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Molecular and cellular events underlying the response of CNS neurons to structural injury

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Chuckowree, Jyoti (2006) Molecular and cellular events underlying the response of CNS neurons to structural injury. PhD thesis, University of Tasmania.

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Abstract

The extent of effective regeneration in the adult mammalian brain following
structural injury has been an issue of contention for the last several decades.
Historical views proposed that the adult brain was set in a state of stasis, preventing
effective regenerative alterations and functional recovery following brain trauma.
The irreversible loss of function following injury to the adult mammalian brain has
been attributed to an intrinsic inability of damaged neurons to re-initiate growth
following injury, which is further compounded by a non-facilitative environment.
However, accumulating evidence, based on diverse models of experimental neuronal
and brain lesion, have challenged two major dogmas in neuro-repair research,
namely, that neurons from the adult mammalian brain are incapable of intrinsically
driven regeneration, and that neurogenesis is strictly restricted to developmental
periods. Collectively, these studies have provided compelling evidence indicating
that the adult brain may possess a vast intrinsic capacity for repair following injury.
Furthermore, strategies aimed at facilitating neuronal replacement or re-establishing
lost neuronal connections have made remarkable inroads into understanding the
potential for injury-induced plasticity in the adult brain.
Despite these advances, however, no effective treatment currently exists to target the
full repertoire of pathological alterations that contribute to permanent loss of
function following acquired brain injury. A broader understanding of the specific
molecular and cellular events responsible for the limit in brain repair is still required,
particularly for therapeutic interventions to effectively complement and enhance
endogenous brain repair mechanisms. This thesis, therefore, sought to address three specific aspects associated with the intrinsic capacity for brain and neuronal repair
following structural injury. Initially, the neurogenic potential of the injured adult
brain was evaluated in an experimental model of structural brain injury by examining
populations of proliferating and progenitor cells, to determine whether these cell
populations have the capacity to undergo neuronal differentiation and contribute to
neuronal replacement in injured brain tissue. Secondly, the reactive and regenerative
alterations associated with the neural response to structural brain injury vol
investigated in a range of neuronal and glial cell populations to determine particular
alterations that may be indicative of neuronal regeneration and brain healing.
Finally, utilising an in vitro model of axonal injury in which neurons can be studied
in relative isolation, free of compounding glial responses, the intrinsic regenerative
potential of individual mature brain neurons was determined and the mechanisms
underlying this response were characterised through comparison with developing
neurons and application of agents that specifically disrupt the cytoskeleton.
Results from this study highlighted several important aspects of the neural response
to injury indicating that, rather than responding passively, the adult brain mounts an
adaptive repair process. These alterations involved the coordinated activation of
both neuronal and glial cell populations, which ultimately resulted in the restoration
of relatively normal cytoarchitecture. Specifically, adaptive injury-induced
alterations included the activation of various cell populations, particularly neural
progenitor cells, astrocytes and microglia, which may contribute to brain healing;
evidence of re-vascularisation surrounding the lesion site; and regenerative neuronal
changes, such as a profuse axonal sprouting response and an up-regulation of
regeneration-associated genes. In summary these findings indicate that the adult mammalian brain possesses a remarkable intrinsic capacity for repair following
injury and highlight several aspects of this response that may be therapeutically
targeted to enhance brain repair following injury.

Item Type: Thesis (PhD)
Keywords: Brain damage, Brain
Copyright Holders: The Author
Copyright Information:

Copyright 2006 the Author - The University is continuing to endeavour to trace the copyright
owner(s) and in the meantime this item has been reproduced here in good faith. We
would be pleased to hear from the copyright owner(s).

Additional Information:

Available for library use only and copying in accordance with the Copyright Act 1968, as amended. Thesis (PhD)--University of Tasmania, 2006. Includes bibliographical references

Date Deposited: 25 Nov 2014 00:54
Last Modified: 19 Jul 2016 02:03
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