Traumatic brain injury (TBI) is the primary cause of death and disability in children and young adults. TBI occurs every 21 sec and afflicts approximately two million people annually in the United States. TBI is a heterogeneous insult that precipitates molecular and physiological cascades that culminate in severe long-lasting neuropathologies. The hippocampus and the medial prefrontal cortex (mPFC), brain structures crucial for higher cognitive function, are often damaged in TBI. Optimal brain function requires the delicate balance between excitatory and inhibitory neurotransmission (E/I balance) in these brain regions. Furthermore, E/I balance is essential for the induction and maintenance of neural oscillations, which underlie cognitive and executive function. In TBI, E/I balance is disrupted and restoring this network balance is critical to recovering normal cognitive function. Our preliminary data demonstrate that injury- induced E/I imbalance in area CA1 is predominately mediated by alterations in inhibitory synaptic transmission and that brain injury diminishes mPFC network excitability. Furthermore, distinct components of inhibitory neuronal circuitry contribute to E/I imbalances following TBI and also underlie the pharmacologic re-establishment of E/I balance which brings about comprehensive cognitive restoration in brain injured animals. Based on these results, we hypothesize that inhibitory circuits-crucial for the induction and maintenance of hippocampal and cortical theta and gamma rhythms-are selectively altered by TBI, thus causing cognitive and working memory impairments. Moreover, branched chain amino acids (BCAAs), administered in vivo following TBI, rescue normal cognitive functions by restoring hippocampal and cortical E/I balance and normal oscillations. To test this hypothesis, in vivo recordings as well as assays of excitatory and inhibitory function in hippocampal and cortical subregions will be studied at the systemic to molecular level in a well-established mouse model of TBI. Network excitability, as a measure of E/I balance, will be recorded extracellularly with field recording techniques and voltage sensitive dyes. Determining the specific inhibitory circuitry that causes regional hippocampal and cortical E/I imbalances and identifying the distinctive elements of altered inhibitory circuitry responsive to BCAA intervention will enable development of targeted therapeutic interventions to alleviate cognitive impairments caused by TBI.

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 determine the underlying mechanism(s) that cause injury induced cognitive impairment and continue to optimize 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)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37HD059288-11A1
Application #
8761881
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Michel, Mary E
Project Start
Project End
Budget Start
Budget End
Support Year
11
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
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