134 / 198
enhanced stimulated response amplitudes in all rats, while CCI sig-
nificantly attenuated these effects in males, females, but not in OVX
rats (% attenuation: 104%, p
<
0.05; 80%, p
<
0.05; and 26%, p
=
0.48,
respectively). DA release rates were similar between all groups. Vmax
was similar between naı¨ve males and females, but was relatively
decreased in OVX rats (naı¨ve female vs. OVX: 54.0
–
3.8 vs.
38.7
–
5.3
l
M/s, p
<
0.05). Vmax was decreased in male and female
rats 2 wks post-CCI (naı¨ve vs. CCI: 51.80
–
2.4 vs. 40.68
–
2.2
l
M/s,
p
<
0.005), but again, not in OVX rats (p
=
0.72). After initial reduc-
tions in Vmax following MPH in all groups, there were notable sex-
based differences in the temporal regulation of Vmax; female and
OVX rats had a progressively decreasing Vmax, while male rats,
regardless of injury status, had a progressive increase in Vmax to
restore reuptake kinetics over the sampling window. These findings
demonstrate that CCI and hormonal manipulation alter DA neuro-
transmission kinetics, and that there may be a need to tailor clinical
MPH therapy in relation to sex and hormone status.
Keywords: Rehabilomics, TBI, Dopamine, Gender, Neuro-
transmission, DAergic
C9-02
DOPAMINE SYSTEM GENETICS AND SEX INTERACT TO
AFFECT COGNITIVE DYSFUNCTION AFTER TBI
John Myrga
1
, Michelle Failla
1,2
, Yvette Conley
4,6
, Joseph Ricker
7
,
C. Edward Dixon
5,6
, Patricia Arenth
1
, Amy Wagner
1,2,6
1
Univ Pittsburgh, Physical Med/Rehab, Pittsburgh, USA
2
Univ Pittsburgh, Neuroscience, Pittsburgh, USA
3
Univ Pittsburgh, Human Genetics, Pittsburgh, USA
4
Univ Pittsburgh, Health Promotion & Development, Pittsburgh, USA
5
Univ Pittsburgh, Neurosurgery, Pittsburgh, USA
6
Univ Pittsburgh, Safar Center, Pittsburgh, USA
7
New York University, Rehabilitation Medicine, New York City, USA
There is evidence that genetic variation within dopamine (DA) systems
has a sex-specific relationship to cognitive function in healthy popula-
tions. TBI results in a hypo-dopaminergic state, thus, DA genetic var-
iation may prove important in understanding cognitive heterogeneity in
TBI populations. We assessed sex and genetic variability at 4 loci
within three DA genes in 99 Caucasian adults (n
=
18 women; n
=
81
men) with moderate/severe TBI on cognitive outcomes. We used
normed data from eight neuropsychological tests to measure cognitive
impairment. Four cognitive domain scores capturing information about
memory, attention, language fluency, and executive function were used
to generate an overall cognitive composite score. We then created a
Gene Risk Score (GRS) using the following polymorphisms:
COMT
Val158Met,
ANKK1
Taq1A,
DRD2
rs6279, and
VMAT
rs363226. These
variants were selected based on previous association with cognition and
their coverage of DA systems. GRS was created by analyzing mean
differences between sexes for each variant and assigning risk values
based on their significance with respect to overall composite scores at
both 6 and 12 months. GRS was significantly associated with overall
cognitive composite score at 6 months (r
= -
0.27, p
=
0.011), with a
trend for significance at 12 months (r
= -
0.20, p
=
0.111) post-injury.
When adjusting for age, sex, injury severity, and education, GRS was a
significant predictor of cognition 6 months (p
=
0.0017, model
r
2
=
0.277) and 12 months (p
=
0.0096, model r
2
=
0.313) post-TBI, with
the GRS capturing 0.076 and 0.095 of each model’s variance (r2) re-
spectively. GRS approaches reflect multiple sources of biological var-
iation that provide important contributions to complex signaling
pathways such as DA systems with cognition. These results suggest the
potential importance of both sex and DA genetics when assessing and
managing cognitive dysfunction post-TBI.
Keywords: sex-specific, gender, dopamine, genetics, cognitive re-
covery, rehabilomics
C9-03
ADMINISTRATION OF LITHIUM IMPROVES NEURO-
TRANSMISSION AND INCREASES VESICULAR DOCKING
PROTEINS IN THE STRIATUM AFTER CCI
Shaun Carlson
1,2
, Anthony DeSana
1
, Emad Madha
1
, Hong Q. Yan
1,2
,
C. Edward Dixon
1,2
1
UPitt, Neurosurgery, Pittsburgh, USA
2
VAPHS, GRECC, Pittsburgh, USA
Traumatic brain injury (TBI) impairs neuronal function and can cul-
minate in lasting cognitive impairment. While impaired striatal dopa-
mine release is reported after experimental TBI, little is known about the
mechanisms underlying this consequence. Our previous work suggests
that reductions in proteins comprising the soluble N-ethylmaleimide-
sensitive factor attachment protein receptor (SNARE) complex, the
machinery facilitating vesicular fusion, may contribute to altered
synaptic vesicle properties and impaired neurotransmission. Cysteine-
string protein
a
(CSP
a
) is an important chaperone protein that facil-
itates SNARE complex formation and is increased in response to
lithium treatment. The objective of this study was to evaluate the
effect of lithium administration on CSP
a
abundance and neurotrans-
mission in the striatum after controlled cortical impact (CCI).
Methods:
Sprague-Dawley rats received CCI (2.7 mm) or sham
injury. Animals were treated with vehicle or 1.0 mmol/kg/ml lithium
chloride daily (i.p. injection) for 1 wk, beginning 5 minutes post-
injury. The brains were dissected at 1 wk post-injury and processed for
immunoblotting of CSP
a
(n
=
3–4/group). At 1 wk post-injury, CCI-
injured and sham-injured rats were subjected to microdialysis and
evoked dopamine release was measured by high-performance liquid
chromatography (n
=
4–5/group).
Results:
CCI results in a 40% reduction in CSP
a
abundance in the
striatum following injury. Treatment with lithium after CCI increased
CSP
a
in the striatum by 15%, compared to vehicle treatment. CCI was
associated with a significant reduction in peak dopamine release fol-
lowing high-potassium stimulated release (p
<
0.05). The peak dopa-
mine levels with post-traumatic treatment of lithium were not
different from sham injury (p
=
0.75).
Conclusions:
These findings provide the first evidence of altered
SNARE protein abundance in the striatum after CCI. We demonstrate
for the first time that lithium improves neurotransmission following
TBI. These findings suggest that treatment with lithium after TBI may
increase the abundance of important proteins that facilitate neuro-
transmitter release into the synaptic cleft.
Acknowledgement
5T32HD040686-14, The Pittsburgh Foundation, NIH-NS40125,
NIH-NS060672, VAI01RX001127
Keywords: Synapse, neurotransmission, vesicle, CCI
C9-04
TRAUMATIC BRAIN INJURY PRECEDES ENHANCED FEAR
CONDITIONING AND SUBREGIONAL CHANGES IN HIP-
POCAMPAL EXCITATORY/INHIBITORY TONE
Brandy Schneider
1
, Farhad Ghoddoussi
3
, Jennifer Charlton
1
, Robert
Kohler
2
, Matthew Galloway
2
, Shane Perrine
2
, Alana Conti
1,2
A-98