The psychology department at Memorial University provided a supportive environment in which I was surrounded and encouraged by eminent scholars

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Claude Logan
6 years ago
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1 The highlight for November is by Steve Reilly from the Department of Psychology at the University of Illinois at Chicago. Dr. Reilly s interest in conditioned taste aversion (CTA) learning dates back to his post-doctoral work with Sam Revusky at Memorial University where among other things he worked on the effects of stress on the acquisition of aversions. Subsequent to this work, Dr. Reilly began his initial investigations into the neural basis of aversion learning, focusing initially on brainstem mediation. As he and his colleagues demonstrated, parabrachial nucleus (PBN) lesions disrupted aversion learning induced by LiCl, raising the issue that the brainstem was instrumental in the acquisition of such aversions. Following this, Dr. Reilly and his colleagues extended their analysis of the brain mediation of aversion learning by examining the effects of lesions to ascending pathways (from the PBN to the gustatory thalamus and to the amygdala, lateral hypothalamus and insular cortex) as well as to a number of the forebrain structures themselves. His work has shown convincingly that simple interpretations of the effects of such lesions, e.g., effects on associations, are not likely mediating the lesion effects and has instead indicated that other effects of the lesions, including disruptions in perception of taste novelty and the processing of the taste stimuli, may play a larger role in aversion learning. Dr. Reilly s work has been characterized by a rigorous methodology and a patient and thorough overview of possible physiological and psychological processes in CTAs (see Reilly and Bornovalova, Neuroscience and Biobehavioral Reviews, 2005, 29, ). His research summary highlights these research efforts over nearly 20 years and his continuing interest in assaying these mediating processes. My research interest in CTA can be traced back to a wonderful 2-year period that I spent as a postdoc in Sam Revusky s lab at Memorial University in Newfoundland, Canada in the late 1980 s. At that time I began avidly reading about and investigating CTA and related phenomena. My first significant publication involving taste aversion learning concerned the influence of stressors and glucocorticoids on the acquisition of taste aversions produced with a quintessential malaise-inducing agent (lithium chloride), a chemotherapy drug (cisplatin) and a drug of abuse (morphine). In addition to the results (see Revusky & Reilly, 1989) what was most memorable for me was the scale of this endeavor: nine experiments and over 500 subjects in one publication. I also became involved in an area of research that developed out of Sam s previous discovery of an effect that he termed Avfail (see Revusky, 1985). When two drugs states are sequentially induced, the first drug loses some or all of its capacity to serve as a US for CTA, perhaps because an antisickness reaction becomes associated with that drug state (Lett, 1983). We ran many experiments that investigated drug-drug interactions and reported a number of important results (e.g., Revusky & Reilly, 1990a, 1990b; Reilly & Revusky, 1992). Drug-drug conditioning is a fundamentally important phenomenon that has profound theoretical and medical implications that have not yet been widely appreciated. In my opinion, this research area is a gold mine waiting to be more fully explored. 1

