75 / 162
stimuli are common after TBI, and might influence the encoding of
traumatic events. Our lab has shown enhanced contextual fear after
lateral fluid percussion injury (LFPI) when fear conditioned after in-
jury with white noise cues paired with footshocks (Reger et al.,
Biol.
Psychiatry
, 2012). In the current study we show that compared to
sham, LFPI did not impact acquisition, context, or cued fear when
conditioned with low frequency (2800 Hz), pure tones. Given that
white noise encompasses a greater frequency range, we hypothesize
that LFPI enhances contextual fear to white noise-signaled condi-
tioning due to injury-induced altered sensory processing. In a second
experiment, LFPI or sham rats were pre-exposed to white noise trials,
then were fear conditioned and tested for contextual and cued fear on
subsequent days. Interestingly, LFPI rats showed elevated freezing to
the white noise (16.8% vs. 4.2%, p
<
0.001) and context (32.6% vs.
7.1%, p
<
0.001) during the pre-exposure session, and during baseline
the next day (6.9% vs. 1.2%, p
=
0.035), suggesting that LFPI rats
conditioned to white noise alone. Furthermore, LFPI rats displayed
enhanced contextual fear in the days after conditioning (day 1
freezing: 83.1% vs. 56.6%, p
=
0.001). These data provide implica-
tions for altered sensory processing after TBI, where otherwise neutral
stimuli may adopt aversive properties and impact encoding of trau-
matic memories.
Supported by: UCLA Brain Injury Research Center; Joseph Drown
Foundation; 1PO1NS058489: PI DH; 1R01NS27544: PI DH; Centre
for NeuroSkills: DH; R01MH062122: MF
Keywords: sensory, fear conditioning, post traumatic stress disor-
der, amygdala
C1-11
APOE-
e
4 IS ASSOCIATED WITH DECREASED SIX-MONTH
VERBAL MEMORY PERFORMANCE AFTER MILD TRAU-
MATIC BRAIN INJURY
John Yue
1
, Caitlin Robinson
1
, Ethan Winkler
1
, Adam Ferguson
1
,
Thomas McAllister
2
, Jonathan Rosand
3
, Hester Lingsma
4
, Sourabh
Sharma
1
, Marco Sorani
1
, Shelly Cooper
1
, Jessica Nielson
1
, Gabriela
Satris
1
, Mary Vassar
1
, Frederick Korley
5
, Kevin Wang
6
, Esther Yuh
7
,
Pratik Mukherjee
7
, Alex Valadka
8
, David Okonkwo
9
, Ramon Diaz-
Arrastia
10
, Geoffrey Manley
1
1
UCSF, Neurosurgery, San Francisco, USA
2
Indiana Univ., Psychiatry, Indianapolis, USA
3
Harvard Univ., Neurology, Boston, USA
4
Erasmus MC, Public Health, Rotterdam, Netherlands
5
Johns Hopkins Univ., Emergency Medicine, Baltimore, USA
6
Univ. Florida, Neuroscience, Gainesville, USA
7
UCSF, Radiology, San Francisco, USA
8
Seton Brain & Spine Institute, Neurosurgery, Austin, USA
9
Univ. Pittsburgh, Neurosurgery, Pittsburgh, USA
10
USUHS, Neurology, Bethesda, USA
Mild traumatic brain injury (MTBI) is a cause of cognitive impair-
ment, which may be modulated in part by genetic susceptibility.
