Partial recovery of gustatory function after neurol tissue transplantation to the lesioned gustatory neocortex

The ability of homotypic cortical tissue grafts to induce recovery of function after a gustatory neocortex (GN) lesion was studied using the conditioned taste aversion (CTA) paradigm. On acquisition day, 26 GN-lesioned and 8 sham-lesioned rats were presented with a saccharin solution, followed by an injection of the illness-inducing agent lithium chloride (LiCl). On the test day, 2 days later, saccharin was presented again. The GN-lesioned rats showed significantly less aversion to saccharin on the test day, indicating that the lesion impaired their ability to form taste-illness association. Nine of the lesioned rats were then bilaterally transplanted with fetal GN tissue. Nine weeks after the transplantation, the rats were presented with a LiCl solution, which served as both a tastant and an illness-inducing agent. An NaCl solution, which tasted very similar to the LiCl solution, was used to test the CTA to salt 3 days later. The nontransplanted rats consumed significantly more LiCl than the transplanted and sham-operated rats on the acquisition day, but both transplanted and nontransplanted rats consumed more NaCl than sham-operated rats on the test day. Nissl and Golgi stainings showed numerous somata and extensive arborization of neurons within the grafts. The results indicate that fetal GN grafts can restore the ability to integrate gustatory and visceral inputs but not to form long-lasting taste-illness associations.     

Correlation between acetylcholine release and recovery of conditioned taste aversion induced by fetal neocortex grafts

Rats with lesions of the gustatory neocortex (GN) show deficits in the acquisition of taste aversion. Fetal GN grafts to a lesioned animal restore taste aversion learning and establish connections with the host brain. In this work, we examined whether the grafts are biochemically functional and whether this fact can be related to behavioral recovery. Gustatory or occipital cortices from rat fetuses were transplanted to GN-lesioned rats. Two months later, taste aversion recovery was tested and the release of labeled gamma-aminobutyric acid (GABA), acetylcholine (ACh), dopamine and glutamate from the grafted tissue was assayed. Fetal GN grafts promoted recovery of learning and released GABA, ACh and glutamate in response to K+ depolarization. Occipital cortex grafts did not induce behavioral recovery, although they were capable of releasing GABA. In contrast, these grafts did not release ACh. Moreover, GN-grafted rats in which behavioral recovery was not seen also failed to release ACh. These results are in agreement with previous findings that cholinergic transmission is important in the GN and suggest that ACh may play a role in the graft-mediated behavioral recovery observed in this model.     

Differential involvement of gustatory insular cortex and amygdala in the acquisition and retrieval of conditioned taste aversion in rats.

Lesion studies of the role of the gustatory insular cortex (GC) and amygdala (Am) in conditioned taste aversion (CTA) are confounded by the irreversibility of the intervention. Functional ablation methods allow more specific influencing of different phases of CTA acquisition and retrieval. Bilateral tetrodotoxin (TTX) blockade of GC (10 ng) or Am (3 ng) before or after saccharin drinking in rats with chronically implanted intracerebral cannulae showed that GC is indispensable for the initial processing of the taste stimulus but not for the association of the gustatory trace with the symptoms of LiCl poisoning. Gustatory signals can by-pass the blocked Am, the inactivation of which, however, impairs the gustatory trace-poisoning association. TTX injection into both GC and Am impairs CTA retrieval more than isolated blockade of either of these structures. It is argued that GC and Am implement processing of gustatory and visceral signals, respectively, but that formation and consolidation of the CTA engram proceeds outside forebrain, probably at the level of the brainstem.     

A test of conditioned taste aversion with mouse interferon-alpha

Interferon-alpha treatment induces anorexia in cancer patients and in mice. The ability of interferon-alpha to induce a conditioned taste aversion (CTA) in mice was explored. Mice were injected with doses of interferon-alpha that had been shown to induce anorexia (M. A. Segall & L. S. Crnic, Behav. Neurosci., 1990; 1600 or 800 U/g of mouse) after being given a novel solution (chocolate milk). Neither dose of interferon resulted in a decrease of milk intake on the test day. To determine whether the known cognitive effects of interferon interfere with the ability of a mouse to learn CTA, a combined injection of interferon-alpha and LiCl (an illness-inducing agent) was given. The combination of interferon-alpha with LiCl did not interfere with the LiCl-induced CTA. Thus, any possible cognitive effects of interferon did not interfere with conditioned taste aversion. To test the possibility that repeated trials might establish a conditioned taste aversion to interferon, mice were given three conditioning trials spaced 3 days apart. No aversion developed. Doses of interferon-alpha that produce anorexia do not produce a conditioned taste aversion, indicating that separate mechanisms are activated in these two behaviors.     