2 The psychology department at Memorial University provided a supportive environment in which I was surrounded and encouraged by eminent scholars including Virginia Grant, Carolyn Harley, Mark Holder, Bow Tong Lett, Gerard Martin, and, of course, Sam. Carolyn was instrumental in encouraging me to return to my primary research interest: the neural basis of learning and memory. We found that neurotoxic lesions of the hippocampus enhanced latent inhibition in CTA. This was a surprising finding that flew in the face of all other published results which reported that hippocampal lesions impaired latent inhibition (for a review of this literature see Lubow, 1989). So concerned was I that this finding was anomalous, and therefore meaningless, that it was not published until four years after my departure from Memorial (Reilly, Harley & Revusky, 1993). It was reassuring when our finding was subsequently replicated by, among others, Purves, Bonardi, and Hall (1995) and Stone, Grimes and Katz (2005). My next port of call was the Pennsylvania State University College of Medicine in chocolate town USA. I moved to this institution because of the opportunity to collaborate with an expert, Tom Pritchard, on the central gustatory system of primates. However, one of my first publications from Hershey involved research conducted with Sue Grigson and Ralph Norgren. Building on previous work (e.g., DiLorenzo, 1989; Flynn, Grill, Schulkin, & Norgren, 1991; Spector, Grill, & Norgren, 1992), our research demonstrated that lesions of the gustatory region of the parabrachial nucleus (PBN) prevented CTA acquisition (Reilly, Grigson, & Norgren, 1993), a deficit that seemed best interpreted as a lesion-induced disruption of the associative mechanism that links the gustatory CS with the lithium-induced US (for a review see Reilly, 1999). This finding, which we subsequently replicated and extended (e.g., Grigson, Reilly, Shimura, & Norgren, 1998: Grigson, Reilly, Scalera, & Norgren, 1998), is the centerpiece upon which much of my later CTA research was based. At that time, my research plan began to crystallize. I felt, and still believe, that in order to understand the neural basis of CTA it would first be necessary to define the neurocircuitry involved in first-order taste aversion learning. In other words, what brain structures are essential for a taste CS to be associated with a visceral US? About 20 years earlier, Grill and Norgren (1978) had demonstrated that decerebrate rats cannot acquire CTAs. This result seemed to provide compelling evidence that brainstem structures were not involved with CTA acquisition and that CTA was a forebraindependent learning phenomenon. Our finding, along with similar results from other labs, that lesions of the gustatory PBN, a brainstem structure, also abolished CTA acquisition called for a revision of the interpretation of the decerebrate results such that an interaction between the PBN and unidentified forebrain structures was necessary for first-order taste aversion learning. Given that CTA is a taste-guided behavior it seemed reasonable to focus our investigation on the component nuclei of the central gustatory system. From the PBN, taste information ascends along two routes to the forebrain: the dorsal pathway which synapses in the gustatory regions of the thalamus (or GT) and the insular cortex; and the ventral pathway which projects to areas such as the amygdala, lateral hypothalamus, bed nucleus of the stria terminalis, and the insular cortex (e.g., Lundy & Norgren, 2004). Prior to the 1990 s, published studies fairly consistently showed that lesions of the GT were very debilitating for almost all taste-guided behaviors that had been 2

