NEURAL CORRELATES OF EXERCISE THERAPY IN PD MODEL

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The goal of this project is to characterize the neurophysiological changes induced during the recovery of function in awake behaving rat by the depletion of dopamine in striatum by the unilateral administration of 6-hydroxydopamine as a model for Parkinson's disease. Preliminary studies have shown that depletion of dopamine results in an elevation of resting firing rates of neurons in the neostriatum. This effect is maximum of the depleted side but is nearly equally apparent on the intact side with no depletion of DA. Activation of rotation activates reciprocal changes in neighboring neurons on both sides with no net changes in means rates, thus indicating the presence of an effective synaptic input to both intact and DA depleted striatum. An interpretation is that absence of dopamine induces a motor dysfunction directly on the affected side. This in turn activates a widespread motor recovery adaptive mechanism that engages both sides of the cortical striatal nigral thalamic system. Forced use of the limb on the DA depleted side by application of a cast to restrict use of the unaffected limb, specifically in the first 7 days after 6-OHDA, has recently been found to offer neuroprotection against 6-OHDA, and thus raised the possibility that the widespread bilateral elevation of activity may play both a neuroprotective as well as a compensatory role. An aim of this project is to record activity of populations of neurons recorded simultaneously from 64 microwires implanted bilaterally in striatum, substantia nigra reticulata/compacta, and forelimb sensorimotor cortex. These advanced recording procedures developed in this laboratory will determine activity of populations over the two weeks after 6-OHDA administration. Casting to restrict limb use will be done on both the DA depleted and intact side to compare effects of restriction of movement and to determine the neural signals during movements during tests of motor impairment. Casting will be done prior to 6-OHDA to test whether elevation of activity appears during the early period of motor reorganization and may serve to activate neuroprotection. Recordings made from dopamine neurons will test the emerging concept of a role in motor learning and reorganization. A prediction is that the novel movement patterns during forced use will produce many signals in striatum and cortex correlated with movement that are not present in over-trained circuits.