The failure of axonal growth in the adult spinal cord has been strongly associated with the presence of chondroitin sulfate proteoglycans (CSPGs) and enzymatic degradation of these molecules in vivo with the enzyme chondroitinase abc has been reported to increase axonal growth in rodent models of central nervous system damage. The central hypothesis to be tested is that intrathecal chondroitinase abc can promote axonal growth that leads to the reconstruction or augmentation of compromised host circuitry and results in enhanced motor function following spinal cord injury. Adult cats will receive low thoracic hemisections and be placed into one of three groups: hemisection-only, de-activated chondroitinase abc or active chondroitinase abc. Cats will be evaluated using a variety of locomotor tasks that demand the involvement of different levels of neural control. These will range from bipedal treadmill locomotion requiring only segmental networks to complex overground runways requiring specific descending supraspinal input. Thus, the type of behavioral recovery seen on these tasks will strongly suggest what neural substrates (pathways) are involved in the recovery process. Cats also will be tested for cough, which is an essential pulmonary defensive reflex that requires premotor input from the medulla. To our knowledge, this is the first effort to determine the influence of any therapeutic agent on spinal cord injury-induced impairment of cough. This will be done using nonterminal, as well as terminal, electrophysiological methods. Basic stains and immunohistochemistry will be used to characterize the lesion sites. Immunohistochemistry, tract tracing, and electrophysiological assays will be used to identify potential mechanisms of plasticity, and quantitatively assess axonal growth and the neuronal populations projecting to and/or past the lesion/treatment site. Results from these studies will allow us to identify the mechanisms of spontaneous recovery and how they may be enhanced or altered by chondroitinase abc treatment. The analyses of these two diverse motor behaviors (locomotion and cough) will allow us to differentiate selective from generalized recovery mechanisms induced by chondroitinase abc. This multi-system approach to recovery and plasticity after chronic spinal cord injury will provide a foundation on which other promising therapies for spinal cord injury can be tested (alone or in combination with chondroitinase abc).
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