3 examined, including innate taste preferences and aversions, salt appetite, instrumental responding for liquid rewards, and CTAs. Predicated upon these earlier results, we began to investigate the functional role of the GT and ran into an immediate problem: we found little influence of GT lesions on taste-guided behaviors, including first-order taste aversion learning (Reilly & Pritchard, 1995, 1996a, 1996b, 1997; Reilly & Trifunovic, 1999a; see also Flynn, Grill, Schulkin, & Norgren, 1991; Flynn, Grill, Schwartz, & Norgren, 1991). Our failure to replicate the earlier results likely was due to between-study differences in the size of the lesion damage induced. That is, whereas we used circumscribed electrophysiologically-guided GT lesions, the stereotaxicallyplaced lesions reported in the earlier literature had, for the most part, destroyed the GT and a significant amount of surrounding tissue as well as, perhaps, transecting the ascending ventral gustatory pathway that passes near the GT (for a review see Reilly, 1998). In this way, larger lesions would not only destroy the GT they would also deprive the forebrain of all ascending gustatory information by interrupting both the dorsal and ventral taste pathways. During these years in Hershey, Sue Grigson was educating me on incentive relativity phenomena and in particular consummatory contrast effects. Discrete lesions of the GT eliminate both successive negative contrast and anticipatory negative contrast (ANC; Reilly & Pritchard, 1996b; Reilly & Trifunovic, 1999b). These findings provide the foundation of my second major area of research interest... but that s another story. Of more relevance to present purposes, GT lesions also abolish ANC when a drug of abuse, rather than a high concentration of sucrose, serves as the US (Grigson, Lyuboslavsky & Tanase, 2000; an effect that we replicated, Reilly & Trifunovic, 1999a). The findings that GT lesions have no influence on lithium-induced suppression of saccharin intake (i.e., CTA) but abolish saccharin suppression induced with a drug of abuse (i.e., ANC) provided a building block from which Sue developed the reward comparison hypothesis which claims that drugs of abuse induce ANC effects not CTAs (see Sue Grigson s 2005 CTA database highlight). By now I had moved to the University of Illinois at Chicago. With Radmila Trifunovic I began investigating the role of the visceral region of the PBN in CTA. To cut a long story short, we believe that lesions of this part of the PBN abolish taste aversion learning because of a disruption of ascending viscerosensory information (see Reilly & Trifunovic, 2000a, 2000b, 2001). As an aside, it might be noted that the two regions of the PBN (gustatory and visceral) not only have different roles in CTA, they also appear to have different roles in drug-induced suppression of food intake (e.g., Trifunovic & Reilly, 2001, 2002, 2003, 2006). We also continued to examine the role of the GT in CTA. This is proving a very difficult enterprise. As noted above, GT lesions do not seem to influence first order CTA. Similarly, GT lesions have no influence on latent inhibition or taste-potentiated odor aversion. But, they seem to enhance the overshadowing effect of taste on odor aversion learning and have an even more difficult to interpret influence in a CTA blocking design (Reilly, Bornovalova, Dengler & Trifunovic, 2003; Reilly & Pritchard, 1996b; St. Andre & Reilly, in preparation). The pattern of deficits and spared CTA functions consequent to GT lesions does not have an easy or straightforward interpretation. Our original hypothesis, long since abandoned, was that GT lesions might disrupt the decremental and/or incremental attentional processing in higher-order CTA phenomena. Currently, our best guess is that GT lesions may be disrupting 3

4 perceptual processing when multiple gustatory stimuli are present at the time of conditioning. In recent years we have been examining the influence on CTA of lesions of forebrain structures that receive taste information from the PBN. Predicated on the significance and meaning of the decerebrate results discussed above, our goal is to determine the forebrain structure or structures that interact with the PBN during CTA acquisition. In our hands, electrolytic lesions of the bed nucleus of the stria terminalis have no influence on CTA or COA (conditioned odor aversion). Although inducing hypodipsia, neurotoxic lesions of the lateral hypothalamus similarly do not seem to have a major influence on CTA or COA. NMDA lesions of the insular cortex have no influence on COA but they do attenuate CTA (Roman, Nebieridze, Sastre & Reilly, 2006), a deficit that may be related to a lesion-induced disruption in the perception of taste novelty (Roman & Reilly, in preparation). As far as we can tell, lesions of the central nucleus of the amygdala have no influence on CTA, whereas lesions of the basolateral amygdala disrupt CTA in a manner highly similar to the effects of insular cortex lesions (St. Andre & Reilly, under review; for a review of the amygdala-cta literature see Reilly & Bornovalova, 2005). That is, both insular cortex and basolateral amygdala lesions have little, if any, affect on CTA when the CS is familiar but retard acquisition when the CS is novel. These deficits seem best characterized as a disruption in the processing of the taste stimulus that will become the CS rather than an impairment of association formation, US processing, retrieval or performance. Despite systematic efforts with a fairly standardize behavioral procedure, we find no compelling evidence that lesions of the GT, insular cortex, central nucleus of the amygdala, basolateral amygdala, bed nucleus of the stria terminalis, or lateral hypothalamus abolish CTA acquisition in a manner comparable to PBN lesions or decerebration. What does this all mean? Which forebrain structures are interacting with the PBN during CTA acquisition? Is there an as yet unidentified forebrain nucleus that will prove to be the missing link? Future research will answer these questions. But what if no such structure is found? How then can one reconcile the CTA data obtained from rats with PBN lesions and decerebrate rats? We seek to solve this conundrum. References DiLorenzo, P.M. (1988). Long-delay learning in rats with parabrachial pontine lesions. Chemical Senses, 13, Flynn, F.W., Grill, H.J., Schulkin, J., and Norgren, R. (1991). Central gustatory lesions: II. Effects on sodium appetite, taste aversion learning, and feeding behavior. Behavioral Neuroscience, 105, Flynn, F.W., Grill, H.J., Schwartz, G.J., and Norgren, R. (1991). Central gustatory lesions: I. Preference and taste reactivity tests. Behavioral Neuroscience, 105, Grigson, P.S., Lyuboslavsky, P., and Tanase, D. (2000). Bilateral lesions of the gustatory thalamus disrupt morphine, but not LiCl-induced conditioned taste aversions in rats: Evidence for the reward comparison hypothesis. Brain Research, 858,

