Blast-induced mild-traumatic brain injury : identifying molecular biosignatures associated with post-traumatic deficits and disease progression
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Blast-induced mild traumatic brain injury (mTBI) is a critical concern for active-duty military personnel and veterans, leading to both acute and chronic neurological comorbidities that can greatly impact one's life. In recent years, it has become more widely recognized that low-intensity blast (LIB) exposure can cause a unique type of brain injury, differing from direct impact injuries to the head, which are the predominant cause of mTBI in the civilian population. LIB-induced mTBI is most common in military settings, particularly in training scenarios and combat-related operations. However, it was not until 2022 that blast exposure was established as a true cause of TBI, despite cases being tracked back to World War I. Since then, combined research efforts from government and military-funded programs have led to an increased understanding of the impact that LIBs have on brain health and neuropsychiatric function. However, much remains unknown about its pathophysiology and the factors driving chronic symptoms. Our lab addresses this critical gap by studying the behavioral and biochemical changes that occur in mice following LIB (< 50 kPa) exposure in a military-relevant open-field blast (OFB) setting. Our previous work showed that LIB-induced mTBI causes acute and chronic changes in neuronal structure at the nanoscale, alters protein expression related to metabolism as well as synaptic activity and plasticity in eloquent brain regions, induces neuropsychiatric symptoms, impairs cognition, and increases the expression of proteins found in neurodegenerative disorders. This thesis investigated the molecular, structural, and behavioral impact of LIB exposure, with a focus on region-specific molecular alterations, neurovascular unit (NVU) integrity, molecular changes linked to cognitive decline, and tauopathy-driven disease progression. Results showed that (i) exposure to LIB in the prone position induces greater acute changes to brain proteomes, most apparent in the cortex; (ii) LIB damages all structural constituents of the NVU, which may cause leakage of molecules into the plasma; (iii) LIB causes learning deficits post-LIB, which correlate with dysregulated phosphorylation events linked to synaptic dysfunction and cognitive decline; and (iv) the Tau-mTBI interaction drives neuropsychiatric impairments and ADRD progression. We also show that network analyses leveraging of artificial intelligence (AI) algorithms can identify LIB-exposed subjects at high risk for mTBI disease progression toward neurodegenerative disorders, which can transform the TBI screening process. Collectively, this work integrates behavioral, neuropathological, molecular, and computational approaches to advance our understanding of LIB-induced mTBI.
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Ph. D.