Traumatic Brain Injury Animals Research Articles

The impact of minocycline in inhibiting glial scar formation in rats with traumatic brain injury: A mini scoping review

Minocycline, a second-generation tetracycline derivative, is proven to inhibit glial scar formation in several neurological diseases. However, studies associating micocycline in traumatic brain injury (TBI) is very limited. This review aims to determine the role of minocycline in inhibiting glial scar or astrogliosis formation in TBI animal models. This scoping review includes original studies in PubMed, Science Direct, and Google Scholar databases published between 1 January 2012 to 31 December 2022, in full text, involving rodent research, and written in English. Two authors who followed the Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines, conducted the assessment independently. Of 2687 studies, 13 studies are reviewed. Two studies describe the benefits of minocycline in inhibiting glial scar formation in TBI, while 11 studies show that minocycline inhibits glial scar formation in diseases other than TBI. An explanation of the signaling pathways and cells involved in the mechanism of glial scar inhibition by minocycline can be found in ten articles, of which four observe the role of microglial cells, four observe the role of astrocyte cells, and two do not explain the mechanism. Research on the impact of minocycline in inhibiting glial scar formation in rats with TBI is limited. The results of this review support early research on the role of minocycline in inhibiting glial scar or astrogliosis in TBI, and similar studies in several other CNS diseases support this. However, the mechanism of minocycline's inhibitory pathway to glial scarring remains unclear.

Increased incidence of weight-loss-associated humane endpoints in rats administered buprenorphine slow-release LAB formulation following traumatic brain injury: a retrospective study.

Traumatic brain injury (TBI) remains a significant global public health epidemic with adverse health and cost implications. Due to its complex, heterogeneous nature and wide-ranging impacts, definitive TBI treatments remain elusive. As such, continued laboratory research using animal models is warranted. In accordance with guidelines set forth for the humane treatment of research animals, TBI animal models are often administered analgesics for pain management. The choice of drug, timing, dose, and formulation of analgesic can vary depending on the study's unique needs and can potentially and unintentionally influence experimental results. In TBI studies utilizing rats as animal models, buprenorphine is a common analgesic administered. In addition to pain management in such studies, investigators must also monitor the research animals post-operatively and make the decision for humane euthanasia before intended experimental survival timepoint if the animals are assessed to be excessively suffering. This study investigated the differences in adult, male Sprague Dawley rats used for various TBI studies that reached weight-loss-induced humane endpoints following a single administration of buprenorphine slow-release LAB (bup-SR-LAB) or buprenorphine slow-release HCl (bup-SR-HCl). Our findings indicate that TBI-induced rats receiving bup-SR-LAB in conjunction with a secondary surgical insult such as artificial intracranial pressure elevation and/or osmotic pump implantation reach a weight-loss-induced humane euthanasia endpoint more often compared to sham-injured rats. When stratifying into the same groups, we did not find this pattern to hold true for rats administered bup-SR-HCl. Overall, this study contributes to the limited body of literature addressing different analgesic formulations' effects on laboratory animals.

Selective COX-2 Inhibitors as Neuroprotective Agents in Traumatic Brain Injury.

Traumatic brain injury (TBI) is a significant contributor to mortality and morbidity in people, both young and old. There are currently no approved therapeutic interventions for TBI. Following TBI, cyclooxygenase (COX) enzymes generate prostaglandins and reactive oxygen species that perpetuate inflammation, with COX-1 and COX-2 isoforms providing differing responses. Selective COX-2 inhibitors have shown potential as neuroprotective agents. Results from animal models of TBI suggest potential treatment through the alleviation of secondary injury mechanisms involving neuroinflammation and neuronal cell death. Additionally, early clinical trials have shown that the use of celecoxib improves patient mortality and outcomes. This review aims to summarize the therapeutic effects of COX-2 inhibitors observed in TBI animal models, highlighting pertinent studies elucidating molecular pathways and expounding upon their mechanistic actions. We then investigated the current state of evidence for the utilization of COX-2 inhibitors for TBI patients.

