HIPPOCAMPAL/CEREBELLAR LEARNING INTERACTIONS

Northwestern University, Evanston IL

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Abstract

The goal of this revised competitive renewal application is to understand the function of the elements of a brain circuit which interconnects the hippocampus and cerebellum during learning and consolidation of trace eyeblink conditioning. The working hypothesis is that the hippocampal formation temporarily potentiates the response of the conditioning stimulus (CS) when it is paired with an unconditioned stimulus (US). This potentiated response facilitates the input from the pontine nuclei to the cerebellum and becomes necessary for learning when the temporal demands of the associative task are more complex, as in trace conditioning. Tetrodes for neuron ensemble recording will be placed in: the medial septum (MS) to detect changes related to the cholinergic and inhibitory neuron drive to the hippocampus; area CAl and the subiculum to follow changes in responsiveness of the hippocampal formation; the retrosplenial cortex (RSCtx) to follow the response to the CS through acquisition and consolidation o the CR; pontine nuclei (pN) to measure the timing and amplitude of the tone CS input to the cerebellar circuit and changes in the response to the CS; cerebellar anterior interpositus nucleus (IPA) to record cerebellar circuit output and a neural "assay" o behavioral learning; the ventral anterior thalamus (vaTh) to monitor changes related to feedback from the IPA; prefrontal cortex (PFCtx) and anteroventral thalamus (AvTh) to evaluate the loop through the prefrontal cortex by which the cerebellum is hypothesized to transfer information about the developing conditioned motor response to the hippocampus. Reversible lesions will be made at various points in the circuit to evaluate their contribution to acquisition and consolidation of the eyeblink CR. Retrosplenial and/or prefrontal cortices are hypothesized to serve as long term storage sites for changed activity relevant to the learned association. Modern single neuron ensemble recording and analysis techniques will be used. These will include recording 25-50 single neurons simultaneously in the behaving rabbit with several tetrodes; computerized waveform separation with advanced cluster cutting techniques; neuron-behavior response analysis with poststimulus time histograms, multiple between neuron cross correlations, and multivariate analysis techniques; use of reversible lesions for probing the function of specific sites during learning and consolidation.. It is known that both the cerebellum and the hippocampus are intimately engaged in mediating the eyeblink conditioning task, especially when the stimulus demands are enhanced as in the trace eyeblink conditioning task. The dynamics of this interaction are not understood. Further understanding of how the hippocampal-cerebellar circuit functions in the rabbit brain during learning will have direct parallels to its operation in the human brain. This information has relevance to understanding and treating disorders of learning such as those which occur alter stroke, in aging, in dementing diseases such as Alzheimer's Disease, and in disorders which may involve hippocampal dysfunction such as schizophrenia or epilepsy.