We propose to use morphological and morphometric, electrophysiological, immunocytochemical, and behavioral methods in mature adult and aging cerebellar cortex to determine 1) which synapse and neuron types in the cerebellar cortex exhibit morphologically detectable plasticity in response to learning and to physical exercise, 2) which non-neuronal elements exhibit plasticity in response to learning and to physical exercise, 3) molecular mechanisms underlying this plasticity in gene expression patterns, 4) possible involvement of the fragile X protein in synapse stabilization, and 5) the functional correlates of this plasticity in electrophysiological characteristics of the cerebellum, largely the paramedian lobule. The cerebellum is a particularly good region for these studies because its vascular and neural morphology are responsive to learning and to physical exercise and because it shows substantial aging effects in rats and humans at a comparatively early point in the lifespan, correlating with motor deficits that often interfere with optimal healthy aging. The goal is to generate a map of the synapses that are alterable as a basis for studying both the functional consequences of and the mechanisms leading to their alteration by behavior. This map will then be compared with network models of cerebellar function in motor behavior, particularly with a current model that models cerebellar function in the context of other neural systems. The behavioral paradigm used separates the effects of routine physical exercise-associated neural activity, which largely alters the capillary network with limited effects upon the synaptic network, from the effects of (non-exercise-related) motor learning, which alters synapses, with minimal effects upon vasculature. In this paradigm, learning with relatively minimal exercise occurs in the """"""""Acrobat"""""""" condition (AC), which requires rats to traverse an elevated obstacle course. Exercise with minimal learning is accomplished in rats forced to exercise (FX) on a treadmill or allowed voluntary exercise (VX) in an activity wheel. For baseline purposes, an inactive condition (IC) involves rats kept individually in standard cages, and other control and exercise conditions are occasionally also used. We have found changes in cerebellar cortical synapses in the AC group but not in the other 3 groups. In contrast, increased vascularization, relative to IC, occurs in the FX and VX groups, but not in the AC group. These groups will be used to detail the effects of learning and of exercise upon the mature adult and the aging adult brain at the level of the synaptic wiring diagram, the vascular and astrocytic support systems, electrophysiological functioning, and possible molecular mechanisms whereby behaviorally-induced neural activity is translated into synaptic change.
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