Progressive long-term spatial memory loss following repeat concussive and subconcussive brain injury in mice, associated with dorsal hippocampal neuron loss, microglial phenotype shift, and vascular abnormalities.

There is considerable concern about the long-term deleterious effects of repeat head trauma on cognition, but little is known about underlying mechanisms and pathology. To examine this, we delivered four air blasts to the left side of the mouse cranium, a week apart, with an intensity that causes deficits when delivered singly and considered "concussive," or an intensity that does not yield significant deficits when delivered singly and considered "subconcussive." Neither repeat concussive nor subconcussive blast produced spatial memory deficits at 4 months, but both yielded deficits at 14 months, and dorsal hippocampal neuron loss. Hierarchical cluster analysis of dorsal hippocampal microglia across the three groups based on morphology and expression of MHCII, CX3CR1, CD68 and IBA1 revealed five distinct phenotypes. Types 1A and 1B microglia were more common in sham mice, linked to better neuron survival and memory, and appeared mildly activated. By contrast, 2B and 2C microglia were more common in repeat concussive and subconcussive mice, linked to poorer neuron survival and memory, and characterized by low expression levels and attenuated processes, suggesting they were de-activated and dysfunctional. In addition, endothelial cells in repeat concussive mice exhibited reduced CD31 and eNOS expression, which was correlated with the prevalence of type 2B and 2C microglia. Our findings suggest that both repeat concussive and subconcussive head injury engender progressive pathogenic processes, possibly through sustained effects on microglia that over time lead to increased prevalence of dysfunctional microglia, adversely affecting neurons and blood vessels, and thereby driving neurodegeneration and memory decline.

A new model of repeat mTBI in adolescent rats.

Sports-related injury is frequently associated with repeated diffuse and mild traumatic brain injury (mTBI). We combined two existing models for inducing TBI in rats, the Impact Acceleration and Controlled Cortical Impact models, to create a new method relevant to the study of cognitive sequelae of repeat mTBI in adolescent athletes. Repeated mTBI, such as those incurred in sports, can result in a wide range of outcomes, with many individuals experiencing no chronic sequela while others develop profound cognitive and behavioral impairments, typically in the absence of lasting motor symptoms or gross tissue loss appreciable antemortem. It is critical to develop models of mTBI and repeat mTBI that have the flexibility to assess multiple parameters related to injury (e.g. number and magnitude of impacts, inter-injury interval, etc) that are associated with brain vulnerability compared to normal recovery. We designed a 3D-printed plastic implant to permanently secure a metal disc to the skull of adolescent rats in order to induce multiple injuries without performing multiple survival surgeries and also to minimize pre-injury anesthesia time. Rats were randomly assigned to sham injury (n = 12), single injury (n = 12; injury on P41), or repeat injury (n = 14; injuries on P35, P38, and P41) groups. Compared to single injury and sham injury, repeat injuries caused increased toe pinch reflex latency (F(2,34) = 4.126, p < .05) and diminished weight gain (F(2, 34) = 4.767, p < .05). Spatial navigation was tested using Morris water maze, beginning one week after the final injury (P48). While there were no differences between groups during acquisition, both single and repeat injuries resulted in deficits on probe trial performance (p < .01 and p < .05 respectively). Single injury animals also exhibited a deficit in working memory deficit across three days of testing (p < .05). Neither injury group had neuronal loss in the hilus or CA3, according to stereological quantification of NeuN. Therefore, by implanting a helmet we have created a relevant model of sports-related injury and repeated mTBI that results in subtle but significant changes in cognitive outcome in the absence of significant hippocampal cell death.

Sarm1 loss reduces axonal damage and improves cognitive outcome after repetitive mild closed head injury.

One of the consistent pathologies associated with both clinical and experimental traumatic brain injury is axonal injury, especially following mild traumatic brain injury (or concussive injury). Several lines of experimental evidence have demonstrated a role for NAD+ metabolism in axonal degeneration. One of the enzymes that metabolizes NAD+ in axons is Sarm1 (Sterile Alpha and TIR Motif Containing 1), and its activity is thought to play a key role in axonal degeneration. Using a Sarm1 knock-out mouse, we examined if loss of Sarm1 offers axonal injury protection and improves cognitive outcome after repeated mild closed head injury (rmCHI). Our results indicate that rmCHI caused white matter damage that can be observed in the corpus callosum, cingulum bundle, alveus of the hippocampus, and fimbria of the fornix of wild-type mice. These pathological changes were markedly reduced in injured Sarm1-/- mice. Interestingly, the activation of astrocytes and microglia was also attenuated in the areas with white matter damage, suggesting reduced inflammation. Associated with these improved pathological outcomes, injured Sarm1-/- mice performed significantly better in both motor and cognitive tasks. Taken together, our results suggest that strategies aimed at inhibiting Sarm1 and/or restoring NAD+ levels in injured axons may have therapeutic utility.

Unintentional injuries after TBI: Potential risk factors, impacts, and prevention.

BACKGROUND: The top three causes of fatal unintentional injuries are falls, motor vehicle crashes, and being struck against or struck by objects or persons. These etiologies also happen to be the leading causes of TBI, a serious public health problem, in the US. Reduced cognitive functioning, poor decision making, increased risk taking, disinhibition, diminished safety skills and substance use, place individuals with TBI at an increased risk for subsequent unintentional injuries. The caregiving, psychological, social and financial burden of initial injuries is enormous. Unintentional injuries post-TBI add to that burden significantly. Many unintentional injuries can be prevented with simple education and environment and lifestyle changes. Injury prevention requires collaboration among many. OBJECTIVE: This literature review will share information regarding potential triggers or causes of unintentional injuries after TBI to identify potential issues. The many impacts of these injuries will be reviewed. Best practices in prevention will be presented. CONCLUSION: Ultimately, education, discussion, and awareness across multiple stakeholders can aid in preventing unintentional injuries after TBI.