Page 95 - NNS 2014 Program & Abstract Book

This research was supported by UCLA BIRC, NS027544,

NS05489, Child Neurology Foundation/Winokur Family Foundation,

and the Jonathan Drown Foundation.

Key words

D-cycloserine, FPI, pCaMKII, recovery, severe FPI

B4-11

MODERATE TRAUMATIC BRAIN INJURY (TBI) IN ADO-

LESCENT MICE ENHANCES COCAINE-INDUCED PLACE

PREFERENCE

Merkel, S.F.

1,2

, Tallarida, C.

2,4

, Persidsky, Y.

1,2

, Rawls, S.M.

2,4

,

Ramirez, S.H.

1,2,3

1

Temple University School of Medicine, Department of Pathology and

Laboratory Medicine, Philadelphia, USA

2

Temple University School of Medicine, Center for Substance Abuse

Research, Philadelphia, USA

3

Shriners Hospitals Pediatric Research Center, Philadelphia, USA

4

Temple University School of Medicine, Department of Pharmacol-

ogy, Philadelphia, USA

Clinical evidence indicates a connection between traumatic brain injury

(TBI) and addictive tendencies; however, very few pre-clinical studies

have been performed to understand the effect that brain injury may

have on drug addiction. Therefore, we designed a pilot study to test the

hypothesis that TBI exacerbates the reinforcing properties of cocaine in

a biased, conditioned place preference (CPP) assay. Adolescent, six-

week old C57BL/6 mice underwent craniotomy surgery, after which the

mice sustained a single, moderate TBI (speed: 4.5 m/s, depth of impact:

2.0 mm, dwell time: 0.5s) to the right parietal somatosensory cortex

using an electromagnetically driven piston (diameter: 2.0mm). One-

week post-TBI, an activity-monitoring assay was used to assess loco-

motor deficits arising as a result of surgical/impact procedures. Impacted

animals showed no locomotor deficits when compared to adolescent

control subjects. CPP pre-testing occurred 2 weeks post-TBI, followed

by six days of non-contingent cocaine administration (10 mg/kg)

through intraperitoneal injection. The place preference shift in the drug-

paired environment was significantly enhanced in all treatment groups

receiving cocaine as compared to saline controls. Furthermore, mice

sustaining a moderate TBI during adolescence exhibited a significant

increase in cocaine-induced place preference as compared to uninjured

controls receiving cocaine. These results suggest that adolescent mice

sustaining a single, moderate TBI may be increasingly susceptible to the

reinforcing properties of cocaine.

Key words

behavioral assay, controlled cortical impact, drugs of abuse, glia,

mesolimbic

B4-12

ACETYL-L-CARNITINE IMPROVES METABOLIC DYS-

FUNCTION AND BEHAVIORAL OUTCOME AFTER TRAU-

MATIC BRAIN INJURY IN IMMATURE RAT

Stadick, S.

1

, Su, X.

3

, Fiskum, G.

2

, McKenna, M.C.

2

, Scafidi, S.

1

Johns Hopkins University, Department of Anesthesiology and Cri-

tical Care Medicine, Baltimore, USA

2

University of Maryland, Department of Anesthesiology, Baltimore,

USA

3

University of Maryland, Department of Radiology, Baltimore, USA

Traumatic brain injury (TBI) is the leading cause of permanent life-long

disability in children and is characterized by deficits in cognition, at-

tention and sensorimotor integration. Depressed glucose cerebral energy

metabolism is attributed to mitochondrial dysfunction following pediatric

TBI. Developing brain is able to utilize alternative substrates and support

energy and metabolism by using ketones and fatty acids. Acetyl-L-

carnitine (ALCAR) is an endogenous metabolic intermediate that

provides acetyl moiety directly to the citric acid cycle, as well as

carnitine - which is essential for transport of fatty acids across the mi-

tochondrial membrane for

b

-oxidation. This study tested the hypothesis

that treatment with exogenous ALCAR in the first 24 hrs after TBI

improves neurologic outcome and decreases cell death by supporting cell

specific (astrocytic) metabolism. Postnatal day 21–22 male rats were

isoflurane anesthetized and used in a controlled cortical model (CCI) of

TBI to the left parietal cortex. At 1, 4, 12 and 23 hrs after injury rats were

treated with ALCAR (100 mg/kg/dose) or vehicle (normal saline). Using

Western blot analyses at 6 and 24 hrs after TBI we determined that

carnitine palmitoyl transferases (1 and 2), which facilitate mitochondrial

b

-oxidation, were not decreased in ALCAR treated group. Treatment

with ALCAR increased amount of glutamine and gamma-hydroxybutyric

acid determined by

in vivo

1H MRS, decreased lesion volume and cell

death and improved behavioral outcome after TBI in developing brain.

Key words

acetyl-L-carnitine, metabolism, neuroprotection, pediatric TBI

B4-13

LONG-TERM BEHAVIORAL CONSEQUENCES EMERGE

OVER TIME AFTER CONCUSSIVE INJURIES AT

ADOLESCENCE

Semple, B.D.

1,3

, Sadjadi, R.

1

, Carlson, J.

1

, Ferriero, D.M.

2

, Noble-

Haeusslein, L.J.

1

Department of Neurological Surgery, University of California San

Francisco, San Francisco, USA

2

Departments of Pediatrics and Neurology, University of California

San Francisco, San Francisco, USA

3

Department of Medicine, University of Melbourne, Parkville, Australia

There is growing controversy surrounding the management of concus-

sion in young athletes, with evidence suggesting that repeated concus-

sions result in cumulative and chronic neurological impairments

associated with neurodegeneration. The adolescent brain may be par-

ticularly vulnerable to concussions due to ongoing maturation at this

time in the setting of sports-related impacts. Using a unilateral con-

trolled cortical impact to the intact skull of mice at postnatal day 35, we

here aimed to characterize the consequences of a single concussive

injury or repeated insults (2 impacts, 48 h apart) as the animal matured.

At 24 h post-injury, injured brains were negative for markers of cell

death (TUNEL or active caspase-3), axonal degeneration (beta-amyloid

precursor protein), neuroinflammation (Iba-1 microglia) or gross struc-

tural damage (cresyl violet). Further, volumetric analysis of the dorsal

cortex and corpus callosum at 3 months post-injury failed to detect any

injury-related atrophy, indicating the very mild nature of this insult.

Despite this lack of neuropathology, behavioral assessments detected a

pronounced hypoactive phenotype in the open field and elevated plus

maze, which emerged over time and persisted up to 3 months post-

injury, the last time point studied. These changes were observed in the

absence of any sensorimotor dysfunction (rotarod; cylinder test) or

cognitive deficits (radial arm water maze; novel object recognition),

suggesting a hierarchy of behaviors whereby measures of general ac-

tivity are most sensitive to the mildest forms of concussion. Of note,

both single and repeated injuries at adolescence produced a similar

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