The Surgical Method of Craniectomy Differentially Affects Acute Seizures, Brain Deformation and Behavior in a TBI Animal Model.

Traumatic brain injury (TBI) is the leading cause of morbidity and mortality worldwide. Multiple injury models have been developed to study this neurological disorder. One such model is the lateral fluid-percussion injury (LFPI) rodent model. The LFPI model can be generated with different surgical procedures that could affect the injury and be reflected in neurobehavioral dysfunction and acute EEG changes. A craniectomy was performed either with a trephine hand drill or with a trephine electric drill that was centered over the left hemisphere of adult, male Sprague Dawley rats. Sham craniectomy groups were assessed by hand-drilled (ShamHMRI) and electric-drilled (ShamEMRI) to evaluate by MRI. Then, TBI was induced in separate groups (TBIH) and (TBIE) using a fluid-percussion device. Sham-injured rats (ShamH/ShamE) underwent the same surgical procedures as the TBI rats. During the same surgery session, rats were implanted with screw and microwire electrodes positioned in the neocortex and hippocampus and the EEG activity was recorded 24 hours for the first 7 days after TBI for assessing the acute EEG seizure and Gamma Event Coupling (GEC). The electric drilling craniectomy induced greater tissue damage and sensorimotor deficits compared to the hand drill. Analysis of the EEG revealed acute seizures in at least one animal from each group after the procedure. Both TBI and Sham rats from the electric drill groups had a significant greater total number of seizures than the animals that were craniectomized manually (p<0.05). Similarly, EEG functional connectivity was lower in ShamE compared to ShamH rats. These results suggest that electrical versus hand drilling craniectomies produce cortical injury in addition to the LFPI which increases the likelihood for acute post-traumatic seizures. Differences in the surgical approach could be one reason for the variability in the injury that makes it difficult to replicate results between preclinical TBI studies.

Commentary: Three questions for the study of traumatic brain injury in animals.

Commentary: Three questions for the study of traumatic brain injury in animals.

Temporal variations in immune and inflammatory markers following rodent juvenile traumatic brain injury

