Prophylactic Activation of Shh Signaling Attenuates TBI-Induced Seizures in Zebrafish by Modulating Glutamate Excitotoxicity through Eaat2a

Approximately 2 million individuals experience a traumatic brain injury (TBI) every year in the United States. Secondary injury begins within minutes after TBI, with alterations in cellular function and chemical signaling that contribute to excitotoxicity. Post-traumatic seizures (PTS) are experienced in an increasing number of TBI individuals that also display resistance to traditional anti-seizure medications (ASMs). Sonic hedgehog (Shh) is a signaling pathway that is upregulated following central nervous system damage in zebrafish and aids injury-induced regeneration. Using a modified Marmarou weight drop on adult zebrafish, we examined PTS following TBI and Shh modulation. We found that inhibiting Shh signaling by cyclopamine significantly increased PTS in TBI fish, prolonged the timeframe PTS was observed, and decreased survival across all TBI severities. Shh-inhibited TBI fish failed to respond to traditional ASMs, but were attenuated when treated with CNQX, which blocks ionotropic glutamate receptors. We found that the Smoothened agonist, purmorphamine, increased Eaat2a expression in undamaged brains compared to untreated controls, and purmorphamine treatment reduced glutamate excitotoxicity following TBI. Similarly, purmorphamine reduced PTS, edema, and cognitive deficits in TBI fish, while these pathologies were increased and/or prolonged in cyclopamine-treated TBI fish. However, the increased severity of TBI phenotypes with cyclopamine was reduced by cotreating fish with ceftriaxone, which induces Eaat2a expression. Collectively, these data suggest that Shh signaling induces Eaat2a expression and plays a role in regulating TBI-induced glutamate excitotoxicity and TBI sequelae.

A Simple and Cost-Effective Weight Drop Model to Induce Contusive Spinal Cord Injury: Functional and Histological Outcomes

Background: Animal spinal cord injury (SCI) models have provided a better perception of the mechanisms related to traumatic SCI and evaluation of the effectiveness of experimental therapeutic interventions. Objectives: The aim of this study is to develop a cost-effective modified Allen's device to induce contusive spinal cord injury. Methods: Adult male Wistar rats were subjected to contusive spinal cord injury using a customized weight drop model through 10-g weights delivered from a 25-mm height onto an exposed spinal cord. Locomotor and sensory function during 28 days were assessed. Moreover, histopathological changes were assessed at one week and 28 days post SCI. Results: All the SCI rats showed hind limb paralysis up to 48 h post SCI and neuropathic pain after injury. Histological changes similar to the previous reports for contusion model were observed. Conclusions: According to our findings, little variability was observed in the BBB score of individual rats at 28 days after injury. Our customized device to induce spinal cord injury is a simple and inexpensive alternative method to the highly sophisticated contusion device commonly used to induce SCI.

Localized, time-dependent responses of rat cranial bone to repeated mild traumatic brain injuries

While it is well-established that bone responds dynamically to mechanical loading, the effects of mild traumatic brain injury (mTBI) on cranial bone composition are unclear. We hypothesized that repeated mTBI (rmTBI) would change the microstructure of cranial bones, without gross skull fractures. To address this, young adult female Piebald Viral Glaxo rats received sham, 1x, 2x or 3x closed-head mTBIs delivered at 24h intervals, using a weight drop device custom built for reproducible impact. Skull bones were collected at 2 or 10 weeks after the final injury/sham procedure, imaged by micro computed tomography and analyzed at predetermined regions of interest. In the interparietal bone, proximal to the injury site, modest increases in bone thickness was observed at 2 weeks, particularly following 3x mTBI. By 10 weeks, 2x mTBI induced a robust increase in the volume and thickness of the interparietal bone, alongside a corresponding decrease in the volume of marrow cavities in the diploe region. In contrast, neither parietal nor frontal skull samples were affected by rmTBI. Our findings demonstrate time- and location-dependent effects of rmTBI on cranial bone structure, highlighting a need to consider microstructural alterations to cranial bone when assessing the consequences of rmTBI.

Chronic Histological Outcomes of Indirect Traumatic Optic Neuropathy in Adolescent Mice: Persistent Degeneration and Temporally Regulated Glial Responses

Injury to the optic nerve, termed, traumatic optic neuropathy (TON) is a known comorbidity of traumatic brain injury (TBI) and is now known to cause chronic and progressive retinal thinning up to 35 years after injury. Although animal models of TBI have described the presence of optic nerve degeneration and research exploring acute mechanisms is underway, few studies in humans or animals have examined chronic TON pathophysiology outside the retina. We used a closed-head weight-drop model of TBI/TON in 6-week-old male C57BL/6 mice. Mice were euthanized 7-, 14-, 30-, 90-, and 150-days post-injury (DPI) to assess histological changes in the visual system of the brain spanning a total of 12 regions. We show chronic elevation of FluoroJade-C, indicative of neurodegeneration, throughout the time course. Intriguingly, FJ-C staining revealed a bimodal distribution of mice indicating the possibility of subpopulations that may be more or less susceptible to injury outcomes. Additionally, we show that microglia and astrocytes react to optic nerve damage in both temporally and regionally different ways. Despite these differences, astrogliosis and microglial changes were alleviated between 14–30 DPI in all regions examined, perhaps indicating a potentially critical period for intervention/recovery that may determine chronic outcomes.