Apolipoprotein E (
APOE)
encodes a lipoprotein released after brain
injury with neurotropic effects. Of its three isoforms (
e
2
/
e
3
/
e
4
),
presence of the
e
4
allele (
APOE-
e
4)
is known to associate with
impaired memory in neurodegenerative diseases. However, its as-
sociation with memory function after MTBI remains unclear. We
utilized the Transforming Research and Clinical Knowledge in TBI
(TRACK-TBI) Pilot study to investigate whether
APOE-
e
4
influ-
ences six-month verbal memory, measured by four subscales of the
California Verbal Learning Test (CVLT): Short-Delay Free Recall
(SDFR), Short-Delay Cued Recall (SDCR), Long-Delay Free Recall
(LDFR) and Long-Delay Cued Recall (LDCR). Results in 114
adult MTBI patients with no surgical intervention demonstrate that
APOE-
e
4
significantly associates with long-term memory (LDFR:
mean decrease 1.19 points, 95% CI [
-
2.31,
-
0.01],
p
=
0.048;
LDCR:
-
1.57, [
-
2.60,
-
0.54],
p
=
0.003) after controlling for effects
of age, race, years of education, and presence of intracranial pa-
thology on CT. The association between
APOE-
e
4
and short-term
memory showed significance in SDCR (-1.04, [-2.06,
-
0.01],
p
=
0.047) and a statistical trend in SDFR (-1.08, [-2.34, 0.17],
p
=
0.090) after controlling for age, race, education and CT. These
results support the need for additional research to confirm and extend
these findings.
APOE-
e
4
may confer an increased risk for verbal
memory disturbances in patients with MTBI, with implications for
prognosis following MTBI.
Keywords: Clinical Trial, Human Studies, Mild TBI, Outcome
C1-12
POSITIVE ALLOSTERIC MODULATION OF THE
a
7 NICO-
TINIC ACETYLCHOLINE RECEPTOR REVERSES CHRON-
IC COGNITIVE DEFICITS AFTER TBI
David Adaikkalasamy
1
, Furones Concepcion
1
, Timothy Johnstone
2
,
Derk Hogenkamp
2
, Kelvin W Gee
2
, Coleen M Atkins
1
1
University of Miami Miller School of Medicine, Neurological Sur-
gery, Miami, USA
2
School of Medicine University of California Irvine, Pharmacology,
Irvine, USA
Traumatic brain injury (TBI) causes profound changes within the
hippocampus that chronically hinder cognitive recovery. Both clin-
ical and preclinical studies have established that cholinergic sig-
naling is decreased following TBI. This decreased signaling is
reminiscent of Alzheimer’s disease, where cholinesterase inhibitors
are successful, major clinical therapeutics. Clinical trials for TBI
have had only modest success using cholinesterase inhibitors, and
are limited by only broadly and nonspecifically raising acetylcholine
levels. As an alternative therapeutic strategy, we hypothesize that
targeting the
a
7 nicotinic acetylcholine receptor (nAChR) with a
positive allosteric modulator will promote cognitive functioning in
the chronic recovery period of TBI, by potentiating cholinergic
signaling only when endogenous ligand is bound to the receptor. To
test this hypothesis, adult male Sprague Dawley rats received
moderate parasagittal fluid-percussion brain injury or sham surgery.
At 3 months after recovery, animals were treated with vehicle (2%
DMSO, 8% solutol, 90% saline), or AVL-3288 (0.3 mg/kg, i.p)
30 min prior to behavioral training. Animals were trained on fear
conditioning and the water maze. TBI-induced learning and memory
deficits in cue and contextual fear conditioning and the water maze
were significantly reversed with AVL-3288 treatment. We further
assessed the effects of AVL-3288 on the expression of long-term
potentiation (LTP) in area CA1 of the hippocampus. Our preliminary
data from hippocampal slices at 3 months after TBI or sham surgery
revealed that expression of LTP was significantly decreased after
TBI as compared to sham animals. AVL-3288 treatment (1
l
M)
during LTP induction reversed the TBI-induced deficits in LTP.
These results indicate that AVL-3288 improves learning and mem-
ory performance after TBI in the chronic recovery period. These
findings support the feasibility of using positive allosteric modula-
tors of the
a
7 nAChR for the treatment of cognitive deficits after
TBI.
Keywords: Traumatic Brain Injury,
a
7 nicotinic acetylcholine re-
ceptor, Long-term potentiation, Learning and memory
A-75