NNS 2015 Program & Abstract Book

Instituto Mexicano del Seguro Social, Laboratorio de Neurobiologı´a

del Desarrollo, Morelia, MX

To establish an efficacious therapy for traumatic brain injury (TBI) a

variety of relatively invasive strategies have been evaluated. En-

vironmental enrichment (EE) is a non-invasive paradigm that pro-

motes significant cognitive recovery after experimental TBI and has

the potential to mimic post-TBI neurorehabilitation. However, the

typical EE paradigm consists of continuous exposure, which is in-

consistent with the clinic where physiotherapy is typically limited

(Matter et al., 2011). Moreover, females make up approximately 40%

of the clinical TBI population, yet they are rarely studied in TBI

research. Hence, the goal of this study was to

test the hypothesis that

abbreviated EE would confer neurobehavioral and cognitive benefits

in brain injured female rats

. Anesthetized female rats received a

controlled cortical impact (2.8 mm tissue deformation at 4 m/s) or

sham injury (i.e., no impact) and were randomly assigned to TBI

(4 hr), TBI

EE (6 hr), TBI

EE (continuous), or TBI

STD groups,

and respective sham controls. Motor function (beam-balance/beam-

walk and rotarod) was assessed on post-operative days 1–5 and every

other day from 1–19, respectively. Spatial learning/memory (Morris

water maze) was evaluated on days 14–19. The data showed that EE,

regardless of dose, improved motor function compared to STD

housing (

0.0001). However, only continuous and 6-hr EE en-

hanced cognitive function (

0.0001). These data demonstrate that

abbreviated EE confers robust neurobehavioral and cognitive benefits

in TBI female rats, which supports the hypothesis and strengthens the

validity of EE as a pre-clinical model of neurorehabilitation. Ongoing

studies from our laboratory are evaluating further the benefits of ab-

breviated EE by combining it with pharmacotherapies, which may

result in additive or synergistic benefits, thus facilitating recovery

after TBI.

Keywords: Brain Injury, Controlled Cortical Impact (CCI), En-

vironmental Enrichment, Females

S10-04

NEUROINFLAMMATORY MYELOID CELL PROCESSES

ASSOCIATE WITH DIFFUSELY INJURED AXONS FOL-

LOWING MILD TRAUMATIC BRAIN INJURY IN MICRO-

PIGS

Audrey Lafrenaye

, Masaki Todani, John Povlishock

Virginia Commonwealth University, Anatomy and Neurobiology,

Richmond, USA

Mild traumatic brain injury (MTBI) is a prevalent disease that exacts

significant personal and societal cost. The pathophysiology of MTBI

is complex, with reports of diffuse axonal injury (DAI) being highly

correlated to prolonged morbidity. Progressive chronic neuroin-

flammation has also recently been correlated to morbidity, however,

the potential association between neuroinflammatory myeloid cells

and DAI is not well understood. The majority of studies exploring

neuroinflammatory responses to TBI have focused on more chronic

phases of injury and phagocytosis associated with Wallerian change.

Little, however, is known regarding the neuroinflammatory re-

sponses seen acutely following diffuse MTBI and potential rela-

tionships to early DAI, an issue that has significant clinical

relevance. Additionally, inflammation has recently been shown to be

drastically different in rodents as compared to gyrencephalic hu-

mans. Accordingly, we employed a modified central fluid percussion

model of MTBI in gyrencephalic micropigs and assessed potential

associations between acute DAI and neuroinflammation within 6h of

injury. This model generated substantial DAI in the thalamus

(10.31

–

1.34 APP

swellings/0.72 mm

field), an area commonly

affected across the spectrum of TBI. Extensive neuroinflammation

was also observed following MTBI in the same thalamic sectors.

Importantly, physical contact between Iba-1

myeloid cell pro-

cesses and the APP

swellings of axons sustaining DAI was nearly

double (0.16

–

0.02 contacts/mm) compared to uninjured myelinated

axons in sham animals (0.09

–

0.01 contacts/mm). While active

phagocytosis was observed in association with Wallerian degener-

ation, the Iba-1

cells that contacted DAI swellings did not reveal

ultrastructural changes consistent with phagocytosis. This is the first

study to show direct physical correlation between the acute phase

proximal axonal swellings and non-phagocytic neuroinflammation

in a higher order animal. These findings could lead to a more

complete understanding of acute neuroinflammation following

MTBI and its potential as a diagnostic and/or a therapeutic target.

This work was performed as a component of the Operation Brain

Trauma Therapy consortium, which is supported by DoD grant

W81XWH-10-1-0623.

Keywords: Neuroinflammation, Diffuse axonal injury, Micropig,

Central fluid percussion injury, Quantitative image analysis

S10-05

CHARACTERIZATION OF ENDOGENOUS BRAIN-DERIVED

NEUROTROPHIC FACTOR EXPRESSION IN RESPONSE TO

PENETRATING BALLISTIC-LIKE INJURY

Ying Deng-Bryant

, Sindhu Kizhakke Madathil, Lai Yee Leung,

Zhilin Liao, Frank Tortella, Deborah Shear

Walter Reed Army Institute of Research, Center for Military Psy-

chiatry and Neuroscience, Silver Spring, USA

Brain-derived neurotrophic factor (BDNF) has been shown to play a

key role in mediating neurogenesis and synaptic plasticity in the

adult central nervous system. However, little is known about the

changes in this endogenous molecule following penetrating ballistic-

like injury (PBBI). The aim of this study was to identify the regional

and temporal alterations in BDNF levels in relationship to down-

stream neuroplasticity markers in the PBBI model. Adult male

Sprague-Dawley rats received either sham (craniotomy only) or

PBBI (10% injury severity) surgery, and were euthanized at 24h,

48h, 72h, and 7 days post-injury for BDNF quantification, and at 7,

14 and 28d post-injury for neuroplasticity assessments (n

5–6/time-

point). BDNF levels were quantified in hippocampus and cerebral

cortex by ELISA assay, and growth-associated protein-43 (GAP-43)

and synaptophysin (SYN) immunohistochemistry was performed to

assess axonal and synaptic plasticity, respectively. Following im-

munostaining, the integrated density in the hippocampal region was

determined using NIH Image J software. Results showed significant

reductions in BDNF levels that were detected bilaterally in cortical

and hippocampal regions at 7 days post-injury (p

0.05 vs. sham),

but not at the earlier time points. PBBI significantly decreased GAP-

43 expression in the ipsilateral hippocampus at 14d and 28d post-

injury, and in the contralateral hippocampus at 14d post-injury

0.05 vs. sham). Similarly, significant reductions in SYN staining

were detected at 14d and 28d post-injury in the ipsilateral hippo-

campus and at 14d post-injury in the contralateral hippocampus

0.05 vs. sham). Collectively, these findings demonstrate that

PBBI results in a delayed down-regulation of BDNF levels that

precede subsequent reductions in neuroplasticity markers. These

results suggest a critical role of BDNF in modulating endogenous

neuroplastic response to brain injuries, underscoring the potential

importance of supplementing growth factors to enhance neuroplas-

ticity for promoting functional recovery after PBBI.

Keywords: BDNF, Synaptophysin, GAP-43, PBBI

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