Long-term plasticity and recovery in pediatric TBI rat model

Abstract: Traumatic brain injury (TBI) is a leading concern in children and young adults in the United States, with more than 3,000 deaths and 29,000 hospitalizations annually (Centers for Disease Control and Prevention). Present intensive care management does not offer any neuroprotective therapies that have correlated with improved long-term outcome. Even after recovery, many children face significant neurologic complications, which potentially persist into adulthood (1, 2). It has been shown that the injury mechanisms and responses in the immature brains of children and animals are distinct from those in adults and require age-specific injury prevention strategies and treatments (3). Nevertheless, little is known about the neuroplasticity mechanisms that are involved in re-shaping brain functions after TBI and how these changes dictate the degree of rehabilitation. To address these questions, we applied the well-established rat model for TBI, the controlled cortical impact (CCI) model, with adaptations for immature rats (4). Our preliminary in vivo electrophysiology recordings and functional magnetic resonance imaging (fMRI) findings suggest that TBI in immature rats results in decreases in neuronal responses both in the injured cortex and the healthy cortex (contralateral to the injury). These decreases in cortical activity may account for the long-term physical, cognitive, psychological, and emotional impairments that survivors of pediatric TBI suffer from.

Thus, the overall goal of this proposal is to develop a novel “guided-plasticity” strategy to promote recovery following TBI in the immature animal by optogenetically increasing the activity of neurons located in the injured and the healthy cortices. We will use a combination of electrophysiology, behavioral testing, optogenetics technology and high resolution non-invasive fMRI to identify the architectural and neurophysiological mechanisms required for post-TBI recovery and monitor the outcome of the optogenetics recovery strategy. Results obtained from this study could be directly translated into clinical applications in terms of: 1) Predicting the long-term recovery potential following TBI; 2) Improving pharmacological interventions such as delivery of psychostimulants (i.e. serotonin uptake inhibitors and Ritalin) that aim to increase neuronal excitability in pediatric TBI victims; and 3) Improving recovery strategies which are based on cortical manipulations and stimulation such as with transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS).