The cerebellum and its associated brainstem circuitry are required for learning and retaining simple conditioned reflexes of striated muscles, and the hippocampus is required to acquire and temporarily store stimulus associations for more complicated conditioning paradigms, such as trace conditioning. The overall goals of this proposal are to continue to characterize the neural substrates of these intermediate events in the hippocampus and other forebrain regions and, additionally, to begin to localize the brain regions underlying permanent storage of memory using hippocampally-dependent trace eyeblink conditioning in the rabbit. Our analysis of this circuit should lead to a more thorough understanding of the interrelationships among the cerebellum, hippocampus, and hippocampally-related forebrain structures, including the caudomedial prefrontal cortex (cmPFC), cortical association areas and the basal ganglia. Our aims will test a common hypothesis that the "memory trace" is transferred from the hippocampus to the cortex during acquisition and consolidation of learned responses. Our recent single neuron recordings indicate that the hippocampus and caudomedial prefrontal cortex mediate only a temporary role in learning the hippocampus-dependent trace eyeblink conditioned response. We propose that an increased excitability of association cortex neurons provides a necessary facilitation of pontine / mossy fiber inputs to the cerebellum, and that the basal ganglia provide necessary feedback from the cerebellum to the forebrain required to establish the neocortical changes. Single neuron activity will be recorded from large numbers of cells in rabbits during learning with multiple, independently moveable tetrodes to characterize activity at several key sites on the developing conditioned reflex arc. Inactivation will be done with reversible lesions, combined with single neuron recording and behavioral measurements, to evaluate the role of some regions. Our experimental program will begin testing the hypothesis that memories are stored in neocortical regions in a process dependent upon the engagement of the hippocampus and basal ganglia earlier in the learning process. Our data will have considerable relevance to better understanding the processes by which learning occurs in mammalian brain, including in human brain as we and others have shown important parallels in the processes by which humans and experimental animals acquire eyeblink conditioning. The results of these experiments will also be useful in the design of more appropriate treatments for learning deficits in young and aging individuals.
NIH ExPorter
NIH ExPorter