A better understanding of neural circuits underlying associative learning and memory may be obtained by studying their activity in parallel with changes in behavior during and after learning a well-defined behavioral paradigm and in reference to appropriate control conditions. Functional magnetic resonance imaging (fMRI) will be used in the conscious rabbit to simultaneously examine conditioning-specific hemodynamic changes related to eyeblink conditioning. First, the hemodynamic activation of three different stimulus pathways (light and vibrissae/touch conditioned stimulus (CS) and corneal air puff unconditioned stimulus (US)) will be examined with fMRI. Second, activity within the thalamocortical sensory, limbic/forebrain and cerebellar circuitry activated during simple delay conditioning will be examined during and after each trial on which a CS is paired with airpuffs to the eye (US). A sequence of functional images taken after sessions of pseudoconditioning, conditioning and consolidation in each rabbit will allow comparisons within each animal of hemodynamic responses during and after learning as compared to the control conditions. Attention will be focused on several regions hypothesized to be involved in the CR reflex arc based on neuropsychological and physiological analyses done using other techniques, as well as on the rest of the brain to find regions not yet identified with learning. Third, the circuit activated during hippocampally- dependent discrimination reversal eyeblink conditioning will be examined. This paradigm should activate the components of the limbic system and offer an interesting comparison between sensory system function when a CS in a modality is used as a CS+ or CS-. The active regions in this paradigm will be compared with the regions active during the simpler delay paradigm to determine the locations or magnitude of activity that is critical for hippocampally-dependent learning. These experiments will yield significant information regarding the location and sequence of changes in hemodynamic activity during and after associative learning throughout the sensory-limbic-cerebellar system. They will also provide the basis for a noninvasive functional technique to evaluate the effectiveness of potential therapeutic agents for enhancing neural system function during learning and memory in conditions such as normal aging and Alzheimer's Disease as well as enhance our ability to further understand the neurobiological substrates of associative learning in mammalian brain.
