In Vivo Hippocampal Studies in Rats
Longitudinal In Vivo Study of Hippocampal Structure and Function, and
Relationship to Neurocognitive, Neurobehavioral and Epileptic Outcomes, in a
Model of Human Traumatic Brain Injury
Chief Investigators: Associate Professor Terence O’Brien, Dr Damien Myers,
Professor Rod Hicks
Associate Investigators: Associate Professor David Howells, Mr John Williams, Dr
Dennis Velakoulis, Professor Chris Pantelis, Associate Professor Gary Egan, Dr
Stefanie Dedeurwaerdere, Dr Nigel Jones, Associate Professor Edward Hogan, Dr
Peter Batchelor, Dr Bianca Jupp, Dr Ke Fang
Lead Organisation: The University of Melbourne
TAC Neurotrauma Funding: $973,324
Project Dates: 9 October 2006 - 8 October 2009
Background:
Traumatic brain injury (TBI) is a leading cause of death and disability in children and
young adults around the world. Long-term disability following TBI include: cognitive
disabilities such as disorders in attention, memory, learning and executive
functioning; psychiatric and behavioural problems including depression, anxiety,
aggression, agitation and social inappropriateness; and epilepsy. This all comes at
significant cost to the individual, their families and to society because of the health
burden. There are currently no effective interventions to reduce the incidence or
severity of these problems post-TBI. The current study was designed to investigate
the underlying neurobiological processes that lead to these outcomes to facilitate a
more comprehensive approach for the development of new therapeutic strategies.
Aims:
Using an animal model of TBI, we have studied the acute and chronic changes that
occur in the hippocampus and other relevant brain regions, by investigating:
(1) Progressive structural and functional changes with advanced in vivo imaging;
(2) Cognitive, behavioural and epileptic outcomes using defined testing procedures;
and,
(3) The underlying cellular and network changes at post-mortem by histology.
Methods:
We used serial neuroimaging, with small animal MRI (saMRI) and [18F]
fluorodeoxyglucose positron emission tomography (saPET), to investigate progressive
brain atrophy and metabolism changes long-term following experimental TBI in the
rat. These changes were correlated with behavioural, cognitive and epilepsy outcomes
in the rats over the 6 months following the TBI.
Results:
The study demonstrated that morphological and functional changes after TBI are
dynamic and continue to progress and evolve for months. Widespread decreases in
brain functioning on the saPET are seen in specific brain regions, many of which are
remote from the site of direct trauma and unaccompanied by signs of injury on the
MRI. The hippocampus, a brain structure critical to memory and emotion, is the key
area of these changes. The severity of the neurological deficits and changes on MRI
soon after the injury are predictive of severity of these long-term neurodegenerative
changes. TBI rats showed increased anxiety behaviour and decreased cognitive
performance, indicating that these psychiatric outcomes in at least part have a
neurological basis. Furthermore approximately 30% of the rats had developed
evidence of epilepsy by 6 months.
Conclusion:
The findings of this study indicate that secondary structural and functional changes in
the brain continue to occur for many months post-TBI, which has implications for
understanding the pathophysiology and evolution of the long-term neurological and
psychiatric consequences. Importantly, this indicates that there is a time-window in
which intervention could modulate these processes and mitigate against these
disabling consequences of TBI. This study has provided a practical paradigm for
testing the biological effectiveness of potential therapies prior to embarking on
expensive and lengthy clinical trials.
Publications:
JONES NC, CARDAMONE L, WILLIAMS J, SALZBERG MR, MYERS DE, O’BRIEN TJ.
Experimental traumatic brain injury induces a pervasive hyperanxious phenotype in rats. J
Neurotrauma. 2008;25:1367-1374.
JONES NC, SALZBERG MR, KUMAR G, COUPER A, MORRIS MJ, O'BRIEN TJ. Elevated anxiety
and depressive-like behavior in a rat model of genetic generalized epilepsy suggesting common
causation. Experimental Neurology. 2008;209(1):254-260.
BOUILLERET V, CARDAMONE L, LIU YR, FANG K, MYERS DE, O’BRIEN TJ. Progressive
brain changes on serial manganese-enhanced MRI following traumatic brain injury in the rat. J
Neurotrauma. 2009;26:1-15.
