Investigating blast-related overpressure injury and recovery at the neuronal, structural, and behavioral levels - PROJECT SUMMARY/ABSTRACT Blast-related traumatic brain injury (bTBI) results from exposure to rapid overpressure waves and is prevalent in military settings but also affects civilian populations. These acute mechanical disruptions lead to a cascade of secondary effects that lead to neurodegeneration and persistent cognitive symptoms. It remains unclear how these effects, including neural hyperactivity, increased oxidative stress, and inflammation, contribute to post- injury recovery or long-lasting damage. As a result, no neuroprotective therapies are conclusively recommended. Experimental TBI studies are challenging due to wide variability among experimental methods, animal models, and treatment protocols, which has hampered understanding of underlying pathology mechanisms as well as the development of effective therapeutics. This project proposes a new, reproducible bTBI model in the nematode C. elegans that allows precise control of the blast pressure waveform and real-time measurement of neuronal activity and behavior in vivo. Invertebrates show striking similarities to mammals and, despite important differences in cell types, pathways, and molecules, have been instrumental in uncovering fundamental principles in neurobiology. Mammalian brains are vastly more complex, and blast overpressure waves reflect and refract through brain structures resulting in wide spatial and temporal variation. Nonetheless, our central hypothesis, supported by preliminary data, is that blast overpressure elicits injury in C. elegans similar to mammals at the microscale, neuron level, thus enabling thorough and efficient exploration of blast-induced injury conditions and cellular mechanisms. The objectives will be accomplished by two specific aims: Specific Aim 1 will assess the effects of a broad range of blast parameters, including magnitude, duration, waveform shape, and repetition on behavior, neural function, and structural damage, defining injury thresholds by their recovery potential. Specific Aim 2 will validate the method by examining the role of two secondary responses: neural hyperactivity and oxidative stress/inflammation. We will modulate them broadly using genetic and pharmacological techniques and specifically via TRPV4 ion channels and the Akt signaling pathway. Effective methods, doses, and time windows for suppressing each process will be identified by monitoring recovery in neural function, structure, and behavior over hours. This study is innovative because it uses a novel experimental approach that permits, for the first time, live neural recordings during overpressure injury, parallel exposure of many (up to 100's) animals at once, and the ability to track TBI progression within individuals. The proposed project is significant because it will (1) expand understanding of overpressure thresholds and repetitions that cause injury, (2) delineate how and when secondary effects contribute to neurodegeneration, (3) enable high-throughput evaluation of therapeutic targets for future verification studies in mammals, and (4) create meaningful research opportunities for undergraduates. p. 17
