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Introduction The pathology resulting from concurrent traumatic brain injury (TBI) and hemorrhagic shock (HS; TBI+HS) are leading causes of mortality and morbidity worldwide following trauma. However, the majority of large animal models of TBI+HS have utilized focal/contusional injuries rather than incorporating the types of brain trauma (closed-head injury caused by dynamic acceleration) that typify human injury. Objective To examine survival rates and effects on biomarkers from rotational TBI with two levels of HS. Methods Twenty-two sexually mature Yucatan swine (30.39 ± 2.25 kg; 11 females) therefore underwent either Sham trauma procedures (n = 6) or a dynamic acceleration TBI combined with either 55% (n = 8) or 40% (n = 8) blood loss in this serial study. Results Survival rates were significantly higher for the TBI+40% (87.5%) relative to TBI+55% (12.5%) cohort, with the majority of TBI+55% animals expiring within 2 h post-trauma from apnea. Blood-based neural biomarkers and immunohistochemistry indicated evidence of diffuse axonal injury (increased NFL/Aβ42), blood-brain barrier breach (increased immunoglobulin G) and inflammation (increased glial fibrillary acidic protein/ionized calcium-binding adaptor molecule 1) in the injured cohorts relative to Shams. Invasive hemodynamic measurements indicated increased shock index and decreased pulse pressure in both injury cohorts, with evidence of partial recovery for invasive hemodynamic measurements in the TBI+40% cohort. Similarly, although both injury groups demonstrated ionic and blood gas abnormalities immediately postinjury, metabolic acidosis continued to increase in the TBI+55% group ∼85 min postinjury. Somewhat surprisingly, both neural and physiological biomarkers showed significant changes within the Sham cohort across the multi-hour experimental procedure, most likely associated with prolonged anesthesia. Conclusion Current results suggest the TBI+55% model may be more appropriate for severe trauma requiring immediate medical attention/standard fluid resuscitation protocols whereas the TBI+40% model may be useful for studies of prolonged field care.

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.

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., 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.

In songbirds and mammals, brain injury results in the upregulation of aromatase (estrogen synthase) expression in astroglia. The resulting, presumed synthesis of neural estradiol (E(2)) has neuroprotective effects including a decrease in neurodegeneration, neuroinflammation, and apoptosis. The development of therapeutic tools that exploit estrogenic neuroprotection in the treatment of neurotrauma require a precise quantification of the endogenous changes in neural aromatase and estradiol following brain injury. Surprisingly, the expected increase in neural estrogens following brain injury has not been demonstrated. Further, we are just beginning to unravel the mechanisms behind the protective effects of centrally synthesized estradiol. In the current study, levels of aromatase immunoprotein, neural estradiol, and steroid receptor mRNA were quantified in adult male and female zebra finches 48 hours following a unilateral penetrating brain injury. Both aromatase and estradiol were upregulated in the injured hemisphere of the brain compared to the uninjured hemisphere, demonstrating, for the first time, a robust increase in neural estradiol levels following injury. We did not detect an effect of injury on mRNA expression of the estrogen receptors (ER)-α, ER-β, or GPER-1, but observed a significant decrease in androgen receptor (AR) transcription in the injured lobe relative to the contralateral uninjured hemisphere. We conclude that mechanical damage causes a dramatic increase in local aromatization, and the resultant high levels of central estradiol are available to modulate steroid sensitive targets. Studies using alternate methods of receptor detection and/or time points may be necessary to understand the complete suite of mechanisms underlying the neuroprotective effects of induced estrogen synthesis in this animal model.

Estrogens affect the vertebrate brain throughout life and modulate a diverse set of physiological endpoints, including neuroprotection and repair. Here we narrate our journey through the discovery and continued interest in one particular form of estradiol provision during neurotrauma—the induced expression of aromatase (estrogen synthase) in astrocytes, and its effects on the protection and repair of neural circuits. We discuss what we have learned about brain injury and astrocytic aromatization in the songbird, a time-tested animal model in neuroendocrinology. We first discuss the discovery of aromatase expression in astroglia, and the molecular and physiological pathways potentially responsible for this induction. Finally, we focus attention on the effects of astrocytic estradiol provision on cell turnover. It is our intent to tell the reader a story about this relatively novel form of spatial and temporally discrete estrogen provision in a resilient vertebrate brain.