BOUILLERET V, HOGAN RE, VELAKOULIS D, SALZBERG M, WANG L, EGAN G, O'BRIEN
TJ, JONES NC. Morphometric abnormalities and hyperanxiety in Genetically Epileptic Rats: a model
of psychiatric co-morbidity? Neuroimage. 2009;45:267-274.
HOGAN RE, BOUILLERET V, RUI LIU Y, WANG L, WILLIAMS JP, JUPP B, MYERS D,
O’BRIEN TJ. MRI-based Large Deformation High Dimensional Mapping of the Hippocampus in Rats:
Development and Validation of the Technique. Journal of Magnetic Resonance Imaging.
2009;29(5):1027-34.
LIU YR, CARDAMONE L, HOGAN RE, GREGOIRE MC, WILLIAMS JP, HICKS RJ, BINNS D,
KOE A, JONES NC, MYERS DE, O’BRIEN TJ, BOUILLERET V. Progressive metabolic and
structural cerebral perturbations following traumatic brain injury: an in vivo imaging study in the rat.
Journal of Nuclear Medicine. 2010;51:1788-1795.
Presentations:
JONES NC, CARDAMONE L, WILLIAMS JP, SALZBERG MR, MYERS DE, O’BRIEN TJ.
Increased anxiety-like behaviour in a rat model of traumatic brain injury. Epilepsy Society of Australia
22nd Annual Scientific Meeting; 2007 November 7-9, Adelaide, Australia.
CARDAMONE L, LIU YR, WILLIAMS JP, MYERS DE, O’BRIEN TJ. Longitudinal diffusionweighted imaging following traumatic brain injury in the rat. Australian and NZ Association of
Neurologists; 2008 May 19-23, Brisbane, Australia.
LIU YR, CARDAMONE L, WILLIAMS J, JUPP B, DEDEURWAERDERE S, BOUILLERET V,
VELAKOULIS D, HOGAN RE, O'BRIEN TJ, MYERS D. Morphometric measures of structural brain
changes in a rat model of closed-head traumatic brain injury. Australian Neuroscience Society; 2008
January 27-30, Hobart, Australia.
JONES NC, CARDAMONE L, WILLIAMS J, SALZBERG MR, MYERS D, O’BRIEN TJ. Persistent
increased anxiety-like behaviour following experimental traumatic brain injury in the rat. Society for
Neuroscience; 2008, USA.
BOUILLERET V, CARDAMONE L, FANG KE, MYERS DE, O'BRIEN TJ. Longitudinal diffusionweighted imaging following traumatic brain injury in the rat. Trauma Melbourne; 2008 November 2122, Melbourne, Australia.
KOE AS, JONES NC, CARDAMONE L, WILLIAMS J, SALZBERG MR, MYERS DE, O'BRIEN
TJ. Increased anxiety-like behaviour in a rat model of traumatic brain injury. Trauma Melbourne; 2008
November 21-22, Melbourne, Australia.
JONES C, CARDAMONE L, WILLIAMS J, SALZBURG M, MYERS D & O'BRIEN T. Increased
anxiety-like behaviour in a rat model of traumatic brain injury Australian Neuroscience Society AGM;
2008 January, Hobart, Australia.
CARDAMONE L, LIU YR, WILLIAMS JP, MYERS DE, O’BRIEN TJ. Longitudinal diffusionweighted imaging following traumatic brain injury in the rat. Trauma Melbourne; 2008 November 2122, Melbourne, Australia.
LIU YR, CARDAMONE L, FANG K, BOUILLERET V, MYERS DE, O'BRIEN TJ. Detection of
functional and structural brain changes by serial manganese-enhanced MRI acquisition following
traumatic brain injury in the rat. Trauma Melbourne; 2008 November 21-22, Melbourne, Australia.
MYERS DE, RYAN CG, KIRKHAM R, PATERSON D, MOORHEAD G, DUNN PA, SIDDONS
DP, DE JONGE MD, HOWARD D, DE GERONIMO G, ALTISSIMO M, O’BRIEN TJ,
STEVENSON AW, MAYO S, WILKINS S. X-ray Fluorescence Microscopy of brain slices: Spatial
mapping of metal elements for the study of neurodegenerative diseases at the Australian Synchrotron.
Trauma Melbourne; 2009 November 20-21, Melbourne, Australia.
BOUILLERET V, CARDAMONE L, LIU YR, KOE AS, FANG K, WILLIAMS JP, MYERS DE,
O’BRIEN TJ, JONES NC. Confounding neurodegenerative effects of manganese for in-vivo MR
imaging in rat models of brain insults. NeuroImage. 2009; in press.
