Page 158 - NNS 2014 Program & Abstract Book

CHIMERA is distinct from existing rodent neurotrauma models in
that it uses a completely non-surgical procedure to precisely deliver
impacts of defined dynamic characteristics to intact animal head while
allowing unconstrained head movement.
In this study we characterized the acute neuropathological and
biochemical outcomes of repeated TBI (rTBI) in mice using CHI-
MERA.
Male, wild-type mice were subjected to two closed-head impacts
spaced at 24 h. Microglial response was assessed by Iba-1 immuno-
histochemistry while axonal injury was assessed by silver staining at
48 h post-rTBI. Protein levels of TNFa and IL-1b were measured at 6,
12 and 48 h post-rTBI using ELISA. Endogenous total and phos-
phorylated tau levels were assessed at 6, 12 and 48 h post-rTBI using
Western blotting.
Injured brains showed significant widespread microglial activation
in white matter as well as diffuse axonal injury (DAI) at 48 h post-
rTBI. Protein levels of TNFa and IL-1b showed *1.7- and 2-fold
increase, respectively at 48 h following rTBI. Injured brains also
showed *1.5 to 3.5-fold increase in the levels of phosphorylated tau
protein, peaking at 12 h following rTBI.
CHIMERA is a simple and reliable model of murine TBI that
replicates several aspects of human TBI such as neuroinflammation,
DAI as well as tau hyperphosphorylation.
Key words
microglial activation, muse closed-head injury model, tau phosphor-
ylation
D2-37
BIOMECHANICAL AND FUNCTIONAL CHARACTERIZA-
TION OF CHIMERA: A NOVEL CLOSED-HEAD IMPACT
MODEL OF ENGINEERED ROTATIONAL ACCELERATION
Cheng, W.H.1, Namjoshi, D.R.1, McInnes, K.2, Cripton, P.A.2,
Wellington, C.L.1
1Department of Pathology and Laboratory Medicine, University of
British Columbia, Vancouver, Canada
2Departments of Mechanical Engineering and Orthopaedics, Uni-
versity of British Columbia, Vancouver, Canada
Traumatic brain injury (TBI) is a leading cause of death and dis-
abilities. A major challenge in TBI research is that many common
experimental models do not faithfully replicate the biomechanical
aspects of TBI in real-life. To address this issue, we have developed a
novel rodent TBI model with high precision, reliability and translat-
ability, called CHIMERA (Closed-Head Impact Model of Engineered
Rotational Acceleration). It is distinct from existing models in that it
delivers precise impact to the intact head in a non-surgical procedure,
and allows unrestrained head movement.
In this study we characterized the biomechanical and acute func-
tional outcomes of repetitive TBI using CHIMERA.
Two TBI at 0.5 J impact energy were induced to adult C57Bl/6
mice at 24 h apart. Head kinematics were assessed using high-speed
videography (5000 fps). Post-injury neurological outcomes, motor
function, and anxiety-like behavior were assessed by loss of righting
reflex duration (immediately post-injury), neurological severity score
(1 h, 24 h, 48 h), falling latency from accelerating Rotarod (24 h, 48 h)
and open-field thigmotaxis (24 h), respectively.
Head kinematic analysis showed a peak linear displacement of
49.6 – 3.5 mm, and a peak angular deflection of 2.6 – 0.28 rad. Peak
linear and angular velocities were 6.6 – 0.8 m/s and 305.8 – 73.7 rad/s,
respectively. The head experienced peak linear and angular acceler-
ations of 385.1 – 52 g and 253.6 – 69.0 krad/s2, respectively. Injured
mice showed significantly prolonged loss of righting reflex, displayed
neurological and motor deficits, and anxiety-like behavior. CHI-
MERA is a simple, reliable model of TBI that offers integration of
biomechanics and functional assessment.
Key words
behavior study, biomechanics, head kinematics, mouse closed-head
injury model
D2-38
LONGITUDINAL EVALUATION OF HISTOLOGICAL AND
NEUROBEHAVIORAL CHANGES IN A MOUSE MODEL OF
R-MTBI: A FOLLOW UP AT 2 YEARS POST INJURY
Mouzon, B.1,2 , Bachmeier, C.1,2, Olubunmi, J.1 , Acker, C.3,
Ferguson, S.1,2, Crynen, G.1 , Davies, P.3 , Mullan, M.1,2 , Stewart,
W.4 , Crawford, F.1,2
1Roskamp Institute, Sarasota, USA
2James A. Haley Veterans’ Hospital, Tampa, USA
3Feinstein Institute for Medical Research, Manhasset, USA
4Southern General Hospital, Glasgow, UK
The mechanisms contributing to TBI-induced neurodegeneration are
unknown and few studies have investigated the long-term impact of
mTBI on neurobehavioral outcome.
Animals were subjected to a single exposure of anesthesia, repeated
anesthetic exposure, a single closed head injury, or 5 repetitive injuries,
1 every 48 hours (r-mTBI). Cognitive function was evaluated at 24
months postinjury/anesthesia using the Barnes maze. Sections were
stained with LFB/CV using standard histological protocols. Sets of
adjacent sections were stained for GFAP, Iba-1, CD45, APP and a panel
of various tau antibodies. For tau biochemistry, tissue homogenates
were coded and sent to Dr. Davies for blinded quantitative assessments.
Consistent with our earlier observations, the performances in the
Barnes maze of the sham and s-mTBI were similar, while the cu-
mulative distance to the target hole for the r-mTBI was approximately
twice that of the other groups. Continuing white matter degradation
accompanied by a significant increase in levels of GFAP, Iba1, and
CD45 was observed in the corpus callosum of the animals exposed to
r-mTBI. No change in soluble cortical/hippocampal Tau was observed
between injured or sham animals at 24 months post injury.
These data provide evidence that, whilst a single mTBI produces a
clinical syndrome which remains static in the period following injury,
repetitive injuries produce behavioral changes that continue to evolve
many months after the initial trauma. Neither single nor repetitive
mTBI were associated with elevated brain levels of abnormal tau
phosphorylation at 24 months post mTBI. In this model, progressive
neuroinflammation rather than tau pathology appear to be the driving
factor and contribute to the neurobehavioral deficits observed.
Key words
behavior, repetitive mild TBI, tau
A-126