Page 128 - NNS 2014 Program & Abstract Book

Miniature swine were subjected to the RAI model of TBI and
compared to shams. IHC was performed specific for SNTF, as well as
the amyloid precursor protein (APP), the current gold-standard for
identifying axonal pathology. Double fluorescent labelling was per-
formed to determine co-localization. In parallel, IHC was performed
on cases of single human TBI (survival < 7 d; n = 17) versus age-
matched controls (n = 16) from the Glasgow TBI Archive.
Following both swine RAI and human TBI, SNTF reactive axons
were observed acutely (6 h) and up to 3 days post-injury. SNTF
positive axons appeared as multiple accumulations like ‘‘beads on a
string’’, potentially indicating degeneration. However, these axons
were of relatively normal diameter versus the greatly swollen APP-
reactive axons indicative of transport interruption. Interestingly, even
at 3 days post injury, there was a distinct subset of SNTF axons that
were APP negative.
Here we show that SNTF mTBI biomarker findings have a bio-
logically plausible pathological correlate. Moreover, SNTF IHC may
elucidate a previously unidentified subpopulation of injured axons
undergoing degeneration by a novel mechanism independent of
transport interruption. This observation may identify an important
therapeutic target in TBI, as well as a novel approach to the com-
prehensive neuropathological analyses of DAI.
Key words
alpha-II spectrin N-terminal fragment, diffuse axonal injury, mild
TBI, rotational acceleration
C3-20
TOLL-LIKE RECEPTOR 4 MEDIATES POST-TRAUMATIC
CHANGES TO THE CIRCADIAN CLOCK
Shields, J.S., Dhandapani, K.M.
Medical College of Georgia, Georgia Regents University, Augusta,
GA
Traumatic brain injury (TBI) is a leading cause of death and
disability. About 2% of the population currently lives with the
long-term consequences of TBI. In particular, 46% of patients are
diagnosed with depression in the 12 months following injury,
making it the most commonly diagnosed neuropsychological ill-
ness after TBI. Despite the high comorbidity between TBI and
depression, the relationship between them remains unclear. Cir-
cadian rhythms are disrupted in TBI patients and have been im-
plicated in the pathology of depression. These rhythms are created
by oscillating molecular patterns and are particularly susceptible to
immune activation, such that occurs after TBI. Previous work from
our lab shows that the innate immune receptor, Toll-like receptor 4
(TLR4) is activated after TBI and inhibition of TLR4 reduced
neuroinflammation and secondary injury. We hypothesize that ac-
tivation of TLR4 after TBI disrupts the molecular clock and con-
tributes to depressive behavior. Using a mouse model of TBI, we
found that gene expression patterns of multiple components of the
molecular clock are decreased 72 hours after injury. This disruption
is temporally correlated with increased depressive phenotype, as
assessed by the open field test and tail suspension test. TLR4
knockout animals do not exhibit post-traumatic gene changes in
molecular clock components and have an attenuated depressive
phenotype. These data indicate that circadian changes after TBI are
mediated at least in part by TLR4 activation and may contribute to
depressive phenotypes.
Key words
circadian, inflammation, microglia, neurobehavioral outcomes
C3-21
APOE INFLUENCE ON DENDRITIC SPINE LEVELS FOL-
LOWING MILD TRAUMATIC BRAIN INJURY
Winston, C.N., Parasadanian, M., Barton, D.J., Neustadtl, A., Zapple,
D., Burns, M.P.
Georgetown University, Department of Neuroscience, Washington,
DC, USA
Dendritic spine loss is an early consequence of traumatic brain injury
(TBI). Spine loss could potentially explain why patients report a va-
riety of symptoms after injury. Genetic predisposition has also been
shown to influence severity and recovery following TBI. The apoE4
allele is synonymous with poorer recovery and death after TBI; the
incidence of this gene is increased in those who suffer from Chronic
Traumatic Encephalopathy (CTE); and a growing number of studies
have associated the detrimental effects of apoE4 with facilitating a
more pro-inflammatory state in the brain. The mechanism by which
apoE isoforms differentially influence recovery and inflammatory
status is not well understood. Here, we wanted to determine the role of
APOE genotype on dendritic spine levels and inflammation, following
single and repeat mTBI. We administered a midline, close-head im-
pact to adult APOE3 and APOE4 targeted-replacement (TR) mice and
visualized neurons and dendritic spines 24 h post injury using Golgi
stain. All mice present with no evidence of cell loss or neuroin-
flammation after a single mTBI; however mTBI caused a 12.4% de-
crease in dendritic spine number on apical oblique (AO) dendrites in
layer II/III of injured APOE3 mice. In contrast, mTBI caused a 15.4%
increase in dendritic spine number on AO dendrites in layer II/III of
injured APOE4 mice. After repeat mTBI (single injury, 30 days),
spine levels returned to baseline in injured APOE3 mice, however
spine levels remained elevated in injured APOE4 mice. We also found
that injured APOE3 mice had an average reflex return time of 105s
following single and repeat mTBI. Interestingly, injured APOE4 mice
had an average reflex return time of 71s after single mTBI, yet fol-
lowing repeat mTBI, average reflex return time wasn’t significantly
different from sham APOE4 mice (51s). Injured APOE4 mice dis-
played more white matter inflammation and damage of the optic tract,
compared to injured APOE3 mice, which persisted up to two months
following the final impact. Here, our findings demonstrate that APOE
genotype differentially influences dendritic spine levels, reflex return
time, and promote a pro-inflammatory state in the brain following
mTBI.
Key words
ApoE genotype, dendritic spines, repeat mTBI
C3-22
ALTERED NEUROGENESIS FOLLOWING A FLUID PER-
CUSSION INJURY IN MICE
Shapiro, L.A.1–3, Huang, J.H.2
1Texas A&M University HSC College of Medicine, Temple, USA
2Baylor Scott & White Health Care, Temple, USA
3Central Texas Veterans Health Care System, Temple, USA
Neurogenesis persists in the hippocampus and subventricular zone
throughout the lifespan of rodents. Neurons born in the subventricular
zone migrate via the rostral migratory stream (RMS), primarily to the
olfactory bulbs, and to other olfactory structures. In the hippocampus,
progenitor cells in the sub-granular zone give rise to newborn granule
cells that can become functionally integrated into the granule cell
A-96