Effect of bilateral cortical spreading depression on the hippocampal theta activity induced by oral infusion of aversive gustatory stimulus

Oral cannula and bipolar hippocampal electrodes were implanted in 36 adult rats. After recovery from surgery a strong conditioned saccharin aversion was established by associating 15-min access to 0.1% saccharin on days 3, 6, and 9 with LiCl injection (0.14 M, 2% body wt). On day 10 hippocampal EEG was recorded during repeated 30-sec periods of oral perfusion with saccharin or water. Power spectral analysis revealed increase of theta activity during saccharin infusion in trained animals, but not in naive controls. However saccharin failed to increase theta activity in trained rats under bilateral cortical spreading depression. Since functional decortication prevented aversive reactions of trained rats to oral infusion of saccharin (spitting, head-shaking), theta activation is probably a correlate of this behavior. It is concluded that conditioned gustatory stimuli cannot trigger aversive behavior and its hippocampal electrophysiological correlate in decorticate rats.     

Forebrain contribution to the induction of a brainstem correlate of conditioned taste aversion: II. Insular (gustatory) cortex

The induction of c-Fos-like immunoreactivity (c-FLI) in the intermediate division of the nucleus of the solitary tract (iNTS) has been shown to be a cellular correlate of the behavioral expression of a conditioned taste aversion (CTA). To further define neuroanatomical structures and pathways that contribute to this cellular response and to CTA learning in general, electrolytic lesions of insular (gustatory) cortex (IC) were combined with immunostaining for c-FLI. Rats were given either unilateral or bilateral electrolytic lesions of insular cortex or `sham' operations. Following surgery, `paired' animals were given a single conditioning trial consisting of intraoral infusion of 5-ml 0.15% sodium–saccharin followed by injection with LiCl (0.15 M, 20 ml/kg, i.p.) while `unpaired' controls received a non-contingent saccharin–LiCl presentation. Rats with bilateral lesions showed no behavioral evidence of having acquired a CTA. Increases in c-FLI in iNTS were evident, but reduced, relative to `sham' animals. Rats with unilateral-lesions displayed a CTA by rejecting the saccharin, although increases in c-FLI on the side of the iNTS ipsilateral to the lesion were reduced relative to that seen in `sham' animals. A comparison of these results with those obtained after amygdala lesions supports the conclusion that amygdala and insular cortex are necessary, but not sufficient, for the behavioral expression of a CTA.     

Nerve growth factor facilitates conditioned taste aversion learning in normal rats

Chronic intracerebroventricular (i.c.v.) infusion of 3.2 μg/day of nerve growth factor (NGF) in normal rats elevated choline acetyltransferase (ChAT) activity of the striatum, medial septum, and basal forebrain and improved performance of a conditioned taste aversion (CTA) task. Relative to bovine serum albumin (BSA) or Cytochrome C treatments, NGF treatment facilitated acquisition and prolonged extinction of a lithium chloride (LiCl)-induced saccharin aversion. This facilitation was evident at saccharin/LiCl intervals ranging up to 1 h. Also, NGF treatment did not increase reactivity to LiCl-induced illness and neither shifted detection thresholds nor altered hedonic reactions to taste stimuli, indicating that NGF did not produce simple changes in sensory function. NGF treatments that elevate ChAT also facilitate memory of CTA in normal, adult rats.     

