Cristina Mediavilla

Concurrent conditioned taste aversion: a learning mechanism based on rapid neural versus flexible humoral processing of visceral noxious substances.

Taste aversion learning (TAL) consists of the avoidance of a taste previously associated with a noxious visceral stimulus. Clinical and experimental studies suggest that this adaptive process can be established by different procedures that imply distinct forms of learning and memory, although the final result is analogous, i.e. avoidance of the gustatory stimulus associated with gastrointestinal discomfort. In fact, a double neurobiological system has been anatomically dissociated and, functionally, may be implicated in nausea and emesis, in food selection, and in neuroimmune interactions. Actually, a dual, parallel, and non-redundant gut-brain system has been proposed that sustain two different TAL modalities, concurrent and sequential. Concurrent TAL requires several trials and is inflexible, requiring simultaneity of the stimuli and the participation of the vagus nerve. In contrast, sequential TAL can be acquired in one trial and is flexible, permits long inter-stimulus delays, and is independent of vagal pathways. These two TAL modalities are analyzed in the light of the recent proposal that different acquisition processes are sustained by distinct cerebral systems.

Bilateral lesions in the cerebellar interpositus-dentate region impair taste aversion learning in rats

Taste Aversion Learning (TAL) has been induced through two different behavioral procedures: a short-term o concurrent (two-daily flavors) and a long-term (one-daily flavor) procedure. For the first, two gustatory/olfactory stimuli are presented separately but at the same time on a daily basis. One of the flavors is paired with simultaneous intragastric administration of hypertonic NaCl and the other is paired with physiological saline. In the long-term procedure, the two stimuli are presented on alternate days, one of them followed by intragastric injection of the aversive stimulus, and the other by saline. The subjects for both types of tests were animals that had been lesioned in the interpositus-dentate region of the cerebellum. The experiments show that the lesions disrupt short-term TAL, but have no effect on long-term TAL. The results are discussed in terms of the role of the cerebellum in relation to TAL and the different anatomical substrates of both learning modalities.

The role of the lateral parabrachial nuclei in concurrent and sequential taste aversion learning in rats.

Abstract. The purpose of this study was to examine the role of the external lateral parabrachial subnucleus (PBNLe) in two different taste aversion learning (TAL) procedures. For the first, short-term (concurrent) TAL, two different-flavored stimuli were presented at the same time, one associated with simultaneous intragastric administration of an aversive product, hypertonic NaCl, and the other with saline. In the second, long-term (sequential/delayed) TAL, each gustatory stimulus was presented every other day and the intragastric products LiCl and saline were administered after a 15-min delay. Electrolytic lesions in the PBNLe blocked acquisition of concurrent TAL, in which the vagal visceral information is critical. But the same lesions failed to interrupt sequential TAL. This result was independent of the order in which the two tasks (concurrent and sequential) were presented. However, as found by other authors, the latter type of learning was impaired in the presence of larger lesions in this same area. This supports the existence of sensory information needed to establish sequential TAL in other subnuclei of the parabrachial complex. The results of these experiments suggest that the different modalities of TAL are anatomically specific.

SB-334867-A, a selective orexin-1 receptor antagonist, enhances taste aversion learning and blocks taste preference learning in rats

Lateral hypothalamus (LH) has been proposed as a possible center for the anatomical convergence of gustatory and postingestive information relevant to taste aversion learning (TAL) and conditioned flavor preference (CFP). Orexin, a neuropeptide that mainly originates in neurons in lateral hypothalamic areas, was recently related to learning and memory processes. The present study was designed to analyze a possible relationship between the orexinergic system and taste learning. We studied the effect of intracerebroventricular administration of three doses (3, 6, and 12 μg/1 μl) of the selective orexin-1 receptor antagonist SB-334867-A on the acquisition of TAL induced by a single administration of LiCl. Infusion of SB-334867-A did not block this learning and appeared to enhance TAL in a two-bottle test. However, SB-334867-A (6 μg/1 μl) blocked taste preference learning when a flavor associated with saccharin (CS+) was offered on alternate days against a different flavor without saccharin (CS-), during three acquisition sessions. These results offer evidence of a relationship between the orexinergic system and taste learning; they tentatively suggest the possibility that endogenous orexin and gustatory and postingestive (visceral and oral) signals converge in brain areas relevant to the acquisition of taste learning.

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.

