Our overall goal is to identify the mechanisms underlying postnatal development of connectional specificity and function in the corticospinal (CS) system. During the present funding period we found that CS terminals can activate spinal neurons before the system's limb motor functions are expressed and that the transition from development to function involves strong facilitation of CS postsynaptic responses. Without activity or normal limb use, CS axons develop an anomalous projection pattern and their terminals have fewer branches and varicosities than normals. These impaired axons have little or no capacity to regrow lost terminations later in development. The lack of compensatory growth is not consistent with development during a brief critical period because we also found that CS axons terminals are normally capable of abundant growth late during development. Our studies show that CS system activity and forelimb use radically transform the distribution and morphology of CS axon terminals, which is established by intrinsic spinal neurotrophic factors and guidance cues, into the mature pattern. We also found that augmenting CS activity by stimulating axons in the medullary pyramid promotes the growth of developing CS terminations and enhances their capacity to compete for synapses with spinal neurons. This finding not only is important for understanding the mechanisms of CS system development but also presents a way to harness activity-dependent processes to re-shape CS system development experimentally. The present application has 3 aims. First, we will determine how activity modifies the anatomical and physiological characteristics of the CS synapse with spinal neurons during early postnatal development. Second, we will determine the differential contributions of neurotrophic and activity-dependent interactions in developing the topographic distribution and morphology of CS terminations. Third, we will develop ways to enhance the long-term survival of CS terminations that have been promoted by early postnatal stimulation and to determine their capacity to activate spinal motor circuits. With these experiments we expect to gain insight into how early development of the corticospinal system sets the stage for its motor control functions later in life. Through this understanding we hope to learn how perinatal damage to the CS system, which typically produces cerebral palsy, can be averted. ? ?
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