An important theme in current research on the nervous system concerns the question of modifiability of neuronal properties and synaptic connections in the CNS. This research program has focused on this area using the synaptic connection between group Ia fibers and motoneurons as a model system. In previous studies it has been demonstrated that synaptic transmission at physiological frequencies is not uniform at this synapse. These non-uniformities depend on the target motoneuron and can be influenced by the state of the sensory and motor axons, i.e., whether axotomized, reinnervating a foreign target (skin) or their normal target (muscle). Studies proposed for the next granting period include examination of the hypothesis that properties of Ia synapses on motoneurons are regulated during development and adult life to maintain correlation between a motor unit and its synaptic input. Specifically tests will be carried out to investigate how these synaptic properties change during development, and as a result of changing motoneuron properties by immobilizing the limb or peripheral nerve cross union. The question is whether correlations between motoneuron and synaptic properties are maintained despite the plastic changes. The second group of experiments will be directed at the hypothesis that neurotrophins carried in sensory and motor axons from muscle or skin act as signals from the periphery to regulate Ia/motoneuron synaptic function. Specifically the effect of neurotrophins NT-3 and BDNF and their antibodies on the function of the Ia/ motoneuron connection in intact preparations will be investigated as will the question of whether these neurotrophins can substitute for the target tissue (skin, muscle) in reversing the effects of axotomy. A later experiment will examine whether antibodies to these neurotrophins interfere with the ability of target tissue to rescue central connections from the effects of axotomy. The final hypothesis to be investigated is that the systematic functional differences in synapses on motoneurons play a significant role in governing the distribution of synaptic input to the different constituents of the motoneuron pool during different types of motor tasks. Here it will be investigated how the properties of transmission are affected as a function of interstimulus intervals within a burst and as a function of interburst interval and tonic presynaptic inhibition, all of which can differ as a function of the motor task being carried out (e.g., stepping or paw shake). The possibility that these synapses in rat and cat are """"""""tuned"""""""" differently in accordance with the mechanical demands of the neuromuscular systems that they control will be evaluated. These experiments will provide information relevant to clinical neurology, specifically the extent to which the CNS connections are sensitive to manipulations in common use today (e.g., limb immobilization). The studies of growth factors will provide useful information as to whether they can be used to manipulate cellular and synaptic function in a specific manner (e.g., after motoneuron disease) and whether such effects if present serious drawbacks to the use of these agents in the treatment of other disease processes.
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