Spreading Depolarizations Contribute to the Acute Behavior Deficits Associated With a Mild Traumatic Brain Injury in Mice.

Concussions or mild traumatic brain injuries (mTBIs) are often described and diagnosed by the acute signs and symptoms of neurological dysfunction including weakness, dizziness, disorientation, headaches, and altered mental state. The cellular and physiological mechanisms of neurological dysfunction and acute symptoms are unclear. Spreading depolarizations (SDs) occur after severe TBIs and have recently been identified in closed-skull mouse models of mTBIs. SDs are massive waves of complete depolarization that result in suppression of cortical activity for multiple minutes. Despite the clear disruption of brain physiology after SDs, the role of SDs in the acute neurological dysfunction and acute behavioral deficits following mTBIs remains unclear. We used a closed-skull mouse model of mTBI and a series of behavioral tasks collectively scored as the neurological severity score (NSS) to assess acute behavior. Our results indicate that mTBIs are associated with significant behavioral deficits in the open field and NSS tasks relative to sham-condition animals. The behavioral deficits associated with the mTBI recovered within 3 h. We show here that the presence of mTBI-induced bilateral SDs were significantly associated with the acute behavioral deficits. To identify the role of SDs in the acute behavioral deficits, we used exogenous potassium and optogenetic approaches to induce SDs in the absence of the mTBI. Bilateral SDs alone were associated with similar behavioral deficits in the open field and NSS tasks. Collectively, these studies demonstrate that bilateral SDs are linked to the acute behavioral deficits associated with mTBIs.

Repeated mild traumatic brain injuries impair visual discrimination learning in adolescent mice.

Cognitive deficits following a mild traumatic brain injury (mTBI) are common and are associated with learning deficits in school-age children. Some of these deficits include problems with long-term memory, working memory, processing speeds, attention, mental fatigue, and executive function. Processing speed deficits have been associated with alterations in white matter, but the underlying mechanisms of many of the other deficits are unclear. Without a clear understanding of the underlying mechanisms we cannot effectively treat these injuries. The goal of these studies is to validate a translatable touchscreen discrimination/reversal task to identify deficits in executive function following a single or repeated mTBIs. Using a mild closed skull injury model in adolescent mice we were able to identify clear deficits in discrimination learning following repeated injuries that were not present from a single mTBI. The repeated injuries were not associated with any deficits in motor-based behavior but did induce a robust increase in astrocyte activation. These studies provide an essential platform to interrogate the underlying neurological dysfunction associated with these injuries.

Spreading Depolarizations Occur in Mild Traumatic Brain Injuries and Are Associated with Postinjury Behavior.

Millions of people suffer mild traumatic brain injuries (mTBIs) every year, and there is growing evidence that repeated injuries can result in long-term pathology. The acute symptoms of these injuries may or may not include the loss of consciousness but do include disorientation, confusion, and/or the inability to concentrate. Most of these acute symptoms spontaneously resolve within a few hours or days. However, the underlying physiological and cellular mechanisms remain unclear. Spreading depolarizations (SDs) are known to occur in rodents and humans following moderate and severe TBIs, and SDs have long been hypothesized to occur in more mild injuries. Using a closed skull impact model, we investigated the presence of SDs immediately following a mTBI. Animals remained motionless for multiple minutes following an impact and once recovered had fewer episodes of movement. We recorded the defining electrophysiological properties of SDs, including the large extracellular field potential shifts and suppression of high-frequency cortical activity. Impact-induced SDs were also associated with a propagating wave of reduced cerebral blood flow (CBF). In the wake of the SD, there was a prolonged period of reduced CBF that recovered in approximately 90 min. Similar to SDs in more severe injuries, the impact-induced SDs could be blocked with ketamine. Interestingly, impacts at a slower velocity did not produce the prolonged immobility and did not initiate SDs. Our data suggest that SDs play a significant role in mTBIs and SDs may contribute to the acute symptoms of mTBIs.

Long-term Reductions in the Population of GABAergic Interneurons in the Mouse Hippocampus following Developmental Ethanol Exposure.

Developmental exposure to ethanol leads to a constellation of cognitive and behavioral abnormalities known as Fetal Alcohol Spectrum Disorders (FASDs). Many cell types throughout the central nervous system are negatively impacted by gestational alcohol exposure, including inhibitory, GABAergic interneurons. Little evidence exists, however, describing the long-term impact of fetal alcohol exposure on survival of interneurons within the hippocampal formation, which is critical for learning and memory processes that are impaired in individuals with FASDs. Mice expressing Venus yellow fluorescent protein in inhibitory interneurons were exposed to vaporized ethanol during the third trimester equivalent of human gestation (postnatal days 2-9), and the long-term effects on interneuron numbers were measured using unbiased stereology at P90. In adulthood, interneuron populations were reduced in every hippocampal region examined. Moreover, we found that a single exposure to ethanol at P7 caused robust activation of apoptotic neurodegeneration of interneurons in the hilus, granule cell layer, CA1 and CA3 regions of the hippocampus. These studies demonstrate that developmental ethanol exposure has a long-term impact on hippocampal interneuron survivability, and may provide a mechanism partially explaining deficits in hippocampal function and hippocampus-dependent behaviors in those afflicted with FASDs.