MYERS DE. Delving the neuronal network in focal epilepsies: Application of advanced imaging
techniques to study animal models of TLE. 3rd Excitable Cells Conference, Melbourne Museum; 2009
June 18-19, Melbourne, Australia.
BOUILLERET V, CARDAMONE L, LIU YR, KOE SA, MYERS DE, O'BRIEN TJ. Progressive
functional and structural brain changes on serial manganese-enhanced MRI acquisition following
traumatic brain injury in the rat. International Epilepsy Congress; 2009 June 28- July 2, Budapest,
Hungary.
GAN K, LIU Y, CARDAMONE L, JONES NC, BOUILLERET V, O’BRIEN TJ, MYERS D.
Hippocampal neuroplasticity in traumatic brain injury: Relationship to post-traumatic epilepsy.
Australian Neuroscience Society; 2009 January 27-30, Canberra, Australia.
JONES NC, CARDAMONE L, BOUILLERET V, LIU YR, KOE AS, FANG K, WILLIAMS JP,
MYERS DE, O’BRIEN TJ. Confounding neurodegenerative effects of manganese for in-vivo MR
imaging in rat models of brain insults. Trauma Melbourne; 2009 November 20-21, Melbourne,
Australia.
CARDAMONE L, LIU Y, HOGAN RE, GREGOIRE M-C, WILLIAMS JP, HICKS RJ, BINNS D,
KOE AS, JONES NC, MYERS DE, O’BRIEN TJ, BOUILLERET V. Progressive structural and
functional cerebral changes in a small animal model of closed-head traumatic brain injury. Trauma
Melbourne; 2009 November 20-21, Melbourne, Australia.
JONES NC, CARDAMONE L, WILLIAMS JP, SALZBERG MR, MYERS DE, O’BRIEN TJ.
Persistent increased anxiety-like behaviour following experimental traumatic brain injury in the rat.
Society for Neuroscience; 2009 October 18-21, Chicago, USA.
JONES NC, CARDAMONE L, BOUILLERET V, LIU YR, KOE A, FANG K, WILLIAMS JP,
MYERS DE, O’BRIEN TJ. Confounding neurodegenerative effects of manganese for in-vivo MR
imaging in rat models of brain insults. Australian Neuroscience Society; 2010 January 31-February 3,
Sydney, Australia.
MYERS DE, RYAN CG, KIRKHAM R, CARDAMONE L, PATERSON D, ALTISSIMO M,
O'BRIEN TJ, JONES NC, MOORHEAD G. Synchrotron X-ray fluorescence microscopy: High
definition mapping of trace metal elements in the hippocampus in a model of closed-head traumatic
brain injury. Australian Neuroscience Society; 2010 January 31-February 3, Sydney, Australia.
MYERS DE, RYAN CG, KIRKHAM R, PATERSON D, MOORHEAD G, DUNN PA, SIDDONS
DP, DE JONGE MD, HOWARD D, DE GERONIMO G, ALTISSIMO M, O’BRIEN TJ,
CARDAMONE L, STEVENSON AW, MAYO S, WILKINS S. High-definition mapping of trace
metal elements in the hippocampus in a model of closed-head traumatic brain injury. 10th International
Conference on Biology and Synchrotron Radiation and 6th International Workshop on Medical
Applications of Synchrotron Radiation; 2010 February 15-18, Melbourne, Australia.
CARDAMONE L, LIU YR, HOGAN RE, GREGOIRE MC, WILLIAMS JP, HICKS RJ, JONES NC,
MYERS DE, BOUILLERET V, O'BRIEN TJ. Progressive structural and functional cerebral changes
following traumatic brain injury in the rat. Australian Neuroscience Society; 2010 January 31-February
3, Sydney, Australia.
Awards:
Trauma Melbourne 2009 Oral Presentation Award, Senior Investigator: Dr Damien
Myers
Free Paper 1.6 High-definition mapping of trace metal elements in the hippocampus
in a model of closed-head traumatic brain injury
Additional Grants:
Australian Synchrotron Beam Time Proposal AS-2010/1 #2332: Trace metal element
changes in the brain in a small animal model of closed-head traumatic brain injury.
The project will be undertaken on the X-ray Fluorescence Microscopy (XFM)
Beamline.