Plasticity, the ability of the brain to modify itself in response to its environment, is fundamental to normal development and cognition. Changes in neural activation have important consequences and can interfere with normal plasticity. Traumatic brain injury (TBI) is the single largest cause of death and disability in children and young persons, and leads to developmental delays and cognitive deficits. Experimental studies have shown that perturbations of excitatory neurotransmission occur after TBI in the immature rat, and that these mechanisms may underlie subsequent impairments of environmental neuroplasticity. Recent investigations have delineated a dichotomous role for activation of the N-methyl-D-aspartate receptor (NMDAR), the predominant excitatory neurotransmitter receptor in the brain. Synaptic activation of NMDARs promotes plasticity and cell survival, while extrasynaptic activation impairs plasticity and enhances apoptotic neuronal death. This proposal hypothesizes that glutamatergic pharmacotherapy will restore disrupted molecular and physiological activation after developmental/pediatric TBI, and that treatment efficacy can be monitored using pharmacological MRI (phMRI) as a noninvasive biomarker. This goal will be achieved through the following three specific aims: 1) To measure the balance of critical molecular markers of plasticity and cell death, and establish the translational relationship between these mechanisms and quantifiable physiological functions such as regional cerebral blood volume changes (as measured using phMRI) and behavioral performance, 2) To enhance post-injury plasticity using D-cycloserine, an NMDAR co-agonist, and show specificity for this mechanism by blocking the DCS effect with an NMDAR antagonist, and 3) To restore experience-dependent plasticity after developmental TBI using rational glutamatergic pharmacotherapy. This basic science proposal has implications for future clinical/translational studies, particularly through the development of a noninvasive physiological biomarker (phMRI), and through treatment with an agent already approved for clinical use (D-cycloserine).

Public Health Relevance

Traumatic brain injury is the #1 cause of acquired death and disability in infants, children and adolescents, and results in long-lasting developmental deficits The majority of TBI occurs under the age of 20 years, and pediatric TBI is distinct in many ways from TBI in adults;however, research investigations and resources dedicated to studying basic mechanisms of recovery from developmental/pediatric TBI are few. Changes in brain neurotransmission play a critical role in the cognitive deficits seen after pediatric TBI. This stuy proposes to use existing medications that act on excitatory neurotransmitters to help restore disrupted brain functions after experimental TBI, and then measure the effectiveness of these therapies with both pharmacological MRI (a new type of functional brain imaging) and cognitive-behavioral testing.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bellgowan, Patrick S F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Hovda, David A (2014) The neurophysiology of concussion. Prog Neurol Surg 28:28-37
Reger, Maxine L; Poulos, Andrew M; Buen, Floyd et al. (2012) Concussive brain injury enhances fear learning and excitatory processes in the amygdala. Biol Psychiatry 71:335-43
Shrey, Daniel W; Griesbach, Grace S; Giza, Christopher C (2011) The pathophysiology of concussions in youth. Phys Med Rehabil Clin N Am 22:577-602, vii
Barkhoudarian, Garni; Hovda, David A; Giza, Christopher C (2011) The molecular pathophysiology of concussive brain injury. Clin Sports Med 30:33-48, vii-iii
Hutson, Che Brown; Lazo, Carlos R; Mortazavi, Farzad et al. (2011) Traumatic brain injury in adult rats causes progressive nigrostriatal dopaminergic cell loss and enhanced vulnerability to the pesticide paraquat. J Neurotrauma 28:1783-801
Babikian, Talin; Marion, Sarah Deboard; Copeland, Sarah et al. (2010) Metabolic levels in the corpus callosum and their structural and behavioral correlates after moderate to severe pediatric TBI. J Neurotrauma 27:473-81
Vespa, P M; McArthur, D L; Xu, Y et al. (2010) Nonconvulsive seizures after traumatic brain injury are associated with hippocampal atrophy. Neurology 75:792-8
Reger, Maxine L; Hovda, David A; Giza, Christopher C (2009) Ontogeny of Rat Recognition Memory measured by the novel object recognition task. Dev Psychobiol 51:672-8
Gurkoff, G G; Giza, C C; Shin, D et al. (2009) Acute neuroprotection to pilocarpine-induced seizures is not sustained after traumatic brain injury in the developing rat. Neuroscience 164:862-76
Griesbach, Grace Sophia; Sutton, Richard L; Hovda, David A et al. (2009) Controlled contusion injury alters molecular systems associated with cognitive performance. J Neurosci Res 87:795-805

Showing the most recent 10 out of 64 publications