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• Research
• Spinal Cord Injury Projects
• Traumatic Brain Injury Projects
• Targeted Initiatives
• Completed TBI and SCI Projects
  • Assessment & Intervention for Mild TBI
  • Development of EphA4 Peptide Inhibitors for the Treatment of Neurotrauma
  • Novel Sodium Channel Blockers
  • Pilot Project: Enhancing Endogenous Neurogenesis
  • Rehabilitation of Attention following TBI
  • Sleep Health in Tetraplegia
• Program Grants

Pilot Project: Enhancing Endogenous Neurogenesis

Pilot Project: Enhancing Endogenous Neurogenesis as a Potential Therapy Following Traumatic Brain Injury

Chief Investigator: Associate Professor Cristina Morganti-Kossmann
Lead Organisation: Bayside Health
VNI Funding: $164,899
Project Dates: 1 July 2007 - 30 June 2008

Background:
Traumatic brain injury is the major cause of death in the population below the age of 40 years. Approximately 25% of the patients that survive head injury remain with permanent neurological disabilities. At the basis of this disability is the massive loss of brain cells (neurons) that occurs after trauma and the lack of specific therapies to restore the damage. The brain tissue presents a limited capacity to regenerate and replenish the cells that have been lost after injury. Although the brain has historically been considered a non-regenerating tissue, neuroscientists have identified immature cells in normal brain that have the potential to grow and differentiate into functional neurons. This process is defined as neurogenesis. Neurogenesis consists in the proliferation, differentiation and survival, of multipotent progenitor cells localised in specific areas of the brain primarily confined to the subventricular zone (SVZ) surrounding the lateral ventricle, and the subgranular zone (SGZ) of the hippocampal dentate gyrus. The progeny gives rise to both neurons and glia that integrate into existing networks in the olfactory bulb and hippocampus for SVZ and SGZ precursors, respectively. Aims: This study aims to characterise the multiple stages of precursor cell proliferation, migration, survival and differentiation during a time period of 8 weeks using a mouse model of focal TBI. In addition we aim at distinguishing neurogenesis from the proliferation of adult glial cells which become activated in response to brain injury.

Methods:
The mouse model of focal brain injury used in this project has been well established in our laboratory over the past 10 years. This model causes a contusion to the left cortex, with a long term neurological deficit which can be quantified using specific sensorimotor tests. The proliferation of the progenitor cells can be measured by labelling the dividing cells with an injected compound (BrdU) specifically labelling duplicating DNA. The brain sections are then sliced and stained with specific markers for immature and mature neuronal and glial cells in order to identify specific cell type these progenitor cells generate following differentiation. All these cells are then counted under the microscope in order to give a precise time course or proliferation, migration, differentiation and survival over the study period.

Results:
The results of this study demonstrate that TBI induces a substantial increase in proliferation in both neurogenic regions of the brain of the injured left hemisphere as compared to the uninjured side; however, only a proportion of these cells survive to 4 and 8 weeks post-injury. Furthermore, we have shown that at 4 weeks post-CHI ~70% of new cells in the hippocampus are mature neurons, and ~60% in the pericontusional cortex are astrocytes, which is consistent with earlier TBI studies; however, we have also demonstrated that the numbers and phenotype-proportions of these new cells are maintained between 4 and 8 weeks post-injury, which could possibly indicate that the cells persisting to 4 weeks have become functionally integrated, thereby ensuring their ongoing survival.

Conclusions:
The precise characterisation of neurogenesis induced after TBI identifies a window of opportunity for the administration of compounds which could enhance the survival of these new cells and increase the number of cells differentiating into neurons, potentially contributing to augment neurogenesis and improved functional outcome. Further experimental work will be pursued to test some of these neurotrophic molecules in the mouse model of TBI.

Presentations (As of October 2009):

Conferences

CARRON S, BYE N, AGYAPOMAA D, TRAN M, MORGANTI-KOSSMANN MC. Characterisation of neurogenesis following diffuse traumatic brain injury in the adult rat. Australian Neuroscience Society 28th Annual Meeting; 2008 January 27-30, Hobart, Australia. (Oral)

SEMPLE B, BYE N, MALAKOOTI N, ZIEBELL J, KOSSMANN T, MORGANTI-KOSSMANN MC. Monocyte Chemoattractant Protein (MCP-1) in Inflammation following Traumatic Brain Injury (TBI). Australian Neuroscience Society 28th Annual Meeting; 2008 January 27-30, Hobart, Australia. (Oral)

YAN E, SATGUNASEELAN L, NGUYEN P, BYE N, WALKER D, AGYAPOMAA D, ROSENFELD J, SEIFMAN M, KOSSMANN T, MORGANTI-KOSSMAN MC. The effect of posttraumatic hypoxia on neuroinflammation, tryptophan oxidation and melatonin production after traumatic brain injury. Australian Neuroscience Society 28th Annual Meeting; 2008 January 27-30, Hobart, Australia. (Oral)

ZIEBELL J, BYE N, SEMPLE B, MALAKOOTI N, KOSSMANN T, MORGANTI-KOSSMANN MC. Role of Fas ligand and TNF in cell apoptosis following focal traumatic brain injury. Australian Neuroscience Society 28th Annual Meeting; 2008 January 27-30, Hobart, Australia. (Oral)

BYE N, TRAN M, MALAKOOTI N, WOODCOCK T, MORGANTI-KOSSMANN C. Characterising endogenous neurogenesis following experimental focal traumatic brain injury (TBI). Trauma Melbourne 2008 Conference; 2008 21-22nd November, Melbourne, Australia. (Oral)

MORGANTI-KOSSMANN MC. From cell death to neurogenesis: the broad spectrum function of brain inflammation after trauma. Trauma Melbourne 2008 Conference; 2008 November 20-21, Melbourne Australia. (Oral)

BYE N, TRAN M, MALAKOOTI N, WOODCOCK T, MORGANTI-KOSSMANN MC. Characterising endogenous neurogenesis following experimental focal traumatic brain injury. 29th Australian Neuroscience Society Meeting; 2008 Jan-Feb 2009, Canberra, Australia. (Poster)

Education Sessions

BYE N, TRAN M, MALAKOOTI N, WOODCOCK T, MORGANTI-KOSSMANN C. Characterising endogenous neurogenesis following experimental focal traumatic brain injury (TBI). Alfred Week, 20-23rd October 2008, The Alfred Hospital, Melbourne, Australia.