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Mild blast-induced traumatic brain injury (mild bTBI) has been labeled the 'signature injury' of modern conflict and has been reported to account for over half of battlefield-related TBIs. The aim of this investigation was to explore physical and biological mechanisms linking mild bTBI to development of post-blast neuropsychiatric abnormalities common among military veterans. Rats were exposed to mild bTBI and evaluated in behavioral metrics under normal and anxiogenic conditions. Post-mortem brain tissue was assessed via immunohistochemistry (IHC) and immunoblotting (IB), and daily postinjury urine samples were analyzed for changes in an oxidative stress metabolite. In addition, wireless deformation sensors were implanted to measure brain deformation in skull-brain phantoms and in vivo during blast exposure. Mild bTBI rats demonstrated psychosocial safety learning deficits from 9-14 days post-injury despite a lack of other motor or cognitive impairments. The severity of psychosocial dysfunction correlated with 24 hr post-injury urine metabolite elevations of a toxic posttrauma neurotoxin, acrolein, which was elevated for up to three days in urine and five days in brain tissue. Further, IB investigation of acrolein revealed significant elevations in regions associated with the psychosocial safety learning paradigm at 24 hours post-injury. Most other brain regions did not demonstrate significant elevation, suggesting intrinsic mechanical or biological susceptibility of these areas to our mild bTBI model. Additionally, IHC revealed blood-brain-barrier disruption and inflammatory activity in and around brain regions where acrolein was elevated. Significant brain deformation is suspected in these regions at the time of injury based on our phantomand in-vivo deformation recordings. Taken together, shock wave exposure can physically disrupt and biochemically dysregulate the brain in key regions involved in psychosocial learning. This study has significant implications suggesting that damage from mild bTBI can, if left unabated, directly lead to long-term neuropsychiatric consequences and reduced quality of life. [ABSTRACT FROM AUTHOR]

The increasing prevalence of blast-induced traumatic brain injury (bTBI) has contributed significantly to the rising incidence of longterm neurological deficits among military TBI victims. Notably, survivors of bTBI have three-fold higher susceptibility to Parkinson's disease (PD), which is characterized by a-synuclein protein-rich inclusions and the progressive degeneration of nigrostriatal dopaminergic neurons. However, preclinical studies on the pathophysiological changes in the brain post-bTBI, particularly for the signature mild injuries common in the military, have not been investigated in detail. The goal of this study is to evaluate biochemical changes in the brain post-mild bTBI that are known to be related to the pathologies of PD, aiming to understand key pathways leading to augmented vulnerability of PD post bTBI. Specifically, we have focused on the expression levels of a-synuclein, regulation of tyrosine hydroxylase (TH), both of which contribute to PD pathology, and acrolein, a marker of oxidative stress with widespread effects in neurotrauma and neurodegeneration, aiming to explore the synergistic mechanisms of bTBI and PD. We have shown that acrolein, a highly reactive aldehyde species and pro-inflammatory compound, persists up to a week following mild bTBI. In addition, we have also noted that acrolein may be a major contributing factor in the aberrant expression of a-synuclein and dysregulation of TH post-m-bTBI. Our data suggest acrolein, and more broadly oxidative stress, is likely a point of convergence between mild blast TBI and PD, and plays a critical role in the higher incidence of PD in bTBI victims. These results are expected to advance our understanding of the long-term consequences of blast-related injuries leading to the development of PD. Such efforts could eventually lead to the establishment of biomarkers for earlier diagnosis as well as strategies for prevention and treatment to curtail the elevating incidence of post-bTBI PD. Ultimately, we hope to significantly improve the quality of life for the military men and women who suffer daily from the long-lasting effects of bTBI. [ABSTRACT FROM AUTHOR]