GOING BALLISTIC: CHARACTERIZING A BALLISTIC IMPACTOR MODEL OF REPETITIVE TRAUMATIC BRAIN INJURY IN DROSOPHILA MELANOGASTER

Abstract

Traumatic brain injury (TBI) is a public health burden with short-term and long-term consequences for those who survive. Many survivors are at risk of additional head injuries and, therefore, neurodegenerative disease; repetitive TBI (rTBI) is highly associated with early aging and neurodegenerative diseases such as Alzheimer’s disease and chronic traumatic encephalopathy. While small mammalian models have been pivotal in understanding TBI, they are limited in recapitulating the full spectrum of injury outcomes and dynamics observed in humans. These models have difficulty replicating accelera- tion and deceleration forces and modeling location-specific neuropathology implicated in neurodegenerative disease. Large animal models offer advantages, in this regard, but are constrained by practical and ethical considerations. Non-mammalian models, such as Drosophila melanogaster, present promising alternatives. Here, we introduce an improved model of repetitive TBI in the Drosophila using a pneumatic ballistic impactor controlled by an Arduino microcontroller. We characterized this model in both male and female files by investigating locomotor, cognitive, proteomic, and neurodegenerative changes following repetitive head trauma. Our results demonstrate sexually dimorphic responses to injury, with injured males exhibiting dose-dependent locomotor deficits and injured females displaying greater tolerance to repetitive injury. However, both sexes exhibit significant deficits in decision-making after rTBI. Further, proteomic analysis revealed alterations in proteins that are associated with locomotory behavior, mitochondria, and energy production post-injury. Changes in proteins associated with locomotory behavior may correlate with the observed locomotor phenotypes after injury. When taken together with our findings of increased vacuolization area in injured flies, these results suggest potential implications for neurodegenerative disease. Overall, our study highlights an enhanced, head-specific model of rTBI in Drosophila for elucidating sexually dimorphic short- and long-term outcomes of rTBI at the proteomic, tissue, and behavioral levels, offering insights into the pathophysiology of repetitive brain trauma.