Page 131 - NNS 2014 Program & Abstract Book

60 seconds of stimulation there was a persistent increase in phase
coherence between the MSN-mPFC and MSN-hippocampus lasting
the duration of the behavioral trial. We now demonstrate that there is a
time-of-stimulation dependent increase in theta phase coherence
across distal nodes of the learning circuit both during stimulation and
persisting for 15 minutes following stimulation. The goal of these
preclinical trials is to optimize stimulation paradigms to entrain
physiological theta and restore cognitive function. These data provide
further support that neuromodulation represents an exciting approach
for improving outcome following TBI.
Key words
deep brain stimulation, neuromodulation, theta oscillations, traumatic
brain injury
C3-28
DECREASED HEMISPHERIC SWELLING FOLLOWING TBI
IN MICE LACKING TREM2
Otani, Y.1, Donovan, V.1,2, Hernandez, A.1,4, Obenaus, A.1,2,5,
Carson, M.J.1,2
1Center for Glial Neuronal Interactions University of California-
Riverside School of Medicine, Riverside, USA
2Cell, Molecular and Developmental Biology University of California-
Riverside, Riverside, USA
3MarcU University of California-Riverside, Riverside, USA
4Department of Pediatrics, Loma Linda University, Loma Linda, USA
The consequences of traumatic brain injury (TBI) vary by individual,
but can include long-term neurological deficits and increased risk of
Alzheimer’s disease. It is difficult to predict which individuals will
develop unwanted TBI associated sequelae. Microglia are brain
resident macrophages and ‘‘first responders’’ to changes in CNS
function. Following neuronal injury, cell death and/or amyloid pa-
thology, microglia rapidly increase expression of the orphan im-
mune-modulatory receptor, Triggering Receptor on Myeloid cells-2
(TREM2). Microglial expression of TREM2 is also increased during
systemic inflammation even without blood-brain-barrier disruption.
Individuals lacking a functional TREM2 reveal the importance of
TREM2 for brain function. Absence of a functional TREM2 causes
early onset cognitive dementia while expression of a TREM2 allele
with a mutation in the putative ligand-binding domain correlates
with a 3-fold higher risk of Alzheimer’s disease. We hypothesized
that inflammatory status and level of TREM2 expression at the time
of TBI would alter the evolution of TBI pathology. Therefore, we
contrasted lesion size, hemispheric swelling and microglial activa-
tion 7 days post-moderate controlled cortical impact (CCI) in wild-
type (WT) mice without systemic inflammation, in WT mice with
LPS systemic challenge 24-hrs before CCI and in TREM2KO mice.
Surprisingly, we found decreased hemispheric swelling following
TBI in both TREM2KO and LPS challenged WT mice, which ex-
hibit elevated microglial TREM2 expression. There were no sig-
nificant differences between lesion size and blood deposition
between the three conditions as detected by MRI, qPCR and nano-
string analysis of gene expression within the impacted cortex and in
purified microglia revealed that both TREM2KO and LPS chal-
lenged mice exhibited similar patterns of TBI associated inflam-
mation. Furthermore, decreased hemispheric swelling correlated
strongly with decreased ratios of Arginase1/iNOS and increased
microglial expression of P2Y12.
Key words
swelling, TREM2
C3-29
EXPERIMENTAL DIFFUSE BRAIN INJURY LEADS TO
CHRONIC ENDOCRINE DYSFUNCTION
Rowe, R.K.1–3, Colburn, T.1,2, Burns, R.S.3, Thomas, T.C.1–3,
Lifshitz, J.1–3
1Child Health-University of Arizona COM, Phoenix, USA
2BARROW Neurological Institute-Phoenix Children’s Hospital,
Phoenix, USA
3VA Healthcare System, Phoenix, USA
Endocrine dysfunction occurs in 35–40% of patients with a history of
traumatic brain injury (TBI), which can impair health, impede reha-
bilitation, and lower life expectancy. The urgent clinical need ne-
cessitates investigation on the time course and underlying
pathological processes. In this study we seek to model chronic en-
docrine dysfunction at rest and under stressed conditions. We hy-
pothesize that diffuse TBI causes discrete neuropathology in
hypothalamic-pituitary brain regions that leads to the development of
endocrine dysfunction with a delayed time course evoked by stress.
In adult rats, moderate diffuse TBI (midline fluid percussion, 2.0 atm),
but not sham injury, induced chronic endocrine dysfunction. Sensory
sensitivity, assessed by whisker nuisance task at 28 d post-injury, was
significantly increased compared to shams (U(18) = 27.00, p = 0.0424). At
54 d post-injury, prior to stress, brain-injured rats had lower plasma corti-
costerone compared to shams (t(9) = 2.952, p = 0.0162), as seen clinically.
Restraint stress significantly increased plasma corticosterone across time in
all rats (F(3,33) = 26.80, p < 0.0001). However, 60 minutes after stress
onset, corticosterone was elevated significantly less in brain-injured rats
compared to shams (F(1,11) = 4.946, p = 0.0480). At 56 d post-injury, de-
pression of serum corticosterone was tested 2 h following a subcutaneous
injection of synthetic glucocorticoid, dexamethasone. Dexamethasone
decreased serum corticosterone equally in both groups compared to 54 d
post-injury (F(3,66) = 23.20, p < 0.0001). Body weights further indicated
injury-related metabolism and endocrine dysfunction. TBI significantly
decreased body weight from 0-3 d post-injury (t(17) = 3.325, p = 0.004),
whereas body weight from 3-56 d post-injury was significantly increased
compred to sham (t(17) = 5.066, p < 0.0001), showing physiological con-
sequences of endocrine dysfunction. Injury-related neuropathology is on-
going in relevant hypothalamic nuclei (Golgi and silver stains).
These data validate a rodent model of diffuse TBI to explore structural,
functional, and hormonal mechanisms involved in the genesis and per-
sistence of endocrine dysfunction. These and future studies will guide
clinical investigations to advance diagnosis, prognosis and therapeutic
approaches improving the quality of life for TBI survivors.
NIH-R01-NS065052, Phoenix-VA Healthcare System
Key words
chronic dysfunction, corticosterone, midline fluid percussion, TBI
C3-30
AXONAL INJURY IN A MOUSE MODEL OF SUBARA-
CHNOID HEMORRHAGE
Kummer, T.T.1,5, Magnoni, S.2, MacDonald, C.L.3, Milner, E.4,
Gonzales, E.5 , Sorrell, J.1, Zipfel, G.J.4, Brody, D.L.1,5
1Washington University School of Medicine, Department of Neurol-
ogy, St. Louis, USA
2Ospedale Maggiore Policlinico, Department of Anaesthesia and In-
tensive Care, Milan, Italy
3University of Washington, Department of Neurosurgery, Seattle, USA
4Washington University School of Medicine, Department of Neuro-
surgery, St. Louis, USA
A-99