Mild traumatic brain injury (TBI) is a silent epidemic in adults and children in the United States affecting over a million young healthy persons annually. The long term neurological consequences and long term pathological changes of repeated mild TBI have recently come to the public's attention through high-profile reports involving professional football players and soldiers with traumatic brain injury. Unfortunately, almost nothing is known about the specific mechanisms leading to acute and chronic brain injury after repeated mild TBI, and no specific therapy other than rest exists to reduce long term cognitive and other sequelae of repeated mild TBI. Several clinical reports suggest that adolescents who suffer one or more concussions may develop cognitive and behavioral sequelae as they mature. However, mechanisms of how concussive TBI in adolescence affects future brain development remain unknown, as few longitudinal studies have been done to examine this question in animal models. To begin to address these knowledge gaps, we have begun development of a repetitive closed head injury (rCHI) model in adolescent mice that produces long term (> 1 year) cognitive and locomotor deficits, as well as deficits in cerebrovascular reactivity to inhaled carbon dioxide, in the absence of structural brain damage. We now propose to develop this adolescent rCHI model with respect to short- and long-term cognitive deficits and histopathology with the following Specific Aims:
Aim 1 A: Characterize the cognitive deficits associated with repetitive closed head injury (rCHI, height = 48 in, weight = 53 g, 1, 3, 5, or 7 daily CHIs) using a battery of well characterized tests in male mice;
Aim 1 B: Determine anatomical correlates to the behavioral deficits by characterizing histopathological changes in brain including cell death, gliosis, axonal damage, brain atrophy, edema, and blood-brain barrier damage.
Aim 2 : Using fMRI/BOLD, characterize the effects of single and 3 hit daily (3HD) vs. 3 hit weekly (3HW) CHI on cerebrovascular reactivity (CVR) at acute and chronic time points after injury. Test the hypothesis that abnormal reactivity of cerebral blood flow to inhaled CO2 is a physiological biomarker of repetitive concussions that occur within a vulnerable time period and are associated with long-term cognitive dysfunction. The proposed studies would lay the groundwork for future mechanistic/treatment studies of repetitive concussive TBI in adolescents.
The proposed work could impact public health in the short term by establishing a new adolescent repetitive concussive traumatic brain injury model in mice. In the long term, the work may help to validate cerebral blood flow reactivity as a potential biomarker for repetitive concussions, and speed development of treatments that would prevent or reduce long-term neurological deficits in adolescents with multiple concussions.
| Wu, Limin; Chung, Joon Y; Saith, Shivani et al. (2018) Repetitive head injury in adolescent mice: A role for vascular inflammation. J Cereb Blood Flow Metab :271678X18786633 |
| Jassam, Yasir N; Izzy, Saef; Whalen, Michael et al. (2017) Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift. Neuron 95:1246-1265 |