5 Grigson, P.S., Reilly, S., Shimura, T., and Norgren, R. (1998). Ibotenic acid lesions of the parabrachial nucleus and conditioned taste aversion: Further evidence for an associative deficit. Behavioral Neuroscience, 112, Grigson, P.S., Reilly, S., Scalera, G., and Norgren, R. (1998). The parabrachial nucleus is essential for acquisition of a conditioned odor aversion in rats. Behavioral Neuroscience, 112, Grill, H.J., and Norgren, R. (1978). Chronically decerebrate rats demonstrate satiation but not bait shyness. Science, 201, Lett, B.T. (1983). Pavlovian drug-sickness pairings result in the conditioning of an antisickness response. Behavioral Neuroscience, 97, Lubow, R.E. (1989). Latent inhibition and conditioned attention theory. Cambridge: Cambridge University Press. Lundy, R.F., Jr., and Norgren, R. (2004). Gustatory system. In G. Paxinos (Ed.), The rat nervous system (pp ). 3rd Edition. San Diego: Academic Press. Purves, D., Bonardi, C., and Hall, G. (1995). Enhancement of latent inhibition in rats with electrolytic lesions of the hippocampus. Behavioral Neuroscience, 109, Revusky, S. (1985). Drug interactions measured through taste aversion procedures with an emphasis on medical implications. Annals of the New York Academy of Sciences, 443, Revusky, S., and Reilly, S. (1989). Attenuation of conditioned taste aversions by external stressors. Pharmacology Biochemistry and Behavior, 33, Revusky, S., and Reilly, S. (1990a). When pentobarbital is the conditioned stimulus and amphetamine is the unconditioned stimulus, conditioning depends on the type of conditioned response. Behavioral Neuroscience, 104, Revusky, S., and Reilly, (1990b). Dose effects on heart rate conditioning when pentobarbital is the CS and amphetamine the US. Pharmacology Biochemistry and Behavior, 36, Reilly, S. (1998). The role of the gustatory thalamus in taste-guided behavior. Neuroscience and Biobehavioral Reviews, 22, Reilly, S. (1999). The parabrachial nucleus and conditioned taste aversion. Brain Research Bulletin, 48, Reilly, S., and Bornovalova, M. (2005). Conditioned taste aversion and amygdala lesions in the rat: A critical review. Neuroscience and Biobehavioral Reviews, 29, Reilly, S., Bornovalova, M., Dengler, C., and Trifunovic, R. (2003). Effects of excitotoxic lesions of the gustatory thalamus on latent inhibition and blocking of conditioned taste aversion in rats. Brain Research Bulletin, 62, Reilly, S., Grigson, P.S., and Norgren, R. (1993). Parabrachial nucleus lesions and conditioned taste aversion: Evidence supporting an associative deficit. Behavioral Neuroscience, 107, Reilly, S., Harley, C., and Revusky, S. (1993). Ibotenate lesions of the hippocampus enhance latent inhibition in conditioned taste aversion and increase resistance to extinction in conditioned taste preference. Behavioral Neuroscience, 107,

