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Brains were collected 7 days post-injury. In this interim analysis,
neuroblast density was greater in the rostral gyrus gray matter in
injured piglets with no effect on BrdU
+
or BrdU
+
/doublecortin
+
(DCX) cells. In rostral gyrus white matter, the density of neuroblasts
was not different from shams and the response was highly variable
among injured piglets, ranging from increased neuroblast density
adjacent to the lesion to a lower density than sham piglets. The density
of BrdU
+
/DCX
+
cells was greater in rostral gyrus white matter, but
comprised only 1% of DCX
+
cells. Neuroblast density in the insular
cortex was not different from shams, but was four-fold greater than
the rostral gyrus, indicating that migration to this region may still be
prioritized. In conclusion, we have observed a modest increase in
neuroblast density in the injured rostral gyrus comprised of existing
neuroblasts, which was highly variable. Future work will aim to de-
termine the factors that result in targeting to the lesion vs. the potential
re-routing of neuroblasts away from the lesion site and investigate the
consequences of neuroblasts targeting white matter lesions, which
may lead to further complications such as post-traumatic epilepsy.
The immature piglet brain is a helpful model of children where re-
sponse to injury is diverse and efforts to repair lesioned tissue may
contribute to post-TBI sequelae.
Keywords: Pediatric TBI, Neurogenesis, Cortical Impact, Swine
A8-05
SPECIFIC MODES OF REMYELINATION ARE ASSOCIATED
WITH IMPROVED BEHAVIORAL OUTCOMES AFTER
CONTROLLED CORTICAL IMPACT
Margalit Haber, Justine Kim, Jessica James, Albana Ramadani,
Michael Sangobowale,
Peter Bergold
State University of New York-Downstate Medical Center, Physiology
and Pharmacology, New York, USA
Damaged white matter in rats does not remyelinate after mild con-
trolled cortical impact (mCCI). Treatment with minocycline (MINO)
plus N-acetylcysteine (NAC) or MINO alone did remyelinate white
matter damaged by mCCI. Using specific antigenic markers, we ex-
amined the fate of oligodendrocytes and oligodendrocyte precursor
cells (OPCs) in the corpus callosum at times of demyelination and
remyelination. During demyelination in rats treated with MINO alone,
resident oligodendrocytes became apoptotic and OPC number in-
creased at the injury site. At times of remyelination, OPCs differen-
tiated into myelinating oligodendrocytes. In contrast, during
demyelination in rats treated with MINO plus NAC, resident oligo-
dendrocytes were retained and OPC proliferation suppressed. These
data suggest that remyelination was mediated by OPCs after treatment
with MINO, but by resident oligodendrocytes after treatment with
MINO plus NAC. Injured rats treated with NAC alone showed no
signs of remyelination. These data strongly suggest that the differ-
ences between MINO- and MINO plus NAC-mediated remyelination
resulted from drug synergy between MINO and NAC.
After mCCI, MINO plus NAC-treated rats have a better functional
recovery than rats treated with MINO alone. Injured rats treated with
MINO or NAC alone were unable to acquire a shock zone location
during a spaced version of the active place avoidance task that utilized
a 24-hour intertrial interval. In contrast, MINO plus NAC-treated rats
both acquired and retained spaced active place avoidance. Acquisition
of active place avoidance requires midline white matter tracts to
function properly. Thus, the repair of white matter by MINO plus
NAC may result in greater recovery of brain function following
traumatic injury than seen with MINO alone.
Keywords: remyelination, repair, drug synergy, off label drug use,
memory
A8-06
GOLLI-MYELIN BASIC PROTEIN IS REQUIRED FOR MA-
TURATION OF OLIGODENDROCYTE PROGENITORS AND
REMYELINATION OF CONTUSED SPINAL CORDS
Duane Oswald
, Sarmistha Mazumder, Choonghyo Kim, Laura
Ngwenya, H. Francis Farhadi
The Ohio State University Medical Center, Neurosurgery, Columbus,
USA
The Golli-Myelin Basic Protein (Golli-MBP) is a transcriptional chi-
mera, consisting of 5
¢
Golli-specific, and shared 3
¢
MBP exons, whose
exact function remains elusive. Quantitative RT-PCR confirmed that in
M3 enhancer knock-out mice (M3KO), Golli-MBP RNA expression is
reduced 5-fold, displaying no phenotypic abnormalities in developing
nor adult mice. However, ES cells derived from M3KO, compared to
wild-type (WT) mice, were unable to mature into oligodendrocyte
progenitor cells (OPCs) in the presence of neither platelet-derived
growth factor (PDGF) nor fibroblast growth factor (bFGF). To test for
the physiological implications of OPC dismaturation, WT and M3KO
mouse spinal cords were contused (90 kD force), and dissected from the
animals for analysis. One week post-injury, M3KO spinal cords ex-
hibited areas of continued demyelination and severely reduced re-
myelination, while remyelination in WT mice was more robust. Using
Basso Mouse Scale hindlimb assessments, injured M3KO recovery was
significantly lower and delayed, compared to WT up to 6 weeks
(p
<
0.05). Phospho-Receptor Tyrosine Kinase protein microarrays,
probed using extractions fromWT and M3KO spinal cords, showed that
a
PDGF and FGF3 receptor activation was reduced by 84.3% and 176%,
respectively, in the M3KO mice at 24 hours. From these data, we
hypothesized that spinal cord M3KO OPC proliferation and differen-
tiation would also be retarded
in vivo
as compared to WT. Im-
munohistochemistry of WT and M3KO mouse spinal cords confirmed
this. Staining for the proliferation marker, Ki67, showed that 12.4% of
cells in WT spinal cords, 1 week post-injury at 1mm rostral from the
epicenter, were pro-proliferative, as compared to 4.7% in M3KO
(p
<
0.009). Additionally, there was a significant reduction of NG2
+
OPCs in 1 week, post-contused spinal cords at 2mm rostral (WT: 3728,
M3KO: 1867, p
<
0.05), 1mm caudal (WT: 2472, M3KO: 1000,
p
<
0.02), and 2mm caudal (WT: 2216, M3KO: 1173, p
<
0.004). These
data show that functional Golli-MBP is required for the rapid prolif-
eration and differentiation of OPCs after contusional spinal cord injury.
Keywords: Remyelination, Golli-Myelin Basic Protein, Oligoden-
drocyte Progenitor, Cell Differentiation
A8-07
EXAMINING THE TIME-COURSE OF D-CYCLOSERINE
ADMINISTRATION IN DEVELOPING RATS FOLLOWING
LATERAL FLUID PERCUSSIVE INJURY
Andrew Segal
1,2
, C.C. Giza
1–3
, Yan Cai
1,2
, D.A. Hovda
1,2
1
UCLA, Brain Injury Research Center, Los Angeles, USA
2
David Geffen School of Medicine, Neurosurgery, Los Angeles, USA
3
David Geffen School of Medicine, Pediatrics, Los Angeles, USA
This study examined the effects of D-cycloserine (DCS) administration
on N-methyl-D-aspartate (NMDA) receptor mediated signaling in the
subacute injury phase following severe lateral fluid percussive injury
(LFPI) on postnatal day 19 (P19) rats. DCS is a partial agonist at the
NMDAR glycine-binding site, and has been investigated as a potential
therapeutic approach to cognitive dysfunction following TBI in the adult,
but not the juvenile, rat. P19 rats underwent LFPI and received 5 DCS
doses (30mg/kg; 0.25ml/kg) every 12 hours starting 24 hours post-injury,
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