MPEP,a selective metabotropic glutamate receptor 5 antagonist,attenuates conditioned taste aversion in rats

Metabotropic glutamate receptors (mGluRs) have been implicated in several types of cognitive and associative learning. Although recent evidence indicates an influence of mGluRs in conditioned taste aversion (CTA), the subtype-specific involvement of mGluRs in this learning paradigm remained to be determined. The aim of this study was to examine the role of Group I mGluR subtypes in CTA using a selective mGluR5 antagonist (2-methyl-6-(phenylethynyl)-pyridine, MPEP) and a selective mGluR1 antagonist (1-aminoindan-1,5-dicarboxylic acid, AIDA). Male, water-deprived, Sprague-Dawley rats were injected i.p. with 6 or 12 mg/kg MPEP or saline. Twenty-five minutes later, all rats received 15-min access to a 0.1% saccharin solution (Sac) immediately followed by an injection of 0.15M LiCl at 1.33% body weight. The animals were tested with 15-min access to Sac on each of four test days. MPEP-treated animals consumed more Sac on the test trials than saline-treated rats. In another experiment, controlled access to Sac was used by infusing the solution on the conditioning trial. Consistent with the above results, MPEP attenuated the degree of CTA. Similar experiments using the mGluR1 antagonist AIDA, have found no effect on CTA learning. These results suggest that the two subtypes of Group I mGluRs are differentially involved in taste aversion learning.     

Comparing immune activation (lipopolysaccharide) and toxin (lithium chloride)-induced gustatory conditioning: lipopolysaccharide produces conditioned taste avoidance but not aversion

Feeding and drinking typically involve both appetitive and consummatory behaviors. Appetitive behaviors include those behaviors produced by an animal prior to the actual consumption, such as approach movements, whereas consummatory behaviors (such as licking and chewing) are involved in the actual consumption of food. The present research compared the gustatory conditioning effects of bacterial lipopolysaccharide (LPS) and lithium chloride (LiCl) in two different paradigms, conditioned taste avoidance and conditioned taste aversion which differentially affect the appetitive and consummatory components of feeding. Male rats were implanted with intraoral cannulae and habituated to a water deprivation schedule and afterwards received two conditioning days (Days 1 and 4). Each conditioning day consisted of 1 h access to a novel sucrose solution (0.3 M) immediately followed by a systemic injection of LPS (200 microg/kg), LiCl (0.15 M, 3 meq) or NaCl vehicle. Conditioned taste aversion was assessed using the taste reactivity test on Day 7, where orofacial and somatic responses were videotaped and analyzed during 3 brief (1 min) exposures to the sucrose solution. Conditioned taste avoidance was assessed on Days 8 and 9 using a two-bottle preference test (sucrose versus water). Animals conditioned with LiCl displayed typical aversive-like responses in the taste reactivity paradigm evidenced by significant reductions in positive ingestive responses (P<0.05) and an increase in active aversive responses (P<0.05) relative to controls. Furthermore, LiCl treatment resulted in conditioned avoidance of sucrose in the two-bottle preference test characterized by a decreased sucrose preference (P<0.05). Conditioning with LPS produced a reduced sucrose preference (P<0.05) relative to controls, comparable to the avoidance seen in LiCl-treated rats. In contrast, conditioning with LPS resulted in similar positive ingestive responses to intraorally infused sucrose as seen in controls. The present results demonstrate that LPS treatment produces conditioned avoidance but not aversion and suggest that LPS can selectively condition the appetitive aspects of feeding whereas the consummatory behaviors remain unaffected.     

Bilateral lesions of the gustatory thalamus disrupt morphine- but not LiCl-induced intake suppression in rats: evidence against the conditioned taste aversion hypothesis

Rats decrease intake of a saccharin conditioned stimulus (CS) when followed by: (1) the administration of an aversive agent such as lithium chloride (referred to as a conditioned taste aversion, CTA); (2) access to a very palatable concentration of sucrose (referred to as an anticipatory contrast effect, ACE); or (3) the administration of a drug of abuse. It is not clear, however, whether the suppressive effects of drugs of abuse are mediated by their aversive or rewarding properties. The present set of experiments addressed this issue by examining the suppressive effects of morphine in rats with a lesion thought to dissociate the two phenomena (i.e., CTA and ACE). The results show that bilateral ibotenic acid lesions of the gustatory thalamus eliminate the suppressive effects of morphine, but fail to disrupt the suppressive effects of the aversive agent, lithium chloride. This pattern of results argues against the CTA account in favor of the reward comparison hypothesis. Specifically, the data suggest that rats suppress intake of a saccharin CS in anticipation of the availability of a preferred drug of abuse and that the gustatory thalamus is essential for this type of reward comparison process.     

