Enhancing the Production of New Neurons to
Promote Neurological Recovery Following Traumatic
Brain Injury
Enhancing the Production of New Neurons to Promote Neurological Recovery
Following Traumatic Brain Injury
Chief Investigator: Associate Professor Cristina Morganti-Kossmann, Dr Nicole Bye
Associate Investigators: Professor Perry Bartlett, Professor Esther Shohami, Associate
Professor Ann Turnley
Lead Organisation: Monash University
TAC Neurotrauma Funding: $506,996
Project Start Date: 1 March 2011
Project Summary:
Traumatic brain injury (TBI) is a devastating condition leading to progressive
neuronal loss and consequent neurological deficit. Numerous clinical trials targeting
neurotoxic cascades in TBI patients have failed pharmacological translation.
Recently, a novel opportunity for therapeutic intervention has been identified with the
discovery of resident neuronal stem cells in the adult brain that have the capacity to
undergo neurogenesis to generate new neurons.
Our preliminary studies have shown that immature neurons are indeed generated in
response to TBI and, for the first time, that these cells migrate into damaged regions
of the brain. Other investigations, including our own, have shown that neurogenesis
can be stimulated by administering factors that selectively promote specific regulatory
stages. We recently demonstrated that the neuroprotective cytokine erythropoietin
(EPO) is a potent stimulator of proliferation of precursor cells, while brain-derived
neurotrophic factor (BDNF) is essential for their differentiation into neurons.
Moreover, we have shown that treatment with EPO leads to improved motor and
memory function after TBI, however, neurogenesis was not investigated. Based on
this work, the proposed studies will explore whether treatment with EPO and BDNF,
individually or combined, enhances the neurogenic response occurring after TBI, and
whether enhanced neurogenesis contributes to improved neurological recovery in TBI
mice.
In rodent models of TBI, robust evidence supports an undeniable association between
increased neurogenesis and improved neurological function, however, the actual
contribution of new neurons to recovery post-TBI has never been definitively shown.
In order to address this issue, we have designed experiments aimed at elucidating the
role of neurogenesis in post-TBI recovery by using our recently developed genetically
modified mouse strain, in which neurogenesis can be specifically ablated. This new
strain will allow us to directly determine for the first time whether new neurons are
necessary for neurological recovery following TBI with and without growth factor
treatment. This study will have a significant impact in the neurogenesis and TBI fields
and may set the ground for new therapies with potential translation into the clinic.
The overall hypotheses of this project are:
1. Endogenous neurogenesis induced after TBI directly contributes to functional
recovery.
2. Administration of EPO and BDNF improves motor and cognitive recovery
following TBI by enhancing neurogenesis.
This study will be the first to establish the contribution of neurogenesis to
neurological recovery after TBI. If neurogenesis is a mechanism leading to improved
cognition and motor function following trauma, we will have identified this process as
an important new target for the development of regenerative therapies. Furthermore,
the neurotrophin administration as proposed here has an imminent relevance to human
TBI, as it explores a novel pharmacological paradigm to direct and augment brain
repair and neurological recovery, which could potentially be implemented in the
clinic.
Publications:
(as at Sept 2012)
ZIEBELL JM, BYE N, SEMPLE BD, KOSSMANN T, MORGANTI-KOSSMANN MC. Attenuated
neurological deficit, cell death and lesion volume in Fas-mutant mice is associated with altered
neuroinflammation following traumatic brain injury. Brain Res 1414: 94-105.
BYE N, CARRON S, HAN X, AGYAPOMAA D, NG SY, YAN E, ROSENFELD JV, MORGANTIKOSSMANN MC. Neurogenesis and glial proliferation are stimulated following diffuse traumatic
brain injury in adult rats. J Neurosci Res 89:986–1000.
BYE N, Turnley AM, Morganti-Kossmann M.C. Inflammatory regulators of redirected neural
migration in the injured brain. NeuroSignals 20(3):132-146.
HELEWELL SC. MORGANTI-KOSSMANN MC. Guilty Molecules, Guilty Minds? The Conflicting
Roles of the Innate immune responses to traumatic brain injury? Mediators of Inflammation: Volume
2012:356494.
BYE N, TURNLEY AM, MORGANTI-KOSSMANN MC. Inflammatory regulators of redirected
neural migration in the injured brain. NeuroSignals, 2012;20(3):132-46.
NG SY, SEMPLE BD, MORGANTI-KOSSMAN MC, BYE N. Attenuation of microglial activation
with minocycline is not associated with changes in neurogenesis after focal traumatic brain injury in
adult mice. J Neurotrauma 29:1410-1425.
Presentations:
(as at Sept 2012)
BYE N, ROSENFELD JV, MORGANTI-KOSSMANN MC. Traumatic brain injury stimulates
production of new immature neurons, but their survival may require exogenous neurotrophic support.
Trauma, 2011 November, Melbourne Australia.
HELLEWELL S, YAN E, MORGANTI-KOSSMANN MC. EPO ameliorates axonal damage,
attenuates macrophage infiltration and restores motor function in a combined model of TAI and
hypoxia. 9th World Congress on Brain Injury 2012 March 21-25, Edinburgh, UK.
YAN E, SATGUNASEELAN L, BYE N, ROSENFELD J, MORGANTI-KOSSMANN MC. A
hypoxic insult in patients with traumatic brain injury enhances cerebral inflammatory cytokines, serum
biomarkers and blood-brain barrier dysfunction associated with unfavourable outcome. 9th World
Congress on Brain Injury 2012 March 21-25, Edinburgh, UK.
BYE N, ROSENFELD JV, MORGANTI-KOSSMANN MC. Traumatic brain injury stimulates
production of new immature neurons, but their survival may require exogenous neurotrophic support.
9th World Congress on Brain Injury 2012 March 21-25, Edinburgh, UK.
BYE N, CONQUEST A, ROSENFELD JV, MORGANTI-KOSSMAN MC. Traumatic brain injury
stimulates production of new immature neurons, but their survival may require exogenous neurotrophic
support. Alfred Medical Research and Education Precinct (AMREP).
BYE N. Stimulating neurogenesis to enhance brain repair and neurological function after brain injury.
World Federation for NeuroRehabilitation’s 7th World Congress for Neurorehabilitation, 2012 May
17-19, Melbourne Convention Centre, Melbourne, Australia.