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Aversive and safe taste memory processing is dramatically disrupted by bilateral lesions of the pontine parabrachial nucleus (PBN). To determine how such lesions affect patterns of neuronal activation in forebrain, lesions were combined with assessment of cFos-like immunoreactivity (FLI) in insular cortex (IC) and amygdala after conditioned taste aversion (CTA) training. Increases in FLI in amygdala and IC, which are normally seen following novel (versus familiar) CS-US pairing, were eliminated after PBN lesions. This suggests that PBN lesions prevent transmission of critical CS and US information to forebrain regions for the processing of both aversive and safe taste memories. Unilateral asymmetrical lesions of PBN and IC blocked CTA acquisition as well as normal patterns of FLI in amygdala after novel CS-US pairing, an effect not seen when unilateral lesions were confined to a single hemisphere. The crossed-disconnection experiments provide compelling evidence that functional interactions between PBN and IC are required for CTA acquisition, but not for safe taste memory formation and retrieval. The dissociation between effects of the different types of lesions on safe and aversive taste memories supports emerging evidence that the neural underpinnings of the two types of taste learning differ.

Sodium depletion is a strong natural motivator that creates a pronounced sodium appetite and has been shown to activate neural regions associated with fluid and sodium balance. However, it is not known whether sodium appetite affects the mesolimbic circuitry associated with reward motivation. The present studies examined expression of the immediate early gene Fos in the nucleus accumbens (NAc) as a marker of neuronal activation following the induction and expression of furosemide-induced sodium appetite. During sodium appetite expression, sham-drinking and normal drinking were used to dissociate effects of NaCl taste stimulation from the repletion that follows absorption of sodium. These studies revealed that the combination of NaCl taste stimulation and persistent sodium depletion experienced by sham-drinking animals dramatically activates the NAc, while neither induction nor expression of sodium appetite alone is sufficient to increase Fos expression in this region. Results are discussed in terms of current theories of reward motivation.

Conditioned taste aversions (CTAs) can be established by exposing rats to a novel taste CS through a bottle or through intra-oral (IO) infusion. Lesion studies suggest differences between the two methods in their engagement of brain circuits, as excitotoxic amygdala lesions have no effect on bottle-conditioned CTAs, but eliminate CTAs produced using IO infusion. Fos-like immunoreactivity (FLI) was used to compare patterns of brain activation after pairing CS taste and US drug using bottle and IO methods. Conditioning rats using the bottle method was associated with widespread elevations in FLI throughout the putative CTA circuit (basolateral and central nuclei of amygdala, insular cortex and nucleus of the solitary tract). In contrast, IO conditioning led to activation only in the central nucleus of amygdala. This supports the suggestion of differences in aversion processing as a function of conditioning method and may explain the greater reliance on amygdala of IO-conditioned CTAs due to engagement of a less distributed neural network.

Conditioned taste aversion (CTA) expression is associated with strong increases in Fos-like immunoreactivity (FLI) in a region of the brainstem identified as the parvicellular subdivision of the intermediate nucleus of the solitary tract (iNTSpc). To identify the projections to and from cells in iNTSpc which display strong FLI in response to expression of a CTA, anterograde and retrograde tract tracing was used. When appropriate, tract tracing was combined with double labeling for FLI in animals which received CTA training as well as tracer injections and were re-exposed to the CS taste. With respect to afferent projections, iNTSpc receives a strong, direct, ipsilateral projection from amygdala and the distribution of the fiber terminals yields a striking match to that of cells expressing FLI after CTA expression. As for efferent projections, these cells in iNTSpc are characterized by a mixed, rather than homogeneous, projection pattern. Targets of these cells include pons and forebrain as well as local medullary sites, all of which are known to be involved in gastrointestinal function. Thus, activation of these cells may provide a circuit through which gastrointestinal/visceral responses are coordinated as a component of the conditioned aversion.

The cAMP-dependent protein kinase (PKA) signaling pathway has been implicated in many forms of learning. The present studies examined conditioned taste aversion (CTA) learning, an amygdala-dependent task, in mice with a targeted disruption of a gene for a specific regulatory subunit of PKA (RIIbeta), which is selectively expressed in amygdala. Null mutant (RIIbeta(-/-)) mice and littermate controls (RIIbeta(+/+)) were tested for protein synthesis-independent short-term memory (STM) and protein synthesis-dependent long-term memory (LTM) for CTAs. The ability of the unconditioned stimulus (US) drug, LiCl, to induce c-Fos in regions thought to be important in this learning was also determined. RIIbeta(-/-) mice showed significant impairment in CTA memory when tested 24h after training (LTM). In contrast, STM was normal. With regard to the c-Fos response to LiCl, the US drug, significant elevations were evident in brainstem (nucleus of the solitary tract) and pontine (parabrachial nucleus) regions, in mutants as well as wild-type controls. However, in amygdala, elevations were seen in controls but were absent in the mutants. These findings suggest that disruption of PKA signaling interferes with LTM consolidation of CTA and that a possible mediator of this effect is interference with c-Fos expression in amygdala which may be necessary for CTA memory.

Increases in Fos-like immunoreactivity (FLI) in the intermediate division of the nucleus of the solitary tract (iNTS) are seen following the expression of a conditioned taste aversion (CTA). In studies limited to behavioral assessment, the pontine parabrachial nucleus (PBN) has been demonstrated to play a critical role in the acquisition, but not the expression, of CTAs. To better define the role of the PBN in taste aversion learning, the present study examined the effects of PBN lesions on FLI in iNTS in animals with lesions placed either before or after CTA training. As is the case with behavioral expression of a CTA, timing of PBN lesions was found to be critical. Lesions placed prior to conditioning blocked evidence of conditioning, including both taste rejection and FLI in iNTS. Lesions placed after conditioning, but before testing, did not interfere with either taste rejection or FLI. These results support and extend prior claims that PBN is critical for CTA acquisition but not expression. They also demonstrate that input from PBN to iNTS is not necessary for the FLI seen there during CTA expression.

The present studies were aimed at further characterizing the role of DA in motivation. Rats, conditioned to expect food in one environment and no food in another, all received food on the test night. Those in the environment in which food was unexpected ate four times as much as those eating where food was expected. The overeating was eliminated by administration of the D2 antagonist raclopride. Another expectancy, timing of light offset in rats entrained to a fixed light--dark cycle, was violated by unexpectedly turning the lights off 1 h early. This provoked an elevation in food intake, which was also eliminated by the administration of raclopride. Feeding in two other situations not involving violation of expectancies (food deprivation; normal light offset) was unaffected by DA antagonism. These findings support the idea that DA signals errors in expectancy and that DA signaling is necessary for certain behavioral responses to unexpected events.

Fos-like immunoreactivity (FLI) can indicate the location of neurons activated following expression of conditioned taste aversion (CTA). After one conditioning trial FLI has been identified in the intermediate nucleus of the solitary tract (iNTS) with little expression in other brain regions. The present study assessed the effect of increasing aversion strength on the magnitude and anatomical distribution of FLI during CTA expression. When animals received three rather than one conditioning trial, significant FLI was seen not only in the iNTS but also in the parabrachial nucleus (PBN), and the central nucleus of the amygdala (CNA), regions thought to be important in taste aversion learning.

Increases in c-Fos-like immunoreactivity (FLI) in the intermediate nucleus of the solitary tract (iNTS) have been seen consistently as a correlate of the expression of a conditioned taste aversion (CTA) when conditioning occurs using taste delivery through intraoral (I/O) infusions. The present study examined whether a similar FLI response would occur when conditioning was accomplished by presenting the taste solution in a bottle. I/O and bottle methods generated aversions that were comparable, when judged by the behavioral response of solution rejection. However, elevations in FLI were seen only in animals conditioned with the I/O method. This finding adds to evidence that the neural pathways underlying CTA learning differ as a function of the type of conditioning method used.

The specific role of insular cortex in acquisition and expression of a conditioned taste aversion was assessed using two different conditioning methods, which vary mode of taste delivery. Involvement of insular cortex in the induction of c-Fos-immunoreactivity in the nucleus of the solitary tract, a cellular correlate of the behavioral expression of a conditioned taste aversion, was also assessed. Electrolytic lesions of insular cortex blocked behavioral expression of a conditioned taste aversion and this was evident not only when lesions were placed prior to conditioning, but also when they were made after conditioning but before testing. In contrast to the effects on behavior, lesions did not completely block the c-Fos-immunoreactivity which accompanies re-exposure to the aversive taste. In addition, the blocking of behavioral evidence of aversion conditioning by cortical lesions was seen both in animals trained under an intraoral acquisition procedure and those trained with bottle-conditioning. This contrasts with previous work with amygdala lesions which showed that amygdala was absolutely necessary for taste aversions conditioned with the intraoral method but not for those conditioned using bottle presentation of the taste. Overall, these findings imply that the details of the neural circuitry involved in taste aversion learning, including its anatomical distribution, complexity and degree of redundancy, vary with the type of conditioning method employed.

Central infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) and intraperitoneal (i.p.) injection of lithium chloride (LiCl) produce similar patterns of c-Fos induction in the rat brain. These similarities led us to assess the hypothesis that neuronal activity caused by i.p. injection of LiCl involves activation of central GLP-1 pathways. We therefore determined if third-ventricular (i3vt) infusion of a GLP-1 receptor antagonist would block LiCl-induced c-Fos expression in the brainstem. Relative to rats pretreated with i3vt infusion of vehicle, pretreatment with the potent GLP-1 receptor antagonist, des His1 Glu9 exendin-4 (10.0 microgram), significantly attenuated LiCl-induced (76 mg/kg; i.p.) c-Fos expression in several brainstem regions, including the area postrema, the nucleus of the solitary tract, and the lateral parabrachial nucleus. While central infusion of des His1 Glu9 exendin-4 also blocked GLP-1-induced (10.0 microgram) anorexia and c-Fos expression, the antagonist produced no independent effects on food intake or c-Fos expression. These results suggest that LiCl-induced c-Fos expression in the rat brainstem is mediated, at least in part, by GLP-1 receptor signaling., (Copyright 1998 Elsevier Science B.V.)

