University of Tasmania
Browse
whole_ChuckowreeJyoti2006_thesis.pdf (35.05 MB)

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

Download (35.05 MB)
thesis
posted on 2023-05-27, 00:29 authored by Chuckowree, Jyoti
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.

History

Publication status

  • Unpublished

Rights statement

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). Thesis (PhD)--University of Tasmania, 2006. Includes bibliographical references

Repository Status

  • Open

Usage metrics

    Thesis collection

    Categories

    No categories selected

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC