Rapid Changes in Synaptic Strength After Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) affects millions of Americans annually, but effective treatments remain inadequate due to our poor understanding of how injury impacts neural function. Data are particularly limited for mild, closed-skull TBI, which forms the majority of human cases, and for acute injury phases, when trauma effects and compensatory responses appear highly dynamic. Here we use a mouse model of mild TBI to characterize injury-induced synaptic dysfunction, and examine its progression over the hours to days after trauma. Mild injury consistently caused both locomotor deficits and localized neuroinflammation in piriform and entorhinal cortices, along with reduced olfactory discrimination ability. Using whole-cell recordings to characterize synaptic input onto piriform pyramidal neurons, we found moderate effects on excitatory or inhibitory synaptic function at 48 h after TBI and robust increase in excitatory inputs in slices prepared 1 h after injury. Excitatory increases predominated over inhibitory effects, suggesting that loss of excitatory-inhibitory balance is a common feature of both mild and severe TBI. Our data indicate that mild injury drives rapidly evolving alterations in neural function in the hours following injury, highlighting the need to better characterize the interplay between the primary trauma responses and compensatory effects during this early time period.

Mild Blast Injury Produces Acute Changes in Basal Intracellular Calcium Levels and Activity Patterns in Mouse Hippocampal Neurons.

Mild traumatic brain injury (mTBI) represents a serious public health concern. Although much is understood about long-term changes in cell signaling and anatomical pathologies associated with mTBI, little is known about acute changes in neuronal function. Using large scale Ca2+ imaging in vivo, we characterized the intracellular Ca2+ dynamics in thousands of individual hippocampal neurons using a repetitive mild blast injury model in which blasts were directed onto the cranium of unanesthetized mice on two consecutive days. Immediately following each blast event, neurons exhibited two types of changes in Ca2+ dynamics at different time scales. One was a reduction in slow Ca2+ dynamics that corresponded to shifts in basal intracellular Ca2+ levels at a time scale of minutes, suggesting a disruption of biochemical signaling. The second was a reduction in the rates of fast transient Ca2+ fluctuations at the sub-second time scale, which are known to be closely linked to neural activity. Interestingly, the blast-induced changes in basal Ca2+ levels were independent of the changes in the rates of fast Ca2+ transients, suggesting that blasts had heterogeneous effects on different cell populations. Both types of changes recovered after ∼1 h. Together, our results demonstrate that mTBI induced acute, heterogeneous changes in neuronal function, altering intracellular Ca2+ dynamics across different time scales, which may contribute to the initiation of longer-term pathologies.

Region-specific alterations in astrocyte and microglia morphology following exposure to blasts in the mouse hippocampus.

Traumatic brain injury (TBI) is a serious public health concern, especially injuries from repetitive insults. The main objective of this study was to immunocytochemically examine morphological alterations in astrocytes and microglia in the hippocampus 48h following a single blast versus multiple blasts in adult C57BL/6 mice. The effects of ketamine and xylazine (KX), two common anesthetic agents used in TBI research, were also evaluated due to the confounding effect of anesthetics on injury outcome. Results showed a significant increase in hypertrophic microglia that was limited to the outer molecular layer of the dentate gyrus, but only in the absence of KX. Although the presence or absence of KX had no effect on astrocytes following a single blast, a significant decrease in astrocytic immunoreactivity was observed in the stratum lacunosum moleculare following multiple blasts in the absence of KX. The morphological changes in astrocytes and microglia reported in this study reveal region-specific differences in the absence of KX that could have significant implications for our interpretation of glial alterations in animal models of injury.

Visual system pathology in humans and animal models of blast injury.

Injury from blast exposure is becoming a more prevalent cause of death and disability worldwide. The devastating neurological impairments that result from blasts are significant and lifelong. Progress in the development of effective therapies to treat injury has been slowed by its heterogeneous pathology and the dearth of information regarding the cellular mechanisms involved. Within the last decade, a number of studies have documented visual dysfunction following injury. This brief review examines damage to the visual system in both humans and animal models of blast injury. The in vivo use of the retina as a surrogate to evaluate brain injury following exposure to blast is also highlighted.