Abstract
Blast induced neurotrauma (BINT) is a prevalent injury within military and civilian populations. The injury is characterized by persistent inflammation at the cellular level which manifests as a multitude of cognitive and functional impairments. Epigenetic regulation of transcription offers an important control mechanism for gene expression and cellular function which may underlie chronic inflammation and result in neurodegeneration. We hypothesize that altered histone acetylation patterns may be involved in blast induced inflammation and the chronic activation of glial cells. This study aimed to elucidate changes to histone acetylation occurring following injury and the roles these changes may have within the pathology. Sprague Dawley rats were subjected to either a 10 or 17 psi blast overpressure within an Advanced Blast Simulator (ABS). Sham animals underwent the same procedures without blast exposure. Memory impairments were measured using the Novel Object Recognition (NOR) test at 2 and 7 days post-injury. Tissues were collected at 7 days for Western blot and immunohistochemistry (IHC) analysis. Sham animals showed intact memory at each time point. The novel object discrimination decreased significantly between two and 7 days for each injury group (p < 0.05). This is indicative of the onset of memory impairment. Western blot analysis showed glial fibrillary acidic protein (GFAP), a known marker of activated astrocytes, was elevated in the prefrontal cortex (PFC) following blast exposure for both injury groups. Analysis of histone protein extract showed no changes in the level of any total histone proteins within the PFC. However, acetylation levels of histone H2b, H3, and H4 were decreased in both groups (p < 0.05). Co-localization immunofluorescence was used to further investigate any potential correlation between decreased histone acetylation and astrocyte activation. These experiments showed a similar decrease in H3 acetylation in astrocytes exposed to a 17 psi blast but not a 10 psi blast. Further investigation of gene expression by polymerase chain reaction (PCR) array, showed dysregulation of several cytokine and cytokine receptors that are involved in neuroinflammatory processes. We have shown aberrant histone acetylation patterns involved in blast induced astrogliosis and cognitive impairments. Further understanding of their role in the injury progression may lead to novel therapeutic targets.
Highlights
Mild traumatic brain injury (TBI) has been deemed the ‘‘signature’’ wound of recent military conflicts (Hoge et al, 2008)
Blue represents minimal time spent in that area while red represents the maximum amount of time spent during the trial
In order to test the hypothesis that aberrant histone acetylation may play a role in the chronic inflammatory response following blast induced neurotrauma (BINT), we investigated levels of inflammatory markers in the prefrontal cortex (PFC)
Summary
Mild traumatic brain injury (TBI) has been deemed the ‘‘signature’’ wound of recent military conflicts (Hoge et al, 2008). The injury is characterized by diffuse neurological damage that leads to long-term cognitive impairments. The molecular sequelae of the injury involves accumulation of reactive oxygen species that overwhelm and deplete endogenous antioxidant systems. Perivascular accumulation of reactive oxygen species can be detrimental to blood brain barrier (BBB) integrity through degradation of tight junctions (Shetty et al, 2014). Pre-clinical studies have focused on elucidating the temporal response of the injury and observed sustained glial cell activation, apoptosis, and cognitive impairments. Histological and neurochemical analyses have revealed sustained neurological damage involving continued neurodegeneration and inflammation 3 months following injury (Sajja et al, 2015)
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