Cortico-limbic Circuits for Learning and Memory

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This renewal extends a basic research project focused on neural mechanisms of synaptic plasticity required for learning and memory. We have made significant progress in understanding the role of synaptic Long-Term Depression (LTD) in the learning of fear conditioning and other aspects of memory including stress-induced disruption of spatial memories. A better understanding of the role of LTD in cognition will enhance our understanding of the biological bases of learning and memory. Success is due to the development of a small artificial peptide (‘3Y-interference peptide’-patent-pending) that disrupts the regulated endocytosis of the AMPA class of ionotropic glutamate receptors the critical final step in the induction of LTD. This allows for the manipulation of LTD at different stages of the learning/memory cascade. Our research strategy also requires sophisticated and reliable behavioral tests to assess specific aspects of learning and memory in rodents. The proposed experiments will utilize : 1) Attentional set-shifting requiring a switch in choice of which lever to press for food reward, based on location of the lever or position of a discriminative light cue; 2) Latent Inhibition (LI) of 2-way active avoidance responding in which repeated pre-exposure to a salient discriminative stimulus causes significant retardation in the acquisition of avoidance responses; 3) Discriminative stimulus learning whereby brief presentation of a specific sensory stimulus such as a tone or light predicts time-limited access to food reward. Related experiments will identify specific brain regions where disruption of LTD causes selective disruption of one or more of the learned behaviors. Direct evidence that the ‘interference peptide’ disrupts LTD in specific regions of the brain, will be provided by blocking LTD within specific brain regions by i.v administration of the ‘interference peptide’. Previous NSERC-funded research on the functional nature of synaptic plasticity revealed that direct electrical stimulation of glutamatergic afferents to the hippocampus can serve as a discriminative stimulus in the acquisition of a new response for food reward which in turn was enhanced significantly by induction of long-term potentiation (LTP). Our highly selective technique for blocking LTD in brain, coupled with our brain-stimulation signal detection procedure will provide a unique opportunity to resolve a fundamental issue in the study of synaptic plasticity and memory the functional effects of ‘ LTD-induced depotentiation” of LTP. In summary, the present proposal builds on our recent success in linking LTD to processes responsible for response flexibility and extinction of previously acquired memory. Collectively this research has significant theoretical importance and should provide new insights into the relationship between synaptic plasticity and information processing in brain.