Spinal cord injury results in widespread changes in the central nervous system. The precise nature and extent of the anatomical reorganization that occurs after spinal cord injury and how it is regulated, however, are not well understood. Our recent studies indicate that interventions that increase neuronal cAMP and those that increase post-injury activity can independently contribute to anatomical plasticity and functional recovery after spinal cord injury. We hypothesize that recovery of function after treatments to increase axonal growth following spinal cord injuries in adult rats is not only due to supraspinal axon regeneration but is also due to reorganization of the neuronal circuitry above the SCI. We also hypothesize that pharmacological interventions to increase the intrinsic neuronal capacity for growth and specific rehabilitative strategies to increase activity act synergistically to increase both neuroanatomical plasticity and functional recovery. Studies proposed will use cervical spinal cord over-hemisection at C3/C4 (CHX) in adult rats. This lesion allows us to compare plasticity in pathways damaged directly and completely with remodeling in undamaged pathways. Our studies indicate that both regeneration of pathways damaged directly and reorganization in spared pathways contribute to the recovery of function. This model also allows us to examine recovery of skilled forelimb function as well as locomotion. The studies proposed will examine the effects of specific pharmacological intervention to increase intraneuronal cAMP and rehabilitation strategies to increase activity on neuroanatomical plasticity and recovery of function. Interventions will be applied immediately after injury (acute), after a 2 week delay (sub-acute) and after a 3 month delay (chronic). We will use quantitative neuroanatomical and behavioral techniques and state-of-the-art functional imaging methods to follow anatomical and functional reorganization longitudinally after injury and to define the contribution of specific remodeling to the recovery of function observed. We will examine the extent of ananatomical ?eorganization that occurs within representative supraspinal and spinal regions: sensorimotor cortex and red nucleus (supraspinal pathways associated with skilled movement), in raphespinal neurons (a pathway associated with locomotion), in the dorsal column system (ascending sensory pathway), and in spinal cord propriospinal and motor neurons rostral and caudal to lesion (segmental pathways associated with balance and coordination). We will also define the time course and extent of recovery of motor function that occurs. The experiments outlined here will lead to a better understanding of the changes that take place within the njured CNS and how they are regulated and will be important in rehabilitation strategies to increase neuroplasticity and functional recovery after spinal cord injury.
