to gustatory neocortex lesions were studied. The lesioned animals received fetal cortical grafts, obtained from 16-day-old fetuses, and were retrained in the behavioral procedure after 15, 30, 45, or 60 days postgraft. Behavioral results showed a very good functional recuperation at 60 days, slight recovery at 45 and 30 days, and a poor recovery at 15 days postgraft. Results with HRP histochemistry revealed that at 30, 45, and 60 days postgrafting there were increased connections with the ventromedial nucleus of the thalamus and with the amygdala. At 15 days postgrafting there was an absence of HRP-labeled cells. In addition, behavioral recovery was correlated with increased acetylcholinesterase activity, detected histochemically, and with morphological neuronal maturation, revealed by Golgi staining. These results suggest that morphological maturity and reconnectivity between grafts and host tissue are important for behavioral recovery in gustatory neocortex-lesioned rats.     

The contextual modulation of conditioned taste aversions by the physical environment and time of day is similar

In a pair of experiments, we have compared the ability of changes of place (Exp. 1) and changes of time of day (Exp. 2) to separately modulate learned saline-aversion memory phenomena in rats. Neither a spatial nor a temporal change disrupted latent inhibition using the present behavioral procedure. However, pre-exposure to the taste increased the contextual control of the learned aversion expression. The aversion reappeared in the place or at the time of conditioning after extinction in a different context. The results indicate that environmental and temporal contexts can independently, but similarly modulate taste aversion learning.     

Conditioning Method Dramatically Alters the Role of Amygdala in Taste Aversion Learning

Although an important role for the amygdala in taste aversion learning has been suggested by work in a number of laboratories, results have been inconsistent and interpretations varied. The present series of studies reevaluated the role of the amygdala in taste aversion learning by examining the extent to which conditioning methods, testing methods and lesioning methods, influence whether amygdala lesions dramatically affect conditioned taste aversion (CTA) learning. Results indicated that when animals are conditioned with an intraoral (I/O) taste presentation, lesions of amygdala eliminate evidence of conditioning whether animals are tested intraorally or with a two-bottle solution presentation. Dramatic effects of amygdala lesions on CTA learning were seen whether lesions were made electrolytically or using an excitotoxin. In contrast, when animals were conditioned using bottle presentation of the taste, electrolytic lesions attenuated CTAs but did not eliminate them, and excitotoxic lesions had no effect. These results are consistent with the hypothesis that neural structures critical for CTA learning may differ depending on the extent to which the method of conditioned stimulus delivery incorporates a response component.     

Involvement of the insular cortex in retention of conditioned taste aversion is not time dependent

In fear-associated learning paradigms, hippocampal lesions induce memory deficits of recent but not remote memories, while amygdala lesions produce retention deficits irrespective of the age of the memory. In conditioned taste aversion (CTA), non-hippocampal mediated learning paradigm, the insular vortex (IC) has shown to have a crucial role in consolidation and storage of CTA memory. Due to the functional and anatomical similarities to the hippocampus, a time dependent role of the IC in CTA retention cannot be ruled out. To test whether the IC shows a time dependent role in CTA memory retention, male Wistar rats were CTA trained on saccharin 0.1% (LiCl 0.15M, 2% b/w, 40 min after drinking) and lesioned with ibotenic acid (200-300 nL, 5mg/mL) unilaterally into the IC 1 week or bilaterally 1 or 6 weeks after CTA. CTA memory was completely disrupted in both bilateral lesion groups but unaffected in the unilateral lesioned group. The resulting preference was comparable to that of the bilaterally IC lesioned animals exposed to the taste for the first time, proving that in these animals a complete amnesic state was achieved. Bilaterally IC lesioned rats showed normal discrimination between preferred (sucrose 5%) and non-preferred (quinone) tastes. Our data indicates that the involvement of the IC in CTA is not time dependent and that CTA memories are stored in each hemisphere separately.     

Blockade of nucleus basalis magnocellularis or activation of insular cortex histamine receptors disrupts formation but not retrieval of aversive taste memory

Recent research, using several experimental models, demonstrated that the histaminergic system is clearly involved in memory formation. This evidence suggested that during different associative learning tasks, histamine receptor subtypes have opposite functions, related to the regulation of cortical cholinergic activity. Given that cortical cholinergic activity and nucleus basalis magnocellularis (NBM) integrity are needed during taste memory formation, the aim of this study was to determine the role of histamine receptors during conditioned taste aversion (CTA). We evaluated the effects of bilateral infusions of 0.5 μl of pyrilamine (100 mM), an H₁ receptor antagonist, into the NBM, or of R-α-methylhistamine (RAMH) (10 mM), an H₃ receptor agonist, into the insular cortex of male Sprague-Dawley rats 20 min before acquisition and/or retrieval of conditioned taste aversion. The results showed that blockade of H₁ receptors in NBM or activation of H₃ receptors in the insular cortex impairs formation but not retrieval of aversive taste memory. These results demonstrated differential roles for histamine receptors in two important areas for taste memory formation and suggest that these effects could be related with the cortical cholinergic activity modulation during CTA acquisition.     

