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


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Blizzard, CA 2011 , 'The response of the mature central nervous system to traumatic brain injury ', PhD thesis, University of Tasmania.

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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
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.

Item Type: Thesis - PhD
Authors/Creators:Blizzard, CA
Keywords: brain, injury, CNS, neuron, regeneration
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Copyright 2011 the Author

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