Traumatic brain injury (TBI) is one of the leading causes of death and disability in the juvenile population. TBI is associated with elevations in inflammatory signaling. However, the temporal changes in immune and inflammatory markers following TBI, particularly in juvenile studies utilizing the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA), have not been fully elucidated. The current study aimed to determine the time course of changes to immune cell expression throughout the first four days following juvenile TBI via the CHIMERA. Male Long Evans rats sustained either a TBI or a Sham TBI via the CHIMERA on post-natal day (PND) 30. Sham animals were euthanized at 3 hours (h) post-injury. TBI animals were euthanized at 0, 3, 6, 12, 24, or 96 h post-injury. Hippocampus samples were collected for use in QRT-PCR. The mRNA expression of cytokines IL1b and TNF-α was significantly elevated at 6 h, and C1q C chain (C1QC), a dendritic cell marker, was significantly elevated at 24 h. The mRNA expression of CD68, a marker for macrophages, was significantly elevated at 6, 24, and 96 h post-injury compared to Sham. CD3G, a marker for T cells, was significantly elevated at 6 hours post-injury. However, the mRNA expression of PTPRC, a marker for leukocytes, was not significantly altered throughout the time periods evaluated. To follow up on these studies, juvenile rats were injured and brains and blood were harvested 48 h post-injury comparing Sham and TBI. Peripheral blood lymphocytes were obtained and sorted by marker-specific antibodies. In the peripheral blood, there was a significantly higher number of CD3+ total T cells, CD3+/CD8 cytotoxic T cells, and CD3+/CD4+ helper T cells in the TBI group compared to the Sham, but CD45R+ total B cells and natural killer (NK) cells were not significantly different. Superior hemi-sected cortices were also used for immune cell extraction. There was a significantly lower number of NK cells and CD45R+ total B cells in the TBI group compared to the Sham, but CD45+ leukocytes and CD3+ total T cells were not significantly different. Further work is needed to understand the relationship between the reduction of specific cells in the brain with the elevation of cells in the peripheral blood. This work is supported by T32HL105324 to AMS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Designer Receptor Exclusively Activated by Designer Drug (DREADD)-Mediated Activation of the Periaqueductal Gray Restores Nociceptive Descending Inhibition After Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) patients frequently experience chronic pain that can enhance their suffering and significantly impair rehabilitative efforts. Clinical studies suggest that damage to the periaqueductal gray matter (PAG) following TBI, a principal center involved in endogenous pain control, may underlie the development of chronic pain. We hypothesized that TBI would diminish the usual pain control functions of the PAG, but that directly stimulating this center using a chemogenetic approach would restore descending pain modulation. We used a well-characterized lateral fluid percussion model (1.3 ± 0.1 atm) of TBI in male rats (n = 271) and measured hindpaw mechanical nociceptive withdrawal thresholds using von Frey filaments. To investigate the role of the PAG in pain both before and after TBI, we activated the neurons of the PAG using a Designer Receptor Exclusively Activated by Designer Drug (DREADD) viral construct. Immunohistochemical analysis of brain tissue was used to assess the location and confirm the appropriate expression of the viral constructs in the PAG. Activation of the PAG DREADD using clozapine N-oxide (CNO) caused hindpaw analgesia that could be blocked using opioid receptor antagonist, naloxone, in uninjured but not TBI rats. Due to the importance of descending serotonergic signaling in modulating nociception, we ablated spinal serotonin signaling using 5,7-DHT. This treatment strongly reduced CNO-mediated anti-nociceptive effects in TBI but not uninjured rats. To define the serotonergic receptor(s) required for the CNO-stimulated effects in TBI rats, we administered 5-HT7 (SB-269970) and 5-HT1A (WAY-100635) receptor antagonists but observed no effects. The selective 5-HT2A receptor antagonist ketanserin, however, blocked CNO's effects in the DREADD expressing TBI but not DREADD expressing sham TBI animals. Blockade of alpha-1 adrenergic receptors with prazosin also had no effect after TBI. Descending pain control originating in the PAG is mediated through opioid receptors in uninjured rats. TBI, however, fundamentally alters the descending nociceptive control circuitry such that serotonergic influences predominate, and those are mediated by the 5-HT2A receptor. These results provide further evidence that the PAG is a key target for anti-nociception after TBI.

Nueroprotection by Anesthetics in Brain Injury Models

The aim of the study was to compare the effect of sevoflurane and chloral hydrate on the neurological status and volume of brain damage after trauma and ischemia in experimental models of traumatic brain injury (TBI) and focal ischemic stroke (IS) induced by photothrombosis (PT).Materials and methods. The experiments were performed on mongrel Wistar rats weighing 250–300 g (N=43). There were 4 groups: the Ischemia + Sevoflurane group (ISSEV) (N=10), the Ischemia + Chloral hydrate group (ISCH) (N=10), TBI + Sevoflurane group (TBISEV) (N=13), and TBI+Chloral hydrate group (TBICH) (N=10). Ischemic brain damage was modelled using Rose Bengal (RB) dye-induced PT, and TBI was modelled using mechanical force-induced concussion.Results. MRI findings indicate lower volumes of brain damage (mm³) in rats from TBISEV group compared with the TBICH group (19±5 vs. 60±5, P&lt;0.0001), and in the ISSEV group compared with the ISCH group (9.8±1.5 vs. 21.5±2, P=0.0016). Moreover, there was a significant difference between ISSEV and ISCH groups based on the protocol assessment of neurological status on day 14 with higher scores in ISSEV (11.4±1.8 vs. 4.9±2.6, P&lt;0.0001).Conclusion. Taking into account the data obtained, we recommend a careful choice of anesthesia when modeling ischemic stroke and traumatic brain injury in animals. In particular, the neuroprotective effect of sevoflurane should be taken into account in the PT and TBI models.

