CHIMERA: A transformational model of rodent traumatic brain injury
University of British Columbia, International Collaboration On Repair Discoveries
One important but poorly understood risk factor for dementia is a history of brain injury, including concussion. Studies in professional football players who have had hundreds of concussions show that their brains can have changes that overlap the brain changes in AD, including neurofibrillary tangles and amyloid deposits. To study how brain injury may set the stage for dementing disorders, we have developed a unique animal model of brain injury that accurately mimics human injury. However, we have so far studied brain injury only under a very specific set of experimental conditions, where male animals received two ‘mild’ TBIs, spaced 24h apart, that were each approximately equivalent to an NFL concussion. Under these conditions, injured animals developed memory and motor problems and had a diffuse patten of axonal damage throughout the brain. These findings are very similar to what happens after concussion in people. However, much remains to be learned.
The first question our project will answer is how the severity of a brain injury affects behavioral and biochemical changes in the brain. This will help us to better predict the long-term risks of a very mild injury, for example a fall off of a bike, compared to a more severe injury, for example a motor vehicle crash with loss of consciousness. Second, we will determine how many concussions can be tolerated before problems persist in the brain. Third, we will determine how long a recovery period must be to prevent additional damage by a second concussion. Importantly, we will answer all three questions using both male and female animals, as men and women may differ in their response to TBI. We will also use both rats and mice in our experiments. Rats are more suitable for studies on behavioral changes that occur after TBI, and clinical management of concussed people largely stems from their behavioral symptoms. However, mice offer a wide variety of genetically modified strains, including models of Alzheimer Disease, Parkinson Disease, and Fronto Temporal Dementia, so that we can study the risk of TBI on each of these neurodegenerative diseases.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
Approximately 200,000 traumatic brain injuries occur every year in Canada, leaving these individuals with perhaps up a 5-fold increased risk for neurodegenerative diseases including Alzheimer Disease, Parkinson Disease, and Fronto Temporal Dementia. However, there are no ‘typical’ TBI patients, as every injury is unique. This poses great challenges to perform controlled clinical studies to understand the long term consequences of brain injury. Our project will use our unique model system of TBI to fill in key knowledge gaps on how impact severity, number of impacts, and time between impacts affects behavioral and biochemical changes in the brain, thereby becoming a validated model for drug discovery efforts.
Our project will provide crucial knowledge about how the severity of brain injury, the number of concussions, and the time between repeated concussions each affect clinically relevant behavioral and biochemical changes in the brain, in both male and female animals. Answers to these questions will greatly help clinicians manage individuals who experience a brain injury and help to identify which patients may be at greatest risk for long-term consequences including eventually developing Alzheimer Disease, Parkinson Disease or Fronto Temporal Dementia.