Modulation of protein tyrosine phosphorylation in rat insular cortex after conditioned taste aversion training.

Abstract

Protein tyrosine phosphorylation is a major signal transduction pathway involved in cellular metabolism, growth, and differentiation. Recent data indicate that tyrosine phosphorylation also plays a role in neuronal plasticity. We are using conditioned taste aversion, a fast and robust associative learning paradigm subserved among other brain areas by the insular cortex, to investigate molecular correlates of learning and memory in the rat cortex. In conditioned taste aversion, rats learn to associate a novel taste (e.g., saccharin) with delayed poisoning (e.g., by LiCl injection). Here we report that after conditioned taste aversion training, there is a rapid and marked increase in tyrosine phosphorylation of a set of proteins in the insular cortex but not in other brain areas. A major protein so modulated, of 180 kDa, is abundant in a membrane fraction and remains modulated for more than an hour after training. Exposure of the rats to the novel taste alone results in only a small modulation of the aforementioned proteins whereas administration of the malaise-inducing agent per se has no effect. To the best of our knowledge, this is the first demonstration of modulation of protein tyrosine phosphorylation in the brain after a behavioral experience.Protein tyrosine phosphorylation is a major signal transduction pathway involved in cellular metabolism, growth, and differentiation (1). Recently, it became apparent that tyrosine phosphorylation also plays a key function in neuronal activity and plasticity. Activation of receptor tyrosine kinases by growth and neurotrophic factors is required for development, remodeling, and possibly also maintenance of neural tissue. Prominent among this class of molecules are members of the trk family that respond to a variety of neurotrophic factors including nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 (2-4). Protein tyrosine kinases appear also to be involved in mediating the effect of neural cell adhesion molecules on neuronal membrane-associated cytoskeleton (5) and in modulating neurotransmitter receptors (6, 7). In addition, activation of nonreceptor protein tyrosine kinases may play a role in encoding intracellular neuronal responses to specific ligands, probably in the context of cross-talk between signal transduction cascades (8-10).The function of protein tyrosine phosphorylation in longterm structural modification of neurons is especially pertinent to the study of behavioral plasticity, since consolidation of long-term memory is postulated to involve modulation of gene expression, culminating in altered synaptic morphology and physiology (11,12). Indeed, inhibitors of protein tyrosine kinase were reported to block long-term potentiation in hippocampal CAl region in the guinea pig (9) and knockout of the fyn gene, encoding a nonreceptor tyrosine kinase, was found to impair long-term potentiation, spatial learning, and hippocampal morphology in transgenic mice (13).Analysis of the modulation of protein tyrosine phosphorylation in brai...

Control of appetitive and aversive taste-reactivity responses by an auditory conditioned stimulus in a devaluation task: A FOS and behavioral analysis

“…Similarly, because rats in group Devalue would respond to sweet with aversive responses, by associatively activating a perception of sweetness, the tone would provoke aversive responses in that group. Notably, although GC is not critical to basic functions of taste detection (e.g., Dunn and Everitt 1988), it has been shown to be importantly involved in many aspects of higher-level processing of taste memories (e.g., Braun et al 1982;Rosenblum et al 1995Rosenblum et al , 1997. Most relevant to the present study, Kiefer and Orr (1992) found that rats with GC lesions failed to replace appetitive taste-reactivity responses to a sweet flavor with aversive responses after flavor-illness pairings, even under circumstances under which those lesioned rats successfully learned to suppress overall consumption of that flavor.…”

Tyrosine Phosphorylation of the 2B Subunit of the NMDA Receptor Is Necessary for Taste Memory Formation

“…These findings were later corroborated in vivo in the dentate gyrus of rats (Rosenblum et al, 1996;Rostas et al, 1996). Since then, tyrosine phosphorylated content of NR2B was shown to increase in response to several learning paradigms, including learning of fear (Kojima et al, 2005;Nakazawa et al, 2006) and of taste aversion (Rosenblum et al, 1995;Miyakawa et al, 1997). However, despite the strong correlation between the increase in tyrosine phosphorylation of NR2B and novel taste learning, it has not been determined whether it is necessary for learning a new taste.…”

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

“…We investigated the possible effect of Src40-49Tat on two forms of NMDAR-dependent learning and memory: contextual fear conditioning 29 and conditioned taste aversion 30,31 . In both tasks, we administered Src40-49Tat prior to training and then examined memory 3 days later.…”