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 in concussed athletes, war veterans, and others 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. Thus, the long term safety of "return to play/battlefield" guidelines after suffering one or more concussive TBIs is not well justified experimentally. To begin to address these knowledge gaps, we recently described a novel model of concussive TBI that produces early cognitive dysfunction in the absence of demonstrable acute and chronic cell death/loss. We have now begun development of a repetitive mild concussive closed head injury (rCHI) model in which injury is delivered daily, weekly, or monthly, and in which robust and long lasting cognitive deficits are induced in the absence of seizures, loss of consciousness, and gross structural brain lesions. We now propose to develop this rCHI model with respect to short- and long-term cognitive deficits and histopathology with the following Specific Aims:
Aim 1 : Characterize the cognitive deficits associated with repetitive CHI (rCHI, height = 28 in, weight = 53 g, energy level = 0.37 J) using three well-characterized tests of hippocampal-dependent and - independent learning: (1) Morris water maze (MWM), (2) working memory using a matching to place version of the MWM, and (3) fear conditioning.
Aim 2 : Characterize histopathological changes in brain at the level of rCHI (0.37 J) assessed in Aim 1: Acute cellular injury and death (Fluoro Jade B, TUNEL, in vivo propidium iodide, and silver staining), axonal injury (APP histochemistry, electron microscopy, and silver staining), and neuroinflammation (GFAP and IBA-1 histochemistry). The proposed studies would lay the groundwork for future mechanistic/treatment studies of repetitive concussion TBI.
The proposed work could impact public health in the short term by establishing a new repetitive concussive traumatic brain injury model in mice. In the long term, the work may speed development of treatments that would prevent or reduce long term neurological deficits in people with multiple concussions.
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|Mannix, Rebekah; Meehan, William P; Mandeville, Joseph et al. (2013) Clinical correlates in an experimental model of repetitive mild brain injury. Ann Neurol 74:65-75|
|Meehan 3rd, William P; Zhang, Jimmy; Mannix, Rebekah et al. (2012) Increasing recovery time between injuries improves cognitive outcome after repetitive mild concussive brain injuries in mice. Neurosurgery 71:885-91|