Lipopolysaccharide inhibits the simultaneous establishment of LiCl-induced anticipatory nausea and intravascularly conditioned taste avoidance in the rat

This study examined the effects of the bacterial endotoxin, lipopolysaccharide (LPS), on the establishment of anticipatory nausea and conditioned taste avoidance in a simultaneous conditioning paradigm using an intravascular/intraperitoneal saccharin taste. 83 na?ve adult male Long-Evans rats were injected (intraperitoneal) with either 200 μg/kg LPS or 0.9% saline (NaCl), 90 min prior to ip treatment with either 64 mg/kg LiCl, 64 mg/kg LiCl+2.0% saccharin, 0.9% NaCl, or 0.9% NaCl+2.0% saccharin, and immediately placed into a distinctive context for 30 min (repeated over 4 conditioning days, spaced 72 h apart). 72 h following the final conditioning day, each animal was re-exposed to the context on a drug-free test day where orofacial responding was recorded. The next day, animals received a 24 h 2-bottle preference test with a choice between water and a palatable 0.2% saccharin solution. Results showed that LPS exposure, prior to LiCl or LiCl+Saccharin treatment, inhibited the establishment of anticipatory nausea, as evidenced by significantly lower conditioned gaping frequencies relative to animals pre-treated with NaCl followed by LiCl or LiCl+Saccharin. LPS pre-treatment also inhibited the formation of LiCl-induced taste avoidance, as evidence by significantly higher saccharin preferences in Group LPS-LiCl+Saccharin relative to Group NaCl-LiCl+Saccharin. The results of the current study provide additional evidence for the deleterious effects of LPS on learning and memory in aversive conditioning.     

Effects of excitotoxic lesions of the gustatory thalamus on latent inhibition and blocking of conditioned taste aversion in rats

The influence of bilateral excitotoxic lesions of the gustatory thalamus on latent inhibition and blocking of conditioned taste aversion (CTA) was examined in two experiments. In Experiment 1, rats with thalamic lesions showed normal latent inhibition by acquiring a CTA that was significantly weaker when the conditioned stimulus (CS) was familiar than when it was novel. In Experiment 2, the preconditioned element (sodium chloride) of a compound CS blocked the acquisition of a CTA to the novel element (sucrose) in normal rats. Irrespective of whether sodium chloride was preconditioned or not, rats with thalamic lesions showed little or no aversion to sucrose following compound conditioning. Overall, the results provide no support for the experimental hypothesis that thalamic lesions disrupt decremental changes in the attentional processing of gustatory stimuli.     

Subhypnotic doses of propofol accelerate extinction of conditioned taste aversion

Subhypnotic doses of propofol accelerate extinction of conditioned taste aversion. Some intravenous anesthetic agents including propofol is known to induce anterograde and retrograde amnesia. We evaluated whether propofol affect the long-term memory formed by the conditioned taste aversion (CTA) paradigm. Rats were allowed a 4h access to water through the experiments. After preconditioning water intake, the rats were offered 0.1% sodium saccharin (Sac) as conditioned stimulus (CS) for 20 min. An intraperitoneal (i.p.) injection of several concentrations (0.5-100 mg/kg) of propofol 10 min after Sac exposure was followed by an i.p. injection of 0.15M LiCl (2% of body weight) as unconditioned stimulus (US) 30 min after CS-exposure. The volumes of intake of Sac for 20 min were measured on the successive 4 days. The rats, which acquired CTA by every CS-US paradigm, strongly avoided Sac on the first test day after conditioning and maintained the avoidance for 3 days. However, when subhypnotic dose of propofol was injected before LiCl-injection, Sac intake abruptly increased on the second test day and the almost complete extinction occurred on the third test day after conditioning. The extinction process of CTA was barely affected by hypnotic dose of propofol. These results suggest that propofol affects the retention mechanism of the CTA memory in a dose-dependent manner. Subhypnotic dose of propofol may affect the sub-cellular process of the memory consolidation in CTA.     