Conditioned taste and taste-potentiated odor aversions in the Syracuse high- and low-avoidance (SHA/Bru and SLA/Bru) strains of rats (Rattus norvegicus).

Syracuse high- and low-avoidance Long-Evans rats (Rattus norvegicus; SHA/Bru and SLA/Bru) were selectively bred for good and poor active-avoidance learning. However, SLA/Bru animals are superior to SHA/Bru rats in conditioned suppression and passive avoidance learning. In this experiment, saccharin taste and almond odor were the components of a compound conditioned stimulus (flavor) in an illness-induced aversive conditioning paradigm. SLA/Bru rats (n = 17) showed stronger conditioned flavor, taste, and odor aversion than did SHA/Bru animals (n = 18). Unselected Long-Evans rats (n = 18) were intermediate between the selected strains. SLA/Bru and Long-Evans rats showed taste-potentiated odor aversions in this experiment, whereas SHA/Bru animals did not. The results provide evidence that genetic factors, as exemplified by the different strains, are importantly involved in the mechanisms underlying interoceptive and exteroceptive aversive conditioning.     

Inferior olive lesions impair concurrent taste aversion learning in rats.

Taste aversion learning can be established according to two different procedures, concurrent and sequential. For the concurrent task, two different taste stimuli are offered at the same time, one associated with simultaneous intragastric administration of an aversive stimulus and the other associated with physiological saline. This discrimination is learned by sham-lesioned control animals and by animals with lesions in the cerebellar cortex but not by rats lesioned in the inferior olive. At the same time, animals with lesions in the inferior olive and sham-lesioned animals achieve sequential learning when the gustatory stimuli are offered individually during each daily session. The results obtained show that electrolytic lesions in the inferior olive impair acquisition of concurrent learning and are analyzed in terms of an anatomical system consisting of the vagus nerve, inferior olive, and cerebellum, which differentiates between the two modalities of taste aversion learning, concurrent and sequential.     

Ontogenetic changes in the modulation of taste aversion learning by home environmental cues in rats

Eight experiments using 611 rats as subjects were conducted to define and analyze an age-related phenomenon of conditioned taste aversion. When consumption of sucrose solution was followed by LiCl-induced illness in the animals' home, acquisition of the aversion to sucrose solution was retarded in preweanling (18-day-old) rats. This effect was not found in adults or in slightly older (21-day-old) rats. Place of testing had no effect in the younger two age-groups, but in adults manifestation of the acquired aversion was retarded when they were tested in the home. There was no interaction between place of conditioning and testing for any age. The locus of the environmental influence on conditioning in preweanling rats was found to be the place of tasting rather than place of illness, retention interval, or testing. Also, the effect was found to be invariant under minor variations in familiarization of the animal with the non-home environment. The principle emerging from these data and others is that the home environment can have a significant influence on learning and conditioning in the immature rat.     

Does taste or odor activate the same brain networks after retrieval of taste potentiated odor aversion?

When simultaneous presentation of odor and taste cues precedes illness, rats acquire robust aversion to both conditioned stimuli. Such a phenomenon referred to as taste-potentiated odor aversion (TPOA) requires information processing from two sensory modalities. Whether similar or different brain networks are activated when TPOA memory is retrieved by either the odor or the taste presentation remains an unsolved question. By means of Fos mapping, we investigated the neuronal substrate underlying TPOA retrieval elicited by either the odor or the taste conditioned stimulus. Whatever the sensory modality used to reactivate TPOA memory, a significant change in Fos expression was observed in the hippocampus, the basolateral nucleus of amygdala and the medial and the orbito-frontal cortices. Moreover, only the odor presentation elicited a significantly higher Fos immunoreactivity in the piriform cortex, the entorhinal cortex and the insular cortex. Lastly, according to the stimulus tested to induce TPOA retrieval, the BLA was differentially activated and a higher Fos expression was induced by the odor than by the taste in this nucleus. The present study indicates that even if they share some brain regions, the cerebral patterns induced by either the odor or the taste are different. Data are discussed in view of the relevance of each conditioned stimulus to reactivate TPOA memory and of the involvement of the different labeled brain areas in information processing and TPOA retrieval.     