Transcranial Photobiomodulation and Chronic Traumatic Brain Injury

Traumatic brain injury (TBI) is a common cause of neurologic morbidity for which few effective therapies exist, especially during the chronic stage. A potential therapy for chronic TBI is transcranial photobiomodulation (tPBM). tPBM is a noninvasive neuromodulation technique that uses light to stimulate the cortex and increase blood flow and metabolism while also enhancing cognition and improving affect. There has been much work focusing on the efficacy of tPBM in acute TBI in small animals, but much less work has focused on chronic TBI. Patients with chronic TBI manifest microvascular injury, which may serve as a modifiable treatment target for tPBM. There is a need to study and improve tPBM, as the currently implemented protocols targeting microvascular injury have been relatively unsuccessful. This review includes 16 studies, which concluded that after tPBM application, there were improvements in neuropsychological outcomes in addition to increases in cerebral blood flow. However, these conclusions are confounded by differing tPBM parameters, small sample sizes, and heterogenous TBI populations. While these results are encouraging, there is a need to further understand the therapeutic potential of tPBM in chronic TBI.

White Matter Integrity and Motor Function Disruption Due to Traumatic Brain Injury in Piglets: Impacts on Motor-Related Brain Fibers.

Pediatric traumatic brain injury (TBI) often induces significant disability in patients, including long-term motor deficits. Early detection of injury severity is key in determining a prognosis and creating appropriate intervention and rehabilitation plans. However, conventional magnetic resonance imaging (MRI) scans, such as T2 Weighted (T2W) sequences, do not reliably assess the extent of microstructural white matter injury. Diffusion tensor imaging (DTI) tractography enables three-dimensional reconstruction of specific white matter tracts throughout the brain in order to detect white matter injury based on anisotropic diffusion. The objective of this study was to employ DTI tractography to detect acute changes to white matter integrity within the intersecting fibers of key motor-related brain regions following TBI. Piglets were assigned to either the sham craniectomy group (sham; n = 6) or the controlled cortical impact TBI group (TBI; n = 6). Gait and MRI were collected at seven days post-surgery (DPS). T2W sequences confirmed a localized injury predominately in the ipsilateral hemisphere in TBI animals. TBI animals, relative to sham animals, showed an increased apparent diffusion coefficient (ADC) and decreased fractional anisotropy (FA) in fiber bundles associated with key brain regions involved in motor function. TBI animals exhibited gait deficits, including stride and step length, compared to sham animals. Together these data demonstrate acute reductions in the white matter integrity, measured by DTI tractography, of fibers intersecting key brain regions that strongly corresponded with acute motor deficits in a pediatric piglet TBI model. These results provide the foundation for the further development of DTI-based biomarkers to evaluate motor outcomes following TBI.

Engineered Dual Antioxidant Enzyme Complexes Targeting ICAM-1 on Brain Endothelium Reduce Brain Injury-Associated Neuroinflammation.

The neuroinflammatory cascade triggered by traumatic brain injury (TBI) represents a clinically important point for therapeutic intervention. Neuroinflammation generates oxidative stress in the form of high-energy reactive oxygen and nitrogen species, which are key mediators of TBI pathology. The role of the blood-brain barrier (BBB) is essential for proper neuronal function and is vulnerable to oxidative stress. Results herein explore the notion that attenuating oxidative stress at the vasculature after TBI may result in improved BBB integrity and neuroprotection. Utilizing amino-chemistry, a biological construct (designated "dual conjugate" for short) was generated by covalently binding two antioxidant enzymes (superoxide dismutase 1 (SOD-1) and catalase (CAT)) to antibodies specific for ICAM-1. Bioengineering of the conjugate preserved its targeting and enzymatic functions, as evaluated by real-time bioenergetic measurements (via the Seahorse-XF platform), in brain endothelial cells exposed to increasing concentrations of hydrogen peroxide or a superoxide anion donor. Results showed that the dual conjugate effectively mitigated the mitochondrial stress due to oxidative damage. Furthermore, dual conjugate administration also improved BBB and endothelial protection under oxidative insult in an in vitro model of TBI utilizing a software-controlled stretching device that induces a 20% in mechanical strain on the endothelial cells. Additionally, the dual conjugate was also effective in reducing indices of neuroinflammation in a controlled cortical impact (CCI)-TBI animal model. Thus, these studies provide proof of concept that targeted dual antioxidant biologicals may offer a means to regulate oxidative stress-associated cellular damage during neurotrauma.