Chronic Histological Outcomes of Indirect Traumatic Optic NEU-Ropathy in Adolescent Mice: Persistent Degeneration and Tem-Porally Regulated Glial Responses

Injury to the optic nerve, termed, traumatic optic neuropathy (TON) is a known comorbidity of traumatic brain injury (TBI) and is now known to cause chronic and progressive retinal thinning up to 35 years after injury. Although animal models of TBI have described the presence of optic nerve degeneration and research exploring acute mechanisms is underway, few studies in humans or animals have examined chronic TON pathophysiology outside the retina. We used a closed-head weight-drop model of TBI/TON in 6-week-old male C57BL/6 mice. Mice were euthanized 7-, 14-, 30-, 90-, and 150-days post injury (DPI) to assess histological changes in the visual system of the brain spanning a total of 12 regions. We show chronic elevation of FluoroJade-C, indicative of neurodegeneration, throughout the time course. Intriguingly, FJ-C staining revealed a bimodal distribution of mice indicating the possibility of subpopulations that may be more or less sus-ceptible to injury outcomes. Additionally, we show that microglia and astrocytes react to optic nerve damage in both temporally and regionally different ways. Despite these differences, as-trogliosis and microglial changes were alleviated between 14-30 DPI in all regions examined, perhaps indicating a potential critical period for intervention/recovery that may determine chronic outcomes.

Noise Suppression Using a Near-Source Wavelet

Denoising becomes a non-trivial task when noise and signal overlap in multiple domains such as time, frequency, and velocity. Fortunately, signal and noise waveforms in general tend to remain morphologically different. This paper shows how morphological differences can be used to separate body-wave signals from other waveforms such as ground roll and cultural noise. The key was finding a wavelet that was a close approximation of the true source signature (SS) and remained uncontaminated by the Green’s function in any significant manner. An inverse filter designed using such a wavelet selectively compressed the body waves which was then extracted using median and low-pass filters. The overall phenomenon is explained with a synthetic example. The idea is also tested on a land dataset that was generated using a large weight drop source where a wavelet recorded ∼3 m from the source location fulfilled the criteria set in the proposed method. Results suggest that the incremental effort of recording an extra trace close to the source location during acquisition may provide previously unavailable denoising opportunities during processing although the trace itself may be redundant for imaging.

Mild Traumatic Brain Injury Contributes to the Development of Delayed Neuroinflammation

<b><i>Introduction:</i></b> In recent years, according to the literature, the problem of mild traumatic brain injury (mTBI) has become more and more urgent. Compared to moderate to severe craniocerebral trauma, mTBI occurs in a far greater number of people. The delayed sequelae caused by a single mTBI or multiple mTBIs are a significant public health problem. <b><i>Methods:</i></b> A weight-drop model was used for the formation of mTBI. A metal rod weighing 337 g with a blunt tip of 3 mm diameter was uplifted at 8 cm height and held by a lever. The trauma was created by lowering the lever and the rod and free-dropping onto the rat skull. In the cerebral cortex of experimental animals, we analyzed the level of microglial activity (Iba-1-positive system) and the expression of pro-inflammatory markers (IL1β, IL6, and CD86). Also, the expression level of the endocannabinoid system receptor (cannabinoid receptor type 1 [CB1]) was assessed in brain samples. <b><i>Results:</i></b> Experiments have shown that mTBI increases (1) the amount of microglia (iba-1) activated by the pro-inflammatory pathway (CD86); (2) the level of pro-inflammatory cytokines IL1β and IL6; and (3) CB1R activity. <b><i>Conclusion:</i></b> Overall, the results of this study indicate that mTBI induces a sustained neuroinflammatory response.

Prediction of one-third-octave band sound and vibration levels from heavy-hard impacts

Noise and vibration due to dropping hard heavy weights is a common source of disturbance and complaint in residential, commercial, and mixed-use building types. The authors and others have worked on developing methodologies to accurately, repeatably, and conveniently measure heavy-hard impact noise and vibration in the field based on a standard weight drop. Separately, systems have been created to measure the force being injected into a building from heavy-hard impact. It has been shown that this force data can be used to successfully predict vibration levels in buildings if in-situ transfer functions are known. In this paper, the authors will present a novel one-third-octave band prediction method using the laboratory force data and a reference impact sheet to predict field performance without the need to measure transfer function. The method is evaluated using both noise and vibration measurements.