Differential effects of beta-adrenergic receptor blockade in basolateral amygdala or insular cortex on incidental and associative taste learning

The importance of central β-adrenergic system has been essentially investigated in aversive/emotional learning tasks. However, recent data suggest that the β-adrenergic system is also required for incidental taste learning. In the present study we evaluated in rats whether β-adrenergic receptor activity is required for taste habituation, an incidental taste learning, and also for conditioned taste aversion (CTA) learning, an associative learning. To address this issue, a low dose of the β-adrenergic antagonist propranolol was infused before learning in either the basolateral amygdala (BLA) or the insular cortex (IC), two forebrain areas reported to play a key role in taste memory formation. Incidental taste learning was assessed using a single presentation of the sweet taste saccharin 0.1%, which is sufficient to increase saccharin consumption (relative to water baseline) during a second presentation. CTA was assessed by pairing the first saccharin 0.1% presentation with a delayed gastric malaise, thus causing a decrease in saccharin consumption (relative to water baseline) during a second presentation. Propranolol infusion in BLA (1 μg/0.2μl) or IC (2.5 μg/0.5 μl) before the first taste exposure impaired incidental taste learning but did not affect CTA. These results highlight the important role played by the β-adrenergic receptor activation in cortical and amygdaloid structures during taste learning. Moreover, they are the first to suggest that incidental learning is more sensitive to blockade of noradrenergic system than associative learning.     

Disruption of conditioned taste aversion: evidence that ECS weakens the gustatory engram

Two experiments are reported concerning the neural substrate of conditioned taste aversion (CTA) and the amnesic mechanisms involved when such learning is disrupted by electroconvulsive shock (ECS). Subjects were adult male rats. In the first experiment it is demonstrated that an aversion established to a 2.5% sucrose solution can simulate the learning loss reported in earlier studies which was caused by interpolating ECS between tasting and illness when the aversion was established using a 10% sucrose cue. It is concluded that if ECS acts to disrupt the memory of the taste cue, it possibly reduces it to only about one-quarter of its original strength, a substantial deficit not readily apparent simply from the degree of aversion displayed. In the second experiment, CTAs were established using either a 2.5% sucrose cue or a 10% cue with ECS interpolated during the taste-illness interval. Animals in the two groups were subsequently confronted with a range of sucrose stimuli and their respective aversions were compared. Near identical responses were observed under all conditions tested. These findings are consistent with the theory that ECS disrupts CTA by weakening the gustatory engram.     

Inactivation of the basolateral amygdala impairs the retrieval of recent and remote taste-potentiated odor aversion memory

Memory reorganization as a time-dependent process can be investigated using various learning tasks such as the taste-potentiated odor aversion (TPOA). In this paradigm rats acquire a strong aversion to an olfactory cue presented simultaneously with a gustatory cue. Together these cues are paired with a delayed visceral illness. The basolateral amygdaloid nucleus (BLA) plays a key role in TPOA acquisition but its involvement in retrieval remains unclear. We investigated the involvement of the BLA in either recent or remote retrieval of TPOA. In each case, the number of licks observed in response to the presentation of either the odor or the taste was used to assess retrieval. Before the retrieval test, rats received a bilateral infusion of lidocaine to inactivate the BLA. We observed that both recent and remote TPOA retrieval tests induced by the odor presentation were disrupted in the lidocaine-injected rats. By contrast, the BLA inactivation had no effect upon the aversion towards the taste cue regardless of the time of retrieval. The present study provides evidence that BLA functioning is necessary for retrieval of aversive odor memory, even with a long post-acquisition delay.     

Taste-mediated potentiation of noningestional stimuli in rats

Holtzman rats drank saccharin in a distinctive environmental chamber prior to lithium-induced toxicosis. This treatment was administered four times. These animals subsequently drank less water or familiar saline in the chamber than animals which received water in the environment during conditioning. In addition, these environmental stimuli blocked the formation of a lithium-mediated coffee aversion more if they were conditioned in the presence of saccharin than if they were conditioned in the presence of water. Such differential blocking provided further evidence that the presence of a taste during conditioning facilitated aversion learning to the environmental chamber.     

Impairments in the perception of odor-induced tastes and their relationship to impairments in taste perception

Certain odors have tastelike qualities when sniffed. To the extent that these qualities are akin to real taste experiences, impairment in perception of odor-induced tastes should be accompanied by taste impairment, and vice versa. Twelve patients were selected with possible odor-induced taste impairments or general taste impairments via a screening test, along with a further 6 patients with a probable taste impairment (insular lesion). These 18 patients, along with 19 normal controls, completed a battery of odor, taste, visual control, and neuropsychological tests to assess impairments in odor-induced taste perception and general taste perception. Four patients had an odor-induced taste impairment and were also impaired on taste perception. A further analysis, using regression on the whole sample, indicated that taste impairments were associated with odor-induced taste abnormalities independent of other predictors. This pattern also held for the patient group alone. The insular patients also exhibited both taste and odor-induced taste impairments. This study is the first to demonstrate a relationship between impaired taste perception and the perception of odor-induced tastes and suggests that both may rely on certain common neural substrates.