Page 132 - NNS 2014 Program & Abstract Book

5Washington University School of Medicine, The Hope Center for
Neurological Disorders, St. Louis, USA
Subarachnoid hemorrhage (SAH) from the rupture of an intracranial
aneurysm shares key mechanical features with traumatic brain injury
(TBI), including exposure to a sudden, global pressure wave generated by
the arterial jet. It might, therefore, be anticipated that the diffuse me-
chanical injury of axons central to TBI pathophysiology is also an im-
portant component of injury after SAH. Elucidating these connections
may lead to novel treatment approaches to both conditions. We undertook
a parallel diffusion tensor imaging (DTI) and histopathology study to
understand the extent of axonal injury following SAH in a mouse model.
We quantitatively compared changes in white matter anisotropy indica-
tive of axonal integrity to histological and ultrastructural evidence of
axonal injury from the same tissue. DTI reveals a significant decrement in
relative anisotropy in white matter regions close to the site of arterial
rupture, with smaller reductions observed in more distant white matter
structures. Histological analysis reveals multifocal axonal injury in a large
halo surrounding the focus of bleeding. Correlation with behavioral tests
suggests that axonal injury may underlie functional deficits observed after
SAH. DTI analysis of human patients with SAH reveals similar decre-
ments in anisotropy. These investigations reveal that axonal injury is a
feature of brain injury following SAH, and suggest that similar patho-
physiological processes may contribute to human disease. Further anal-
ysis of this phenomenon may further illuminate the processes underlying
cerebral injury from SAH and TBI, provide new prognostic indicators,
and suggest novel treatment modalities for this devastating condition.
Key words
subarachnoid hemorrhage
C3-31
GENE NETWORKS ANALYSIS TO ELUCIDATE THE COM-
PLEXITY OF TBI
Meng, Q.C.3 , Agrawal, R.3 , Yang, X.3, Gomez-Pinilla, F.1–3
1UCLA Brain Injury Research Center, Los Angeles, USA
2University of California Los Angeles, Dept. of Neurosurgery, Los
Angeles, USA
3University of California Los Angeles, Dept. of Integrative Biology
and Physiology, Los Angeles, USA
The lack of a comprehensive mechanistic understanding of the com-
plexity of TBI pathology likely explains the poor outcomes of current
therapeutics. We carried out a systems biology study to address these
challenges using state-of-the art methodologies that can capture the
tremendous genomic variability inherent to TBI. The unique aspect of
our approach is to determine the effects of TBI on interaction of genes
within a genome-wide scale to grasp the whole dimension of the pa-
thology. We used next generation sequencing and integrative genomics
analyses to determine how TBI affects gene networks that could char-
acterize main events in the TBI pathology. We report that moderate fluid
percussion injury (FPI) engages the action of master genes such as
Anxa2 and Ogn to coordinate the function of hundreds of genes in the
network. Increasing evidence indicates that TBI poses risks for neuro-
logical disorders such as Alzheimer’s disease, and psychiatric disorders.
We report that gene network reorganization in our rodent model of TBI
overlaps with existing human libraries of gene-wide association studies
(GWAS) for brain disorders such as Alzheimer’s disease, bipolar dis-
order, autism, etc. These results reveal mechanistic information how TBI
impacts specific gene networks which confer vulnerability to neuro-
psychiatric disorders. We also show that the broad spectrum of action of
dietary docosahexaenoic acid (DHA) is instrumental to counteract TBI
pathology by restoring gene network reorganization. These studies may
set basis for development of network-based medicine, a new line of
therapeutic strategy, to improve TBI outcome and prevent TBI-associ-
ated brain disorders (supported by NIH R01NS50461).
Key words
epigenetic, gene networks, genomic, GWAS
C3-32
DISRUPTION OF AUTOPHAGY AFTER TBI IS ASSOCIATED
WITH LYSOSOMAL DYSFUNCTION AND NEURONAL
CELL DEATH
Sarkar, C., Zhao, Z., Aungst, S., Sabirzhanov, B., Faden, A.I.,
Lipinski, M.M.
University of Maryland School of Medicine, Department of Anesthe-
siology and Shock, Trauma and Anesthesiology Reserch (STAR)
Center, Baltimore, MD
Disruption of autophagy, a cellular lysosome-dependent degradation
process, has been implicated in both acute and chronic neurodegener-
ative diseases. Although increase in markers of autophagy has been
reported in the brain after traumatic brain injury (TBI), its cell type
specificity, mechanisms and function remain unknown. Following brain
injury induced by controlled cortical impact (CCI) in mice, we observed
increased autophagosome accumulation in the cortex as indicated by the
autophagic marker LC3-II in Western blot. This was confirmed by LC3
immunofluorescence and using transgenic mice expressing GFP-LC3.
Like LC3-II, the autophagic substrate p62 also increased in the cortex
soon after injury, peaked around day 1 and resolved by day 7. There-
fore, early accumulation of autophagosome in the cortex after TBI is
due to block of autophagosome degradation, rather than increase in their
synthesis. This was supported by ex vivo experiment in which we found
block of autophagic flux in brain slices from injured cortex as compared
to controls. This early impairment of autophagy was at least in part
caused by TBI-induced lysosomal dysfunction, as evidenced by lower
protein levels and enzymatic activity of cathepsin D in the injured
cortex. Accumulation of autophagosomes occurred predominantly
within neurons at day 1 after injury. At that time we observed co-
localization of caspase dependent (cleaved caspase 3, caspase 12) and
caspase-independent (AIF) cell death markers with GFP-LC3 signal in
cells around the injury site. Together, our data demonstrate that au-
tophagic clearance is compromised at the early time points after TBI.
This is at least in part due to decreased lysosomal function and likely
contributes to neuronal cell loss. Autophagic flux is restored by day 7, at
which point autophagy could become neuroprotective. We propose that
restoration of lysosomal function early after TBI and further activation
of autophagy at later time points may provide complementary thera-
peutic strategies to limit neuronal loss after TBI.
Key words
autophagy, autophagy flux, ex-vivo model, GFP-LC3, lysosomal
function, transgenic mouse model
D1-01
METHYLENE BLUE ATTENUATES TRAUMATIC BRAIN IN-
JURY ASSOCIATED NEUROINFLAMMATION AND ACUTE
DEPRESSIVE-LIKE BEHAVIOR IN MICE
Fenn, A.M.1, Skendelas, J.1 , Moussa, D.1, Muccigrosso, M.1, Popovich,
P.G.1, Lifshitz, J.2, Eiferman, D.S.1, Godbout, J.P.1
A-100