Effects of conditioned taste aversion on extracellular serotonin in the lateral hypothalamus and hippocampus of freely moving rats

This study used microdialysis to monitor extracellular levels of 5-HT and its metabolite, 5-hydroxyindole acetic acid (5-HIAA) in the lateral hypothalamus (LH) and hippocampus of freely moving rats that had developed a CTA to a 2.5 mM saccharin solution (CS) following its pairing with illness induced by lithium chloride (US). Results showed that oral infusion of the saccharin CS significantly enhanced extracellular LH 5-HT in animals that had developed a taste aversion compared with control groups, including unconditioned (CS-no US) and pseudoconditioned (no CS-US) subjects. As an anatomical control, the hippocampus was identified based on previous research suggesting that it is not integrally involved in CTA learning or retrieval and that 5-HT in this brain site does not directly mediate feeding behavior but is closely correlated with arousal. In contrast with the results obtained in the LH, hippocampal 5-HT was not preferentially elevated in subjects in the CTA group but rather was increased to the same extend in both CTA and control groups after saccharin infusion. Moreover, the increase in LH 5-HT for the CTA group was nearly twice that observed in the hippocampus for any group. Acute administration of LiCl elevated extracellular 5-HT to similar levels in both sites, well above the changes observed following conditioning. 5-HIAA was unaffected in either brain site by oral infusion of saccharin solution or injection of LiCl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lipopolysaccharide dose dependently impairs rapid toxin (LiCl)-induced gustatory conditioning: a taste reactivity examination of the conditioned taste aversion

There is much debate on how immune activation affects cognitive processing. Research has shown that stimulation of the immune system can significantly impair, have no adverse effects, or enhance learning and memory processes in animals. The present experiment evaluated the effects of the bacterial endotoxin, lipopolysaccharide (LPS) on the acquisition of a rapidly acquired conditioned taste aversion using a toxin-containing food. Male Long Evans rats were fitted with intraoral cannulae and habituated to the taste reactivity procedure. Rats received two conditioning days, 72 h apart, in which they were injected systemically with LPS (200, 100, or 50 microg/kg) or NaCl (0.9% vehicle) and 90 min later placed in the taste reactivity test chamber. Rats were given 5 brief (1 min) intraoral infusions of either a LiCl-adulterated sucrose solution (0.15M LiCl+0.3M sucrose) or NaCl-sucrose solution (0.15M NaCl+0.3M sucrose) across a 1h period. On the test day (72 h after the last conditioning trial), rats were given a 2 min intraoral infusion of the respective taste in a drug-free state. Individual taste reactivity responses were recorded and analyzed. Results demonstrate that rats treated with LPS dose-dependently increased ingestive responding to the LiCl-sucrose flavor while at the same time showing reduced rejection response frequency on the two conditioning days. LPS treatment did not alter taste reactivity responding to the NaCl-sucrose solution. On the test day, the LPS groups again displayed a dose dependent increase in ingestive responses and a decrease in rejection responses to the LiCl-sucrose taste. The present results suggest that LPS-induced immune system activation, significantly impairs the rapid acquisition of a conditioned taste aversion.     

The effects of trimethyltin chloride on the acquisition of long delay conditioned taste aversion learning in the rat

Naive rats injected with LiCl at various times following consumption of a novel saccharin solution subsequently avoided the ingestion of saccharin with the degree of the aversion related to the interval between ingestion and LiCl administration. Although a similar relationship was also evident in animals which had received a single intragastric administration of trimethyltin chloride 21 days prior to the pairing of saccharin and LiCl, the trimethyltin-pretreated subjects receiving delayed injections of LiCl displayed weaker taste aversions than those not exposed to trimethyltin. This disruption in the acquisition of taste aversions over long delays is consistent with other work suggesting that trimethyltin disrupts tasks involving short-term memory. The utility of the conditioned taste aversion paradigm in detecting and characterizing drug toxicity was discussed.     

