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Cognitive dysfunction is a common, often long-term complaint following acquired traumatic brain injury (TBI). Cognitive deficits suggest dysfunction in hippocampal circuits. The goal of the studies described here is to phenotype in both male and female mice the hippocampal-dependent learning and memory deficits resulting from TBI sustained by the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) device—a model that delivers both a contact–concussion injury as well as unrestrained rotational head movement. Mice sustained either sham procedures or four injuries (0.7 J, 24-h intervals). Spatial learning and memory skills assessed in the Morris water maze (MWM) approximately 3 weeks following injuries were significantly impaired by brain injuries; however, slower swimming speeds and poor performance on visible platform trials suggest that measurement of cognitive impairment with this test is confounded by injury-induced motor and/or visual impairments. A separate experiment confirmed hippocampal-dependent cognitive deficits with trace fear conditioning (TFC), a behavioral test less dependent on motor and visual function. Male mice had greater injury-induced deficits on both the MWM and TFC tests than female mice. Pathologically, the injury was characterized by white matter damage as observed by silver staining and glial fibrillary acidic protein (astrogliosis) in the optic tracts, with milder damage seen in the corpus callosum, and fimbria and brainstem (cerebral peduncles) of some animals. No changes in the density of GABAergic parvalbumin-expressing cells in the hippocampus, amygdala, or parietal cortex were found. This experiment confirmed significant sexually dimorphic cognitive impairments following a repeated, diffuse brain injury. [ABSTRACT FROM AUTHOR]

There is strong evidence to suggest a link between repeated head trauma and cognitive and emotional disorders, and Repetitive concussive brain injuries (rCBI) may also be a risk factor for depression and anxiety disorders. Animal models of brain injury afford the opportunity for controlled study of the effects of injury on functional outcomes. In this study, male and cycling female C57BL/6J mice sustained rCBI (3x) at 24-hr intervals and were tested in a context and cued fear conditioning paradigm, open field (OF), elevated zero maze and tail suspension test. All mice with rCBI showed less freezing behavior than sham control mice during the fear conditioning context test. Injured male, but not female mice also froze less in response to the auditory cue (tone). Injured mice were hyperactive in an OF environment and spent more time in the open quadrants of the elevated zero maze, suggesting decreased anxiety, but there were no differences between injured mice and sham-controls in depressive-like activity on the tail suspension test. Pathologically, injured mice showed increased astrogliosis in the injured cortex and white matter tracts (optic tracts and corpus callosum). There were no changes in the number of parvalbumin-positive interneurons in the cortex or amygdala, but injured male mice had fewer parvalbumin-positive neurons in the hippocampus. Parvalbumin-reactive interneurons of the hippocampus have been previously demonstrated to be involved in hippocampal-cortical interactions required for memory consolidation, and it is possible memory changes in the fear-conditioning paradigm following rCBI are the result of more subtle imbalances in excitation and inhibition both within the amygdala and hippocampus, and between more widespread brain regions that are injured following a diffuse brain injury. [ABSTRACT FROM AUTHOR]

In civilian and military settings, mild traumatic brain injury (mTBI) is a common consequence of impacts to the head, sudden blows to the body, and exposure to high-energy atmospheric shockwaves from blast. In some cases, mTBI from blast exposure results in long-term emotional and cognitive deficits and an elevated risk for certain neuropsychiatric diseases. Here, we tested the effects of mTBI on various forms of auditory-cued fear learning and other measures of cognition in male C57BL/6J mice after single or repeated blast exposure (blast TBI; bTBI). bTBI produced an abnormality in the temporal organization of cue-induced freezing behavior in a conditioned trace fear test. Spatial working memory, evaluated by the Y-maze task performance, was also deleteriously affected by bTBI. Reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis for glial markers indicated an alteration in the expression of myelin-related genes in the hippocampus and corpus callosum 1–8 weeks after bTBI. Immunohistochemical and ultrastructural analyses detected bTBI-related myelin and axonal damage in the hippocampus and corpus callosum. Together, these data suggest a possible link between blast-induced mTBI, myelin/axonal injury, and cognitive dysfunction. [ABSTRACT FROM AUTHOR]

• Blast traumatic brain injury causes dynamic changes in brain metabolism. • Both increased and decreased brain metabolism occurs in multiple regions. • Acute changes in brain metabolism appear as early as 1–3 h post blast injury. • Changes in brain metabolism persist for up to 7 days in some regions. • Post-injury time of assessment is important for detecting changes in metabolism. Changes in 18F-fluorodeoxyglucose ([18F]FDG) measured by positron emission tomography (PET) can be used for the noninvasive detection of metabolic dysfunction following mild traumatic brain injury (mTBI). This study examined the time course of metabolic changes induced by primary blast injury by measuring regional [18F]FDG uptake. Adult, male rats were exposed to blast overpressure (15 psi) or sham injury, and [18F]FDG uptake was measured before injury and again at 1–3 h and 7 days post-injury, using both volume-of-interest (VOI) and voxel-based analysis. VOI analysis revealed significantly increased [18F]FDG uptake in corpus callosum and amygdala at both 1–3 h and 7 days following blast, while a transient decrease in uptake was observed in the midbrain at 1–3 h only. Voxel-based analysis revealed similar significant differences in uptake between sham and blast-injured rats at both time points. At 1–3 h post-injury, clusters of increased uptake were found in the amygdala, somatosensory cortex, and corpus callosum, while regions of decreased uptake were observed in midbrain structures (inferior colliculus, ventrolateral tegmental area) and dorsal auditory cortex. At day 7, a region of increased uptake in blast-injured rats was found in a cluster centered on the cortex-amygdala transition zone, while no regions of decreased uptake were observed. These results suggest that a relatively mild primary blast injury results in altered brain metabolism in multiple brain regions and that post-injury time of assessment is an important factor in observing regional changes in [18F]FDG uptake. [ABSTRACT FROM AUTHOR]