Investigating the long-term effects of non-inertial low-intensity blast-induced mild traumatic brain injury in mice
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[EMBARGOED UNTIL 5/1/2024] In military contexts, mild traumatic brain injury (mTBI) is reported more than moderate or severe TBI and is frequently caused by low-intensity blast (LIB) exposure. Affected service members and veterans with an increased risk of neurological consequences that persist long after injury pose significant public health burdens. However, the contribution of LIB-induced mTBI causing these long-term neurological outcomes and their underlying mechanism(s) are incompletely understood. C57BL/6J male mice aged 2 months old were subjected to non-inertial LIB-induced mTBI using a well-defined model of open-field blast (OFB) generated with 350 grams of military grade C4 explosive from a 3-meter distance on 1-meter-tall platforms. Previous studies from our lab observed nanoscale abnormalities in mitochondria, asymmetric (excitatory) synapses, myelin and axonal degeneration examined by transmission electron microscopy. Neurobehavioral assessments revealed acute and sub-acute term deficits in learning and cognition, as well as anxiety-like activities. In the present study, LIB-exposed mice were evaluated 3 months after injury with a battery of the automated home-cage monitoring system and multi-domain behavioral paradigms--evaluating daily living, anxiety-related activities, cognition, sociability, and motor function. LIB exposure led to anxiety-related behaviors, as well as initial discrimination learning and cognitive flexibility deficits. To understand the potential mechanism underlying the neurocognitive deficits, we further used electrophysiology at 1- and 7-days, and 3 months post injury and proteomics at 3 months post injury. These studies revealed that LIB led to glutamatergic hyperexcitability and altered expression of SERPINs and other proteins involved in synaptic plasticity in the hippocampus that may contribute to the chronic cognitive dysfunction persisting 3 months. Overall, this platform offers a basis for future research to investigate the underlying biological mechanism(s) leading to behavioral changes that can provide valuable insights into developing a potential therapeutic strategy to ameliorate consequences of LIB injuries.