1. Concomitant Increase in Cognitive Behavioral Deficits and White Matter Injury Markers Gee
CUBS
~GBover Time in a Gyrencephalic Animal Model of Traumatic Brain Injury
*S.C. Schwerin1·3 , E. Hutchinson3, K. Radomski1 , K. Ngalula1 , C. Pierpaoli3, S.L. Juliano1·2
(~tCNRM1. Anatomy, Physiology & Genetics, 2. Neuroscience, Uniformed Services University of Health Sciences, Bethesda, MD, USA,
3. National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD CENTER FOR NEUROSCIENCE ANO REGENERATIVE MEDICINE
INTRODUCTION
Rodent models of traumatic brain injury (TBI) provide
important insight into the mechanisms of damage and
plasticity following injury. However their low relative
volume of white matter and their lissencephalic cortex
reduce the direct relevance to human pathology.
The ferret is an important animal for TBI research
because it is the smallest mammal with a convoluted
cortex and a ratio of white to gray matter comparable to
humans. In this longitudinal study, we investigated
immunohistochemistry, imaging markers, and behavioral
performance following CCI.
Merits of a Ferret Model of TBI:
High white to gray matter ratio
Complex gyral folding (gyrencephalic)
Mammal with body size compatible
with small animal MRI scanners
Cost effective compared to larger
gyrencephalic animals
Amenable to behavioral testing
Hippocampal location similar to
humans
METHODS
Ferrets: mustela putorius furo
-1.Skg, 6-9 month old adult males
•3 Control (surgically narve)
•3 One Day Survival (1 DPI)
•2 One Week Survival (1WPI)
•2 Four Week Survival (4WPI)
•1 Sixteen Week Survival (16WPI)
CCI Injury Parameters:
•Velocity: 5 m/s
•Depth of Impact: 2 mm
•Dwell time: 100 ms
•Impactor perpendicular to
cortex -20-30°
•Impactor diameter: 3 mm
MRI: Baseline,1DPl, 1WPI, 4WPI, 16WPI, ex vivo
T2W RARE scans (TE=12ms, TR=10 s),0.5 mm isotropic voxels
DTI TE/TR=40/5000ms, 0.75x0.75x0.5 mm voxels, b=700 and
1000 s/mm2 with 30 directions, TORTOISE processing.
]
lmmuno: GFAP (Abeam, ab4674, chicken, 1:500)
IBA1 (Wako, 019-19741, rabbit, 1:1000)
CP-13 (Dan Perl, mouse, 1:300)
DAPI (Sigma-Aldrich, D9542, 1:2000)
RESULTS
CONCLUSIONS
•In-vivo T2 and DTI were abnormal at each time point with T2 hyperintenslty near the CCI site, increased diffusivity and
decreased FA at earlier time points normalized by 4 weeks.
•Ex-vivo DTI also detected abnormalities of increased Trace colocalized with glial reactivity in the white matter and
subtle disruption of cortical laminar structure near the CCI site. Ex-vivo markers were more subtle than in-vivo
changes, highlighting the importance of physiological contributions to DTI and T2.
•Histology showed chronic reactive gliosis extending up to 2mm away from the injury epicenter. The density and
hypertrophy of reactive astrocytes (GFAP+) and activated microglia (lba1+) were most abundant in the subcortlcal
white matter 4 WPI, but remained elevated up to 16 WPI. At 4 WPI we also observed an upregulation of p-tau in the
upper cortical layers within the perilesional astrocytic gliosis.
•Animals displayed difficulty performing the Tmaze test at all time-points after injury, which could indicate an
impairment in short term memory, or cognitive inflexibility, whereas a mild motor impairment resolved by 1WPI.
•This gyrencephalic animal model of TBI demonstrated an evolution correlating with impaired cognitive
function and an increase in injury markers in white matter, strengthening its translational capabilities.
ACKNOWLEDGEMENTS:
•This work was supported by CDMRP grant: 306498-1-00-64056
•Special thanks to LAM surgery personnel, to the USUHS animal MRI personnel, to Aminat Lola Imam-Fulani for assistance with behavioral testing.

2. The views presented here are those of the author and are not to be construed as official or
reflecting the views of the Uniformed Services University of the Health Sciences, the
Department of Defense or the U.S. Government.