Different disruptive effects on the acquisition and expression of conditioned taste aversion by blockades of amygdalar ionotropic and metabotropic glutamatergic receptor subtypes in rats

Conditioned taste aversion (CTA) is based on the gustatory long-term memory established after association of the taste of food (conditioned stimulus, CS) with visceral signals of poisoning (unconditioned stimulus, US). After the acquisition of CTA, hedonics of the taste CS changes from positive to negative as indicated by reduced ingestive and increased aversive taste reactivities in response to re-exposures to the CS. We examined the effects of reversible and selective blockades of the amygdalar glutamate receptor subtypes, AMPA, NMDA and metabotropic glutamate receptors, on the formation of CTA. Blockades of each of the three receptor subtypes between ingestion of saccharin (CS) and malaise-inducing LiCl (US) disrupted the acquisition of CTA. After the acquisition of CTA, however, blockades of only AMPA receptors, but not NMDA or metabotropic receptors, impaired the expression of CTA. This effect was seen only during the period when the antagonistic action to AMPA receptors lasted. These results indicate that both ionotropic and metabotropic glutamate receptor subtypes in the amygdala are indispensable for the acquisition of CTA, but that the expression of acquired CTA is mediated only by AMPA receptors. The present results also suggest that the amygdalar glutamatergic neural transmission is involved in the formation and storage of long-term gustatory memory associated with the altered hedonics from positive to negative.     

Significance of cortical-amygdalar-hypothalamic connections in retention of conditioned taste aversion in rats

Rats were trained to avoid drinking 0.1 m NaCl solution by one to four pairings of this solution with an i.p. injection of 0.15 m LiCl during restricted periods of fluid access. The number of lickings of NaCl and nonpaired other solutions was measured during the preconditioning control period, after conditioning, and after lesions of various brain regions. The acquired learned aversion was abolished after bilateral lesions of the gustatory cortex, perirhinal cortex posterior to the gustatory cortex, or stria terminalis. Ablations of the frontal cortex had no effect. These results suggest that cortical-amygdalar-hypothalamic connections play a significant role in the retention of a conditioned taste aversion.     

Gustatory preference-aversion thresholds are increased by ibotenic acid lesion of the lateral hypothalamus in the rat

The main purpose of this study was to quantitate possible changes in the rewarding and aversive values of certain gustatory stimuli produced by bilateral ibotenic acid lesions of the lateral hypothalamus in the rat. Non-operated rats served as controls. Thirteen days after the operation, rats were placed on a water-deprivation schedule during 5 consecutive days. Rats were then given the choice of one of 5 concentrations of saccharin solution, using a two-bottle procedure. Fluid intake across concentrations generated a preference-aversion curve. The same type of procedure was used to obtain the aversion curve for increasing concentrations of quinine solution. The lesioned rats as well as the control animals showed a clear preference-aversion response to saccharin solutions and an aversive response to quinine solutions. However, the highest preference score of the lesioned rats was obtained with a saccharin concentration 3 times higher than the concentration preferred by the control rats. Moreover, unlike control rats operated animals did not show aversion to the highest concentrations of saccharin solutions. Finally in the lesioned rats the aversion threshold to quinine solutions was obtained with concentration 5 times higher than the concentration inducing aversion in the control rats. At the end of these experiments, rats used as controls were submitted, in turn, to bilateral lesion of the lateral hypothalamus. The change in the preference-aversion threshold of these rats in the saccharin choice procedure was the same as that observed with naive rats. Taken together, these results suggest that in the normal rat the palatability of certain gustatory stimuli is modulated by the intrinsic neurons of the lateral hypothalamus.     

Acute effects of corticosterone on LiCl-induced rapid gustatory conditioning in rats: a taste reactivity analysis

Previous research has shown that acute corticosterone treatment can have rapid effects on learning and memory. Using the taste reactivity test (TRT), the present study examined the effect of acute administration of corticosterone on sucrose palatability and the development of LiCl-induced rapid gustatory conditioning. On each of two conditioning days rats were injected with either a low dose of lithium chloride (LiCl; 0.75 mEq, i.p.) or saline (NaCl; 0.9%, i.p.) and 10 min later, received a second injection of either corticosterone (5 mg/kg, i.p.) or cyclodextrin vehicle. Rats were then placed in the TRT chamber, where 1 min intraoral infusions of sucrose (0.3 M) were delivered every 10 min. Taste reactivity responses were videotaped and later analyzed for frequency of occurrence. Rats treated with both LiCl and corticosterone showed enhanced aversive responding and reduced ingestive responding relative to control rats treated with LiCl and vehicle. The implication that corticosterone may have a rapid enhancing effect on gustatory conditioning is discussed.