6 Reilly, S., and Pritchard, T.C. (1995). The effect of thalamic lesions on primate taste preference. Experimental Neurology, 135, Reilly, S., and Pritchard, T.C. (1996a). Gustatory thalamus lesions in the rat: I. Innate taste preferences and aversions. Behavioral Neuroscience, 110, Reilly, S., and Pritchard, T.C. (1996b). Gustatory thalamus lesions in the rat: II. Aversive and appetitive taste conditioning. Behavioral Neuroscience, 110, Reilly, S., and Pritchard, T.C. (1997). Gustatory thalamus lesions in the rat: III. Simultaneous contrast and autoshaping. Physiology and Behavior, 62, Reilly, S., and Revusky, S. (1992). Drug-drug heart rate conditioning in rats: Effective USs when pentobarbital is the CS. Pharmacology Biochemistry and Behavior, 42, Reilly, S., and Trifunovic, R. (1999a). Progressive ratio performance in rats with gustatory thalamus lesions. Behavioral Neuroscience, 113, Reilly, S., and Trifunovic, R. (1999b). Gustatory thalamus lesions eliminate successive negative contrast in the rat. Behavioral Neuroscience, 113, Reilly, S., and Trifunovic, R. (2000a). Lateral parabrachial nucleus lesions in the rat: Long- and short-duration gustatory preference tests. Brain Research Bulletin, 51, Reilly, S., and Trifunovic, R. (2000b). Lateral parabrachial nucleus lesions in the rat: Aversive and appetitive gustatory conditioning. Brain Research Bulletin, 52, Reilly, S., and Trifunovic, R. (2001). Lateral parabrachial nucleus lesions in the rat: Neophobia and conditioned taste aversion. Brain Research Bulletin, 55, Roman, C., Nebieridze, N., Sastre, A., and Reilly, S. (2006). Effects of lesions of the bed nucleus of the stria terminalis, lateral hypothalamus, or insular cortex on conditioned taste aversion and conditioned odor aversion. Behavioral Neuroscience, 121, Roman, C., and Reilly, S. Effects of insular cortex lesions on conditioned taste aversion and latent inhibition. Manuscript in preparation. Spector, A.C., Norgren, R., and Grill, H.J. (1992). Parabrachial gustatory lesions impair taste aversion learning in rats. Behavioral Neuroscience, 106, St. Andre, J., and Reilly, S. Effects of central and basolateral amygdala lesions on conditioned taste aversion and latent inhibition. Manuscript under review. St. Andre, J., and Reilly, S. Compound conditioning in rats with excitotoxic lesions of the gustatory thalamus. Manuscript in preparation. Stone, M.E., Grimes, B.S., and Katz, D.B. (2005). Hippocampal inactivation enhances taste learning. Learning & Memory, 12, Trifunovic, R., and Reilly, S. (2001). Medial versus lateral parabrachial nucleus lesions in the rat: Effects on cholecystokinin- and d-fenfluramine-induced anorexia. Brain Research, 894, Trifunovic, R., and Reilly, S. (2002). Medial versus lateral parabrachial nucleus lesions in the rat: Effects on mercaptoacetate-induced feeding and conditioned taste aversion. Brain Research Bulletin, 58,

7 Trifunovic, R., and Reilly, S. (2003). Excitotoxic lesions of the lateral parabrachial nucleus do not disrupt cholecystokinin-induced suppression of milk intake in rats. Neuroscience Letters, 348, Trifunovic, R., and Reilly, S. (2006). Medial parabrachial nucleus neurons modulate d- fenfluramine-induced anorexia through 5HT2c receptors. Brain Research, 1067,

Taste Neophobia and c-fos Expression in the Rat Brain

Butler University Digital Commons @ Butler University Scholarship and Professional Work COPHS College of Pharmacy & Health Sciences 2012 Taste Neophobia and c-fos Expression in the Rat Brain Jian-You Lin