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localization and sectioning. To determine the stability of the fiducial,
the coronal sections were injected and scanned with 3T MRI im-
mediately after injections and 7-weeks post injections. A sample of
injected tissue was extracted and H&E staining was performed to
confirm the fiducial. The whole brain was imaged at 3T, following
vacuum impregnation with fluorinated oil to eliminate air. The brain
surface was generated from MR images and used to design a holder/
slicer. A prototype holder/slicer for the whole-brain was printed. The
injected fiducial was visible on 3T T2*-weighted MRI images.
Histology results are pending. Additional examination confirmed
that time did not impact the conspicuity of the fiducial. The two
printer polymers introduced negligible artifact on MRI of the brain
and air bubbles were absent following vacuum impregnation with
fluorinated oil. Work continues on the whole brain to inject a tar-
geted fiducial, detect it on MRI while in the holder/slicer, and use
MRI to guide the sectioning and co-localization in histology. A fi-
ducial marker and 3D-printing method for generating an individu-
alized holder/slicer to aid in MRI guided pathology has been
identified, and will be used to target specific pathology seen on in-
vivo MRI in donated TBI specimens.
Keywords: MRI Guided Pathology, TBI, Fiducial
B7-04
LONG-TERM COGNITIVE DEFICITS INDUCED BY TRAU-
MATIC BRAIN INJURY IN RATS ARE EXAGGERATED BY
PRE-EXPOSURE TO LIFE-THREATENING STRESS
Michael Ogier
1–3
, Amor Belmeguenai
2,3
, Be´atrice Georges
2,3
, Emilie
Carre´
1
, Thomas Lieutaud
2,3
, Laurent Bezin
2,3
1
French Armed Forces Biomedical Research Institute, Neurophy-
siology of Stress Unit, Bre´tigny-sur-Orge, France
2
Lyon Neuroscience Research Center, TIGER Team, Villeurbanne,
France
3
Institute for Epilepsy, IDE´ E, Bron, France
In the military, traumatic brain injury (TBI) is often sustained
under extremely stressful circumstances. However, the influence of
such stress on the outcome of TBI has been overlooked. Here,
using a rat model, we aimed at determining if behavioral and
cognitive outcomes after TBI are affected by prior exposure to life-
threatening stress. Adult male Sprague-Dawley rats were stressed
by exposure to predator odor 2-4-5-trimethyl-3-thiazoline (TMT)
for 7 minutes or were exposed to water (WAT) instead of TMT;
exposure was repeated 8 times at irregular intervals over a 2-week
period. Two days after the last exposure, rats were subjected to
either bilateral mild-to-moderate fluid percussion brain injury
(LFP) or Sham surgery. In our 4 experimental groups (Sham-WAT,
Sham-TMT, LFP-WAT, LFP-TMT), we measured motor activity
and anxiety-like behaviors at 1, 2 and 6 weeks post-trauma, spatial
learning and hippocampal long-term potentiation (LTP) at 1 month
post-trauma, and basal activity and restraint-stress-induced activa-
tion of the hypothalamic-pituitary-adrenal (HPA) axis at 2 months
post-trauma. Compared with Sham-WAT rats, LFP-WAT rats ex-
hibited transient signs of motor hyperactivity but no sign of anxiety
at 1 week post-trauma, minor spatial learning and hippocampal
LTP deficits, and, finally, lower basal activity of the HPA axis with
slightly stronger reactivity to restraint-stress. Exposure to TMT had
negligible effects on Sham rats, whereas it exaggerated all deficits
observed in LFP rats except for motor hyperactivity. Hence, these
data suggest that pre-exposure to stress can aggravate long-term
deficits induced by TBI.
Keywords: TBI, animal model, stress, cognition, behavior
B7-05
NEUROMETABOLIC CONSEQUENCES OF REPEATED TBI
Kate Karelina
, Kristopher Gaier, Zachary Weil
Ohio State University, Neuroscience, Columbus, USA
Head injuries are a major public health concern for youth and adult
athletes, members of the police and armed forces and the general
public. In the US alone, each year approximately 1.4 million people
are hospitalized with a traumatic brain injury. There is an innate
conflict between an institutional desire to return individuals to the
playing field or to duty following a TBI, and the need to protect these
individuals from the catastrophic brain damage that can result from
subsequent head injuries. The pathophysiology of TBI is complex,
but involves diffuse axonal injury, frank neuronal death, inflamma-
tion, and persistent metabolic abnormalities. There is a consistent
phenomenon across brain injury subtypes that the capacity for the
brain to utilize energy (viz. glucose) is significantly modulated fol-
lowing injury. We recently reported that repeated injuries occurring
close in time were associated with greater axonal degeneration,
enhanced inflammatory responses, poorer functional outcomes, and
alterations in central glucose utilization. In order to understand the
metabolic determinants of this phenomenon we investigated the role
of insulin, known both for its role in blood glucose regulation as well
as being a potent neuroprotectant following CNS insults. There is
mounting evidence that central insulin resistance and neuronal
metabolic dysfunction are key components of neurodegenerative
diseases and other neurological conditions. Here, we injured mice
either once or twice and investigated
ex vivo
sensitivity to insulin.
Insulin sensitivity, as assessed by Akt phosphorylation, was signif-
icantly reduced 48 hours after both single and repeated injuries.
Importantly, by 7 days after injury, insulin sensitivity was restored in
animals that were injured once, but not repeatedly. Ongoing work is
investigating the molecular mechanisms and consequences of this
phenomenon for recovery.
Keywords: Glucose Utilization, Insulin Sensitivity, Neurometa-
bolics, Repeated TBI
B7-06
IMPROVEMENTS IN COGNITIVE FUNCTION FOLLOWING
TRAUMATIC BRAIN INJURY VIA EIF2
a
PHOSPHORYLA-
TION AND REDUCTION IN ER STRESS
Michael Hylin
1
, Kimberly Hood
2
, Sara Orsi
2
, John Redell
2
, Andrey
Tsvetkov
2
, Anthony Moore
2
, Pramod Dash
2
1
Southern Illinois University, Psychology, Carbondale, USA
2
University of Texas Health Science Center at Houston, Neurobiology
and Anatomy, Houston, USA
Memory deficits are often seen after an individual has suffered from a
traumatic brain injury (TBI). Typically damage leading to these im-
pairments involves structures such as the hippocampus. Subsequent to
TBI there is a complex cascade of biochemical events that impact
potential recovery. Endoplasmic reticulum (ER) stressors such as in-
creased calcium levels, oxidative damage, and energy/glucose de-
pletion have all been observed in the pathophysiology of TBI. In
response to these events protein kinase RNA-like ER kinase (PERK)
regulates protein synthesis (via phosphorylation of eIF2
a
). Adminis-
tration of the FDA approved drug, guanabenz, has been demonstrated
to increase eIF2
a
phosphorylation and decrease ER stress. In the
current study, guanabenz (5.0 mg/kg) significantly reduced corti-
cal contusion volume and lessened hippocampal cell damage.
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