Functional basis of associative learning and its relationships with long-term potentiation evoked in the involved neural circuits: Lessons from studies in behaving mammals.

While contemporary neuroscience is paying increasing attention to subcellular and molecular events and other intracellular phenomena underlying the acquisition, storage, and retrieval of newly acquired motor and cognitive abilities, parallel attention should be paid to the study of the electrophysiological phenomena taking place at selected cortical and subcortical neuronal and synaptic sites during the precise moment of learning acquisition, extinction, and recall. These in vivo approaches to the study of learning and memory processes will allow the proper integration of the important information collected from in vitro and delayed molecular studies. Here, we summarize studies in behaving mammals carried out in our laboratory during the past ten years on the relationships between experimentally evoked long-term potentiation (LTP) and activity-dependent changes in synaptic strength taking place in hippocampal, prefrontal and related cortical and subcortical circuits during the acquisition of classical eyeblink conditioning or operant learning tasks. These studies suggest that different hippocampal synapses are selectively modified in strength during the acquisition of classical, but not instrumental, learning tasks. In contrast, selected prefrontal and striatum synapses are more directly modified by operant conditioning. These studies also show that besides N-methyl-D-aspartate (NMDA) receptors, many other neurotransmitter, intracellular mediating, and transcription factors participate in these two types of associative learning. Although experimentally evoked LTP seems to prevent the acquisition of classical eyeblink conditioning when induced at selected hippocampal synapses, it proved to be ineffective in preventing the acquisition of operant conditioned tasks when induced at numerous hippocampal, prefrontal, and striatal sites. The differential roles of these cortical structures during these two types of associative learning are discussed, and a diagrammatic representation of their respective functions is presented.