Enhancing axonal myelination: Clemastine attenuates cognitive impairment in a rat model of diffuse traumatic brain injury

Traumatic brain injury (TBI) has a significant impact on cognitive function, affecting millions of people worldwide. Myelin loss is a prominent pathological feature of TBI, while well-functioning myelin is crucial for memory and cognition. Utilizing drug repurposing to identify effective drug candidates for TBI treatment has gained attention. Notably, recent research has highlighted the potential of clemastine, an FDA-approved allergy medication, as a promising pro-myelinating drug. Therefore, in this study, we aim to investigate whether clemastine can enhance myelination and alleviate cognitive impairment following mild TBI using a clinically relevant rat model of TBI. Mild diffuse TBI was induced using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA). Animals were treated with either clemastine or an equivalent volume of the vehicle from day 1 to day 14 post-injury. Following treatment, memory-related behavioral tests were conducted, and myelin pathology in the cortex and hippocampus was assessed through immunofluorescence staining and ProteinSimple® capillary-based immunoassay. Our results showed that TBI leads to significant myelin loss, axonal damage, glial activation, and a decrease in mature oligodendrocytes in both the cortex and hippocampus. The TBI animals also exhibited notable deficits in memory-related tests. In contrast, animals treated with clemastine showed an increase in mature oligodendrocytes, enhanced myelination, and improved performance in the behavioral tests. These preliminary findings support the therapeutic value of clemastine in alleviating TBI-induced cognitive impairment, with substantial clinical translational potential. Our findings also underscore the potential of remyelinating therapies for TBI.

Transplantation of miR-193b-3p-Transfected BMSCs Improves Neurological Impairment after Traumatic Brain Injury through S1PR3-Mediated Regulation of the PI3K/AKT/mTOR Signaling Pathway.

The aim of the present study was to explore the molecular mechanisms by which miR-193b-3p-trans-fected bone marrow mesenchymal stem cells (BMSCs) transplantation improves neurological impairment after traumatic brain injury (TBI) through sphingosine-1-phosphate receptor 3 (S1PR3)-mediated regulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway at the cellular and animal levels. BMSCs were transfected with miR-193b-3p. A TBI cell model was established by oxygen-glucose deprivation (OGD)-induced HT22 cells, and a TBI animal model was established by controlled cortical impact (CCI). Cell apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL), and cell activity was detected by a cell counting kit 8 (CCK-8) assay. Western blot analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of related proteins and genes. In this study, transfection of miR-193b-3p into BMSCs significantly enhanced BMSCs proliferation and differentiation. Transfection of miR-193b-3p reduced the levels of the interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-alpha (TNF-α) inflammatory factors in cells and mouse models, and it inhibited neuronal apoptosis, which alleviated OGD-induced HT22 cell damage and neural function damage in TBI mice. Downstream experiments showed that miR-193b-3p targeting negatively regulated the expression of S1PR3, promoted the activation of the PI3K/AKT/mTOR signaling pathway, and inhibited the levels of apoptosis and inflammatory factors, which subsequently improved OGD-induced neuronal cell damage and nerve function damage in TBI mice. However, S1PR3 overexpression or inhibition of the PI3K/AKT/mTOR signaling pathway using the IN-2 inhibitor weakened the protective effect of miR-193b-3p-transfected BMSCs on HT22 cells. Transplantation of miR-193b-3p-transfected BMSCs inhibits neurological injury and improves the progression of TBI in mice through S1PR3-mediated regulation of the PI3K/AKT/mTOR pathway.

Extracellular cold-inducible RNA-binding protein mediated neuroinflammation and neuronal apoptosis after traumatic brain injury.

Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI. TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay. There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor. These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.

Temporal shifts to the gut microbiome associated with cognitive dysfunction following high-fat diet consumption in a juvenile model of traumatic brain injury.