Orexin-1 receptor antagonist in central nucleus of the amygdala attenuates the acquisition of flavor-taste preference in rats

Previous studies demonstrated that the intracerebroventricular administration of SB-334867-A, a selective antagonist of orexin OX1R receptors, blocks the acquisition of saccharin-induced conditioned flavor preference (CFP) but not LiCl-induced taste aversion learning (TAL). Orexinergic fibers from the lateral hypothalamus end in the central nucleus of the amygdala (CeA), which expresses orexin OX1R receptors. Taste and sensory inputs also are present in CeA, which may contribute to the development of taste learning. This study analyzed the effect of two doses (1.5 and 6μg/0.5μl) of SB-334867-A administered into the CeA on flavor-taste preference induced by saccharin and on TAL induced by a single administration of LiCl (0.15M, 20ml/kg, i.p.). Outcomes indicate that inactivation of orexinergic receptors in the CeA attenuates flavor-taste preference in a two-bottle test (saccharin vs. water). Intra-amygdalar SB-334867-A does not affect gustatory processing or the preference for the sweet taste of saccharin given that SB-334867-A- and DMSO-treated groups (control animals) increased the intake of the saccharin-associated flavor across training acquisition sessions. Furthermore, SB-334867-A in the CeA does not block TAL acquisition ruling out the possibility that functional inactivation of OX1R receptors interferes with taste processing. Orexin receptors in the CeA appear to intervene in the association of a flavor with orosensory stimuli, e.g., a sweet and pleasant taste, but could be unnecessary when the association is established with visceral stimuli, e.g., lithium chloride. These data suggest that orexinergic projections to the CeA may contribute to the reinforcing signals facilitating the acquisition of taste learning and the change in hedonic evaluation of the taste, which would have important implications for the OX1R-targeted pharmacological treatment of eating disorders.

Taste aversion learning induced c-fos expression in the nucleus of the solitary tract after spontaneous flavor intake: Role of the inter-stimulus interval

Taste aversion learning (TAL) can be induced by associating a flavor intake with the immediate or delayed (30 min) intragastric administration of a noxious substance, e.g., hypertonic NaCl. The objective of this study was to analyze the induction of c-Fos immunoreactivity in the intermediate nucleus of the solitary nucleus (iNST) after acquisition of a contiguous or delayed TAL, offering the flavor for voluntary consumption in both cases. The behavioral results obtained indicate that, although the learning was established under both experimental conditions, an increase in c-Fos induction was only produced in the group that learned by means of a non-delayed TAL. Immunohistochemical analyses revealed the participation of different brain structures in these two TAL modalities. Thus, the nucleus of the solitary tract may be involved in the TAL procedure in which voluntary flavor intake and intragastric administration of the noxious visceral stimulus are contiguous but not in delayed TAL, which would depend on other anatomical circuits that do not include the iNST.

Nucleus of the solitary tract and flavor aversion learning: relevance in concurrent but not sequential behavioral test.

Theories relating the nucleus of the solitary tract to taste aversion learning (TAL) have received their main support from immunohistochemical research. In the present study, a behavioral analysis was performed on the effect of lesions of the intermediate nucleus of the solitary tract (iNST) on concurrent and sequential flavor aversion learning tasks. Bilateral lesions of the iNST impaired concurrent flavor learning, in which animals must discriminate between two simultaneously presented flavors paired with intragastric administration of a noxious or innocuous substance, respectively. However, the same iNST lesions did not interrupt the development of sequential flavor aversion learning, in which each flavor is offered individually on consecutive alternate days. These results behaviorally confirm the relevance of the nucleus of the solitary tract in TAL and suggest a functional dissociation between the neural systems underlying concurrent and sequential flavor aversion learning.

Retention of concurrent taste aversion learning after electrolytic lesioning of the interpositus-dentate region of the cerebellum.

Lesions in the interpositus-dentate region of the cerebellum impair short-term, or concurrent, TAL. In this type of learning, animals must discriminate between two flavor stimuli presented at the same time, one of which is associated with an aversive product. The task is learned by the control animals, and within this group the animals that acquire it adequately enough (15/22, 70% criterion) retain the learned taste discrimination when they are subjected to it again after being lesioned in the interpositus-dentate region. These results suggest that the deep nuclei are essential in the concurrent TAL acquisition process, but not in its retention.

Role of anterior piriform cortex in the acquisition of conditioned flavour preference.

Flavour aversion learning (FAL) and conditioned flavour preference (CFP) facilitate animal survival and play a major role in food selection, but the neurobiological mechanisms involved are not completely understood. Neuroanatomical bases of CFP were examined by using Fos immunohistochemistry to record neuronal activity. Rats were trained over eight alternating one-bottle sessions to acquire a CFP induced by pairing a flavour with saccharin (grape was CS+ in Group 1; cherry in Group 2; in Group 3, grape/cherry in half of animals; Group 4, grape/cherry in water). Animals were offered the grape flavour on the day immediately after the training and their brains were processed for c-Fos. Neurons evidencing Fos-like immunoreactivity were counted in the infralimbic cortex, nucleus accumbens core, and anterior piriform cortex (aPC). Analysis showed a significantly larger number of activated cells after learning in the aPC alone, suggesting that the learning process might have produced a change in this cortical region. Ibotenic lesions in the aPC blocked flavour-taste preference but did not interrupt flavour-toxin FAL by LiCl. These data suggest that aPC cells may be involved in the formation of flavour preferences and that the integrity of this region may be specifically necessary for the acquisition of a CFP.