The response of the mature central nervous system to traumatic brain injury

The mature central nervous system (CNS) is unable to repair following traumatic brain injury (TBI). Intervention is difficult as the pathobiology of the brain following injury is a complex sequence of events that needs to be fully elucidated. Understanding the endogenous mechanisms evoked by the damaged brain when attempting repair from injury is vital for devising effective therapies to treat brain injury. The current thesis is based upon the hypotheses that ultimately, recovery following trauma will require the induction of neurogenesis and either appropriate regeneration or compensatory plasticity of pre-existing neural pathways and that the mechanisms underlying regeneration of mature axons is fundamentally different to developmental growth. This thesis investigated the reactive and regenerative alterations associated with the neural response to physical injury in the adult mammalian brain. This thesis studies are focused upon the potential for regeneration following injury and how comparable regenerating neurons characteristics are to their developmental counterparts. It investigated the alterations within the damaged neurons and the surrounding brain area which may be indicative of an intrinsic capacity for regeneration including frank neuronal replacement following injury, and the role of the neuronal cytoskeleton in neuronal regenerative events, as the mechanisms underlying these processes are currently poorly understood. This thesis demonstrated that heterogenous populations of cultured cortical neurons are able to survive and regenerate following severe structural injury, suggesting that neurons have an intrinsic capacity for regeneration, regardless of the mode of injury. Additionally, alteration of the intrinsic cytoskeletal environment, through the knockout of the neurofilament light chain protein, decreased the regenerative ability of mature neurons, providing further evidence for the intrinsic regulation of regeneration. Results from this thesis indicate that the growth cones of regenerative sprouts differ from their developmental counterparts in their predominant morphology, their dynamic behaviour and their ability to respond to critical growth factors. These differences between the regenerating and developing growth cones may account for the inability of regenerative sprouting axons to make accurate pathway decisions and successfully respond to trauma. The presence of neurogenesis was investigated following structural injury in vitro, which indicated no evidence of neurogenesis following injury. While focal brain injury in vivo induced proliferation of neural progenitors, immunohistochemistry confirmed that astrocytic but not neuronal, cell proliferation was evoked by focal injury, consistent with the in vitro data. However focal injury induced an axonal regenerative response into the injury site, which was neuronal cell type specific, and significant remodelling in a subpopulation of interneurons away from the injury, demonstrating that the adult cortex is capable of significant remodelling following brain injury. These studies address the central issues examining the potential for neuronal repair and appropriate regeneration with an emphasis on developmental versus regenerative growth. This thesis provides significant insight into why regenerative attempts are limited or aberrant and how responses exhibited by cortical neurons are specific to subpopulations. This knowledge will provide the evidence base for new therapeutic strategies to improve clinical outcomes for sufferers of TBI.