Traumatic Brain Injury As An Environmental Risk Factor For Neurodegeneration: Elucidating Causal Mechanisms With Drosophila

Janani Saikumar, University of Pennsylvania


Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide. TBI is not just the primary insult caused by a mechanical force impacting the head, but is a complex disease process with repercussions that continue to develop decades after the injury. There are no clinically proven therapeutics to combat this extensive secondary injury process. Even single TBIs contribute to the degenerative mechanisms, putting survivors of TBI at an increased risk for developing various neurodegenerative diseases including dementias such as Alzheimer’s disease, motor neuron disease, Parkinson’s disease and chronic traumatic encephalopathy. To study the neurodegenerative mechanisms associated with TBI, our lab developed a new model of closed-head TBI in Drosophila, termed dTBI. The device used to inflict dTBI employs a piezoelectric actuator to briefly and rapidly compress the fly head against the metal plates of a Heisenberg fly collar. The piezoelectric is supplied with an amplified voltage pulse whose amplitude is controlled through a potentiometer, while an Arduino microcontroller is used to set its duration. Together, these dictate the range of motion of the piezoelectric. By manipulating these variables, we have described 3 levels of injury severity – mild, moderate and severe – that compress the fly head by 35%, 40% and 45%, respectively. Most dTBI-injured flies experience an immediate ataxia, followed by a sustained loss in locomotor function, a progressive brain degeneration that is characterized by vacuoles, and a dose-dependent reduction in lifespan. The severe form of dTBI is characterized by early-onset cognitive loss, transient deficits in the blood-brain barrier and phagocytic glial function, and enhanced antioxidant, proteasomal and chaperone activity. An acute boost of the stress response system through increase of the transcriptional regulator heat shock factor, or through an environmental sub-acute heat stress alleviates the lifespan and brain degeneration deficits of the severe dTBI. Together, these results present a precise, regulatable model of closed-head injury in Drosophila demonstrating a remarkable phenotypic similarity to the mammalian TBI models, which can be used to harness the power of Drosophila genetics to perform large-scale genetic screens and facilitate the identification of fundamental mechanisms of brain injury.