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., (Copyright 1998 Elsevier Science B.V. All rights reserved.)

Selectively bred rat lines, developed to model genetic contributions to alcohol abuse, include the Indiana alcohol-preferring (P) and alcohol-nonpreferring (NP) lines, and the Alko-Alcohol (AA) and Alko-Nonalcohol (ANA) lines. Preferring and nonpreferring lines were compared in their response to intraperitoneal injection of either ethanol or isotonic saline using c-Fos expression as a marker of neuronal activity. Although line differences were noted in several brain regions, the principal finding was that alcohol-nonpreferring lines (NP and ANA) displayed greater c-Fos expression in the locus coeruleus (LC) relative to the alcohol-preferring lines (P and AA) following injection of 3.0 g ethanol/kg. These data point to the LC as an area which may play a role in the differences in voluntary ethanol consumption between rat lines genetically bred for low and high ethanol preference.

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 reliable cellular correlate of the acquisition and/or behavioral expression of a conditioned taste aversion (CTA). To begin to define neuroanatomical structures and pathways that contribute to this cellular response and to CTA learning in general, electrolytic lesions of the amygdala were combined with immunostaining for c-FLI. Rats were given either unilateral or bilateral electrolytic lesions of the amygdala 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. When tested, unilateral-lesioned rats displayed a CTA by rejecting the saccharin, but increases in c-FLI were evident only on the side of the iNTS contralateral to the lesion. Rats with bilateral lesions showed no evidence of having acquired a CTA and no increase in c-FLI in iNTS relative to unpaired controls. These findings support involvement of amygdala in CTA learning and suggest that a lateralized connection between amygdala and iNTS is necessary for the conditioned c-FLI which is induced by exposure to a conditioned aversive taste.

Amphetamine and lithium chloride (LiCl) are both effective unconditioned stimuli (USs) in the establishment of conditioned taste aversions (CTA) in the rat. However, the mechanism of action of these drugs is quite different with the area postrema and related emetic circuitry critical to the response to LiCl but not amphetamine. c-Fos immunohistochemistry was used to define brain regions activated during drug administration and during expression of a CTA using either amphetamine or LiCl as the US drug. Administration of LiCl induced dense c-Fos-like immunoreactivity (c-FLI) in the nucleus of the solitary tract (NTS) while amphetamine induced only light staining in this area. A conditioned stimulus (CS) saccharin solution paired with amphetamine, however, was associated with c-FLI in NTS in a pattern quite similar to that seen to a LiCl-paired CS. This suggests that the pattern of c-Fos expression to a taste CS after conditioning is characteristic of aversion conditioning, in general, and appears not to represent a matching of the conditioned response to specific unconditioned effects of the drug. To examine this conditioned response further, c-FLI to the aversive saccharin CS was compared to the response to quinine hydrochloride, which is innately aversive. Although behaviorally the animals' ingestive responses were quite similar, the saccharin CS induced significant elevations of c-FLI in NTS whereas the quinine did not. Thus, a taste which had become aversive by virtue of conditioning induced c-FLI expression in NTS while a taste which was inherently aversive did not.

Taste aversion conditioning is characterized by its prompt acquisition despite the introduction of long delays between CS (taste) and UCS (toxic drug). Although the dramatic changes in behavioral response to a taste after this conditioning are well documented, relatively little is known about the changes in neural activity that accompany this learning. c-Fos immunohistochemical staining was employed to define brain regions activated during the expression of a conditioned taste aversion (CTA). The present studies examined c-Fos immunoreactivity in the brains of rats after i.p. injection of LiCl or NaCl or after intraoral infusion of a saccharin CS. LiCl administration, a common unconditioned stimulus (UCS) in CTA experiments, was found to induce c-Fos protein in a number of brainstem regions, including the nucleus of the solitary tract (NTS), medial and lateral pontine parabrachial nucleus (PBN), and hypoglossal nucleus. Conditioned animals received a single pairing of the CS saccharin with the UCS LiCl, while controls were exposed to the CS saccharin but received non-contingent LiCl 24 h after saccharin exposure. Following saccharin re-exposure, conditioned animals showed patterns of neuronal activation to a taste which were similar to those activated by the UCS drug. Specifically, the pattern of c-Fos expression in conditioned animals was confined to the same region of the NTS which showed the most activation following the UCS LiCl. This pattern of activation was not evident in controls re-exposed to saccharin.(ABSTRACT TRUNCATED AT 250 WORDS)

The area postrema (AP), a chemoreceptor trigger zone for nausea and vomiting, has been implicated in taste aversion conditioning with LiCl. In addition to taste aversion acquisition, the present studies indicate that a number of other responses to LiCl administration are eliminated by lesions of the AP. These include a behavioral response, 'lying-on-belly' as well as two physiological responses, delayed stomach emptying and hypothermia. These findings suggest that the area postrema is critically involved in the detection of LiCl and in a wide range of responses to this toxin. They also provide strong evidence that the failure to acquire conditioned taste aversions to LiCl-paired flavors after AP lesions can be attributed to the absence of a significant 'illness' response in lesioned animals.