Page 35 - NNS 2014 Program & Abstract Book

is difficulty understanding speech in noisy environments. Given that
many veterans have noise-induced hearing deficits, hearing loss is one
factor that may contribute to such complaints. Specifically, sensori-
neural hearing loss likely interacts with damage to cortical structures
important for controlling selective attention, leading to severe diffi-
culties when trying to communicate in everyday social settings. We
evaluated 10 bTBI veterans’ hearing status as well as their perfor-
mance on a selective auditory attention task. In the veterans tested,
audiograms revealed near normal auditory thresholds (within 20 dB of
normal limits). In addition, a more sensitive test of supra-threshold
temporal coding fidelity in the brainstem recently developed in our
laboratory revealed responses within the normal range for healthy
young adults. Thus, in this pilot study, there was no evidence for
sensorineural hearing deficits, even using new methods for revealing
differences in supra-threshold hearing. The bTBI veterans performed
a selective auditory attention task in which they were instructed to
categorize the pitch contour of one of three simultaneously occurring
melodies presented from three differently perceived locations (either
rising, falling, or alternating). Such a task not only requires fine at-
tentional control, but also temporally precise neural representations
of the incoming sensory information. Performance was significantly
worse compared to 17 normal-hearing, non-TBI controls. EEG-
recorded evoked response potentials to correctly identified trials
showed that in those veterans who could perform the task at above-
chance levels, attention modulated the neural representation of the
auditory input weakly or not at all, whereas healthy controls consis-
tently show such modulation. Although these results do not rule out
auditory sensory deficits as a contributing factor to selective auditory
attention deficits in the general population of bTBI veterans, they
suggest that blast exposure damage affects cortical regions responsible
for controlling selective auditory attention. These findings are a step
toward developing early pre-clinical diagnostic markers for long-term
neurobehavioral disorders commonly associated with bTBI.
Key words
audiotory selective attention, behavioral, blast injury, EEG, veterans
T1-04
CCR2 ANTAGONISM ALTERS BRAIN MACROPHAGE
POLARIZATION AND AMELIORATES COGNITIVE DYS-
FUNCTION INDUCED BY TRAUMATIC BRAIN INJURY
Morganti, J.M., Jopson, T.D., Liu, S., Riparip, L.K., Guandique, C.K.,
Gupta, N., Rosi, S.
University of California, San Francisco, USA
Traumatic brain injury (TBI) initiates a robust innate immune re-
sponse, which has been shown to persist for years following the initial
event, and ultimately affects cognitive function. In patients who sur-
vive TBI, there are increased levels of the chemokine CCL2 in the
cerebrospinal fluid (CSF), suggesting involvement of CCL2-CCR2
signaling axis following trauma. However, it is unclear what role
CCR2 + macrophages play in TBI-induced sequelae. Herein we used
the unique CX3CR1GFP/ + CCR2RFP/ + reporter mice, to define the
temporal kinetics of TBI-induced CCR2 macrophage accumulation in
the brain spanning acute (3–6 hrs), subacute (12–48 hrs) and chronic
(7–28 d) time points. We found that accumulation of CCR2 + mac-
rophages is temporally restricted following to 12–24 hrs post injury.
Interestingly, a significant number of CCR2 + cells began to express
CX3CR1 simultaneously, which persisted through 7 days post injury.
Gene expression analyses of multiple macrophage polarization
markers revealed distinct temporal expression spanning the M1/M2
activation continuum across all time points. Moreover, multivariate
analysis revealed distinct relationships between three macrophage
subsets and their inflammatory gene expression profile. Combined,
these findings identified a therapeutic window for targeting CCR2 +
macrophage accumulation following TBI. In wildtype mice, treatment
with a novel phase-1 CCR2 antagonist, reduced accumulation of pe-
ripheral macrophages, disrupted neurotoxic macrophage polarization
and prevented increased NADPH oxidase gene expression one day post-
injury. Cumulatively, this treatment strategy prevented TBI-induced
hippocampal learning and memory deficits 28 days post-injury. These
data suggest that the accumulation of CCR2+ macrophages contrib-
utes to TBI-induced cognitive decline and that pharmacologic agents
can reverse this cognitive decline, which supports early intervention in
patients with TBI.
Funding
This work was supported by the NIH R01 CA133216 (S.R.), R21
AG042016 (S.R.), Alzheimer Association IIRG-11-202064 (S.R.).
Key words
antagonist, CCR2, hippocampus, macrophage, multivariate analysis
T1-05
INFLAMMATION IN THE PAIN PATHWAY IN A MODEL OF
MILD CLOSED HEAD INJURY: IMPLICATIONS FOR POST-
CONCUSSION HEADACHE
Macolino, C.M.1, Daiutolo, B.V.1 , Tyburski, A.L.1 , Elliott, M.B.1,2
1Thomas Jefferson University Department of Neurological Surgery,
Philadelphia, USA
2Thomas Jefferson University Department of Neuroscience, Phila-
delphia, USA
Headache is a hallmark symptom of concussion. Post-concussion
headache (PCH) can be a new headache resulting from concussion or
worsening of a pre-existing headache disorder. In many patients, it
resolves in three months; in others, it persists for much longer. Un-
derstanding the post-concussion symptomology including headache is
important for concussion management. The goal of this study was to
compare changes in the trigeminal pain pathway and related behavior
between a mild CCI injury (with focal-diffuse features) and a mild
closed head injury (CHI) injury (with diffuse injury only). Male
Sprague Dawley rats were randomized into CCI, single CHI, or re-
petitive (2-hit) CHI and compared to control groups. Baseline and
weekly post-injury testing included von Frey (mechanical) sensory
testing for the presence of allodynia, rotarod for balance, and Barnes
maze for detecting deficits in spatial learning and memory. Changes in
markers of injury/inflammation including beta amyloid precursor
protein (b-APP), glial fibrillary acidic protein (GFAP), Iba-1 micro-
glial, and inducible nitric oxide synthase (iNOS) were determined in
the trigeminal pain pathway using immunohistochemistry, western
blot, or qRT-PCR. Changes in the nociceptive neuropeptide, calcito-
nin gene-related peptide (CGRP) were also compared between in-
juries. Periorbital allodynia along with motor and learning deficits
were dependent on the type of injury and number of injuries
(p < 0.01). Group differences were found in the location and grading
of b-APP accumulation, astrogliosis and microglial activation. Graded
increases in CGRP and iNOS levels were found in the trigeminal
pathway in CCI and CHI groups, p < 0.001. In conclusion, the type of
injury (primarily focal or diffuse) and number of injuries influence the
degree and distribution of inflammation, and nociceptive responses.
Peripheral and central sensitization are evidenced by the presence of
mechanical allodynia, inflammation, and alterations in trigeminal
pain pathway. Findings indicate the importance of post-concussion
A-3