Traumatic brain injury (TBI) is the primary cause of death and disability in young adults and children. It occurs every 21 seconds and afflicts up to two million people annually in the United States. TBI is a heterogeneous insult that precipitates a cascade of ripples that propagate severe long-lasting pathologies. The limbic hippocampus, a brain structure crucial for learning and memory is often damaged in TBI. It is still unknown how regional changes in cellular metabolism and neurotransmitter function contribute to cognitive impairment associated with TBI. However, our preliminary data suggest that post-traumatic regional shifts in hippocampal excitability are due in part to a change in metabolic priorities. Our key observation is that specific amino acids normally employed for neurotransmitter synthesis are potentially diverted to protein synthesis and catabolism for energy thus disturbing the necessary balance between excitation and inhibition. Significantly, dietary administration of branched chain amino acids (BCAAs) after injury results in comprehensive cognitive restoration. We have thus formulated the following CENTRAL HYPOTHESIS: Dietary intervention with branched chain amino acids restores posttraumatic cognitive deficit by ameliorating regional shifts in hippocampal excitability. To test this hypothesis, cellular metabolism, as well as excitatory and inhibitory function in hippocampal subregions will be studied from the molecular to the systemic level in a mouse model of TBI. Better understanding the temporal window and mechanism(s) contributing to our successful dietary intervention will enable the specific formulation of the most efficacious future intervention to alleviate this devastating (i.e. cognitive impairment) pathology.

Public Health Relevance

Traumatic brain injury (TBI) is a major public health issue, which has a significant impact upon our healthcare system. Economic analyses of the annual cost of TBI-related disabilities range from $4.5 billion in direct expenditure (medical care and services) to $20.6 billion in injury-related work loss and disability. Our long-range goal is to continue to formulate an efficacious, safe and well- tolerated dietary intervention that can be rapidly translated from the bench to the clinic to ameliorate cognitive dysfunction in TBI patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069629-05
Application #
8683259
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Bellgowan, Patrick S F
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wolf, John A; Johnson, Brian N; Johnson, Victoria E et al. (2017) Concussion Induces Hippocampal Circuitry Disruption in Swine. J Neurotrauma 34:2303-2314
Yuan, Feng; Xiong, Guoxiang; Cohen, Noam A et al. (2017) Optimized Protocol of Methanol Treatment for Immunofluorescent Staining in Fixed Brain Slices. Appl Immunohistochem Mol Morphol 25:221-224
Kimball, Bruce A; Cohen, Akiva S; Gordon, Amy R et al. (2016) Brain Injury Alters Volatile Metabolome. Chem Senses 41:407-14
Beamer, Matthew; Tummala, Shanti R; Gullotti, David et al. (2016) Primary blast injury causes cognitive impairments and hippocampal circuit alterations. Exp Neurol 283:16-28
Paterno, Rosalia; Metheny, Hannah; Xiong, Guoxiang et al. (2016) Mild Traumatic Brain Injury Decreases Broadband Power in Area CA1. J Neurotrauma 33:1645-9
Palmer, Christopher P; Metheny, Hannah E; Elkind, Jaclynn A et al. (2016) Diminished amygdala activation and behavioral threat response following traumatic brain injury. Exp Neurol 277:215-226
Smith, Colin J; Xiong, Guoxiang; Elkind, Jaclynn A et al. (2015) Brain Injury Impairs Working Memory and Prefrontal Circuit Function. Front Neurol 6:240
Xiong, Guoxiang; Redding, Kevin; Chen, Bei et al. (2015) Non-specific immunostaining by a rabbit antibody against gustducin ? subunit in mouse brain. J Histochem Cytochem 63:79-87
Elkind, Jaclynn A; Lim, Miranda M; Johnson, Brian N et al. (2015) Efficacy, dosage, and duration of action of branched chain amino Acid therapy for traumatic brain injury. Front Neurol 6:73
Johnson, Brian N; Palmer, Chris P; Bourgeois, Elliot B et al. (2014) Augmented Inhibition from Cannabinoid-Sensitive Interneurons Diminishes CA1 Output after Traumatic Brain Injury. Front Cell Neurosci 8:435

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