Using the CHIMERA Model to Dissect the Mechanisms by Which Abeta Modulates Chronic Fear Memory Extinction and Cognitive Flexibility After Traumatic Brain Injury

Every year in the USA, approximately 2.5 million people experience a traumatic brain injury (TBI), and there are currently approximately 3-5 million people living with the long-term effects of TBI. There is a pressing need to understand how TBI may increase the risk of dementias, including Alzheimer's disease (AD). Our team uses animals to understand the connections between TBI and AD. Specifically, we use the CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) animal model, which was developed at the University of British Columbia in 2014 to provide the TBI research community with a simple and non-surgical model of TBI that reliably mimics human TBI. Since CHIMERA was launched, it is increasingly recognized as an excellent model of diffuse brain injury that occurs in most TBIs, especially mild TBI including concussion. We recently used CHIMERA to study the long-term effects of TBI in a mouse model of AD, where mice were genetically engineered to express human Ab, the peptide that builds up as amyloid plaques in the AD brain. We gave AD mice (along with their wild-type littermates) two mild TBIs at 4 months of age and followed them up to 8 months after TBI. We found that the AD mice had the worst memory performance after TBI, where they showed greatly impaired decision-making and an inability to suppress fearful memories. We also found that these changes were unrelated to the development of amyloid plaques in the brains of the AD mice, which is a very important discovery because, in humans, amyloid load does not predict cognitive function. Thus, our newly published results show that we can use CHIMERA to understand how TBI affects cognitive pathways in the brain and to understand how Ab affects these pathways. However, as CHIMERA produces diffuse brain injury (i.e., injury throughout the whole brain), we now need to search through the entire brain to discover where the brain TBI and Ab affect neuronal function, when after TBI these changes occur, and what exactly these changes are. In this project, the Wellington and Cembrowski teams will work together to first map the 3D patterns of activated neurons after CHIMERA TBI in brain tissues using a new approach called light sheet microscopy. We will deliver CHIMERA TBI to mice engineered to 'glow green' wherever there are activated neurons and look through the entire brain at both early time points (6 hour, 2 weeks) and long-term time points (up to 8 months after injury). This will provide answers as to where and when TBI changes the patterns of neuronal activation, including understanding how long it takes the brain to return to normal. Importantly, we will also do this in an AD mouse model, so that effects of Ab on TBI-induced neuronal activation can be studied. Finally, we will zero in on regions in the brain that show the most prominent changes in neuronal activation and identify the entire gene expression patterns in these cells. This will tell us exactly what is different in these cells and help to understand what is caused by TBI and what is caused by Ab. Thus, our results will help to identify new ways to understand how TBI affects the risk of AD and related dementias, including potential new targets to develop or leverage drugs that could reduce the burden of long-term consequences of TBI.