| For over a century, the notion that damaged, mature central neurons were unable to regenerate was neuroscience dogma. In the past twenty years this axiom has been repeatedly disproved in a variety of species and systems. However, the flurry of regenerative findings has brought with it its own brand of doctrine and highlighted the core limitations in studies of functional regeneration. If we hope to enter the injured brain or spinal cord, we must be able to do more than merely entice the regrowth of lesions axons. We must be able to identify axons that have been in an injured state for a long time (often years) we must be able to induce regeneration in those targets and we must be able direct that regeneration such that regrowing axons can reacquire the necessary post-synaptic targets and ultimately lead to a recovery of function at the neuronal and muscular level. These are bold ideals, especially in the context of the paucity of information that exists in our understanding of the normal mechanisms of circuit function underlying behavior.In this dissertation, we systematically, and hopefully convincingly, identify neurons that participate in the control of movements by examining their morphology and activity, as the animal is moving. After identifying neurons that are components of different circuits controlling different movements, we thought to damage them via spinal cord lesions. We then, after waiting up to three weeks post-injury, set out on an educated lark. We injected the lesioned, non-regenerating neurons with a drug---the results were unexpected and unparalleled. Our treatment induced these completely severed, non-regenerating neurons to regrow their axons, through and well past the site of injury. Furthermore, we visualized these events as they were happening, in the living animal. Even more remarkably, not only did our treatment lead to a regeneration of axons well after the injury, it led to a restoration of activity in the putative post-synaptic target spinal interneurons of the regrowing axons and an astonishing recovery in the associated motor function.Our results, and the manner in which we gathered and documented them hinge upon the utilization of the latest imaging methods in a systems level approach. I hope the findings in this dissertation give healthy contribution to our understanding of neurobiology and behavior. |