The gut-brain axis interconnects the central nervous system (CNS) and the commensal bacteria of the gastrointestinal tract. The composition of the diet consumed by the host influences the richness of the microbial populations. Traumatic brain injury (TBI) produces profound neurocognitive damage, but it is unknown how diet influences the microbiome following TBI. The present work investigates the impact of a chow diet versus a 60% fat diet (HFD) on fecal microbiome populations in juvenile rats following TBI. Twenty-day-old male rats were placed on one of two diets for 9 days before sustaining either a Sham or TBI via the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA). Fecal samples were collected at both 1- and 9-days postinjury. Animals were cognitively assessed in the novel object recognition tests at 8 days postinjury. Fecal microbiota DNA was isolated and sequenced. Twenty days of HFD feeding did not alter body weight, but fat mass was elevated in HFD compared with Chow rats. TBI animals had a greater percentage of entries to the novel object quadrant than Sham counterparts, P < 0.05. The Firmicutes/Bacteroidetes ratio was significantly higher in TBI than in the Sham, P < 0.05. Microbiota of the Firmicutes lineage exhibited perturbations by both injury and diet that were sustained at both time points. Linear regression analyses were performed to associate bacteria with metabolic and neurocognitive endpoints. For example, counts of Lachnospiraceae were negatively associated with percent entries into the novel object quadrant. Taken together, these data suggest that both diet and injury produce robust shifts in microbiota, which may have long-term implications for chronic health.NEW & NOTEWORTHY Traumatic brain injury (TBI) produces memory and learning difficulties. Diet profoundly influences the populations of gut microbiota. Following traumatic brain injury in a pediatric model consuming either a healthy or high-fat diet (HFD), significant shifts in bacterial populations occur, of which, some are associated with diet, whereas others are associated with neurocognitive performance. More work is needed to determine whether these microbes can therapeutically improve learning following trauma to the brain.

Polypathologies and Animal Models of Traumatic Brain Injury.

Traumatic brain injury (TBI) is an important health issue for the worldwide population, as it causes long-term pathological consequences for a diverse group of individuals. We are yet to fully elucidate the significance of TBI polypathologies, such as neuroinflammation and tau hyperphosphorylation, and their contribution to the development of chronic traumatic encephalopathy (CTE) and other neurological conditions. To advance our understanding of TBI, it is necessary to replicate TBI in preclinical models. Commonly used animal models include the weight drop model; these methods model human TBI in various ways and in different animal species. However, animal models have not demonstrated their clinical utility for identifying therapeutic interventions. Many interventions that were successful in improving outcomes for animal models did not translate into clinical benefit for patients. It is important to review current animal models and discuss their strengths and limitations within a TBI context. Modelling human TBI in animals encounters numerous challenges, yet despite these barriers, the TBI research community is working to overcome these difficulties. Developments include advances in biomarkers, standardising, and refining existing models. This progress will improve our ability to model TBI in animals and, therefore, enhance our understanding of TBI and, potentially, how to treat it.

Behavioral deficits after mild traumatic brain injury by fluid percussion in rats

Mild traumatic brain injury (TBI) can lead to various disorders, encompassing cognitive and psychiatric complications. While pre-clinical studies have long investigated behavioral alterations, the fluid percussion injury (FPI) model still lacks a comprehensive behavioral battery that includes psychiatric-like disorders. To address this gap, we conducted multiple behavioral tasks over two months in adult male Wistar rats, focusing on mild FPI. Statistical analyses revealed that both naive and sham animals exhibited an increase in sweet liquid consumption over time. In contrast, the TBI group did not show any temporal changes, although mild FPI did induce a statistically significant decrease in sucrose consumption compared to control groups during the chronic phase. Additionally, social interaction tasks indicated reduced contact time in TBI animals. The elevated plus maze task demonstrated an increase in open-arm exploration following fluid percussion. Nonetheless, no significant differences were observed in the acute and chronic phases for the forced swim and light–dark box tasks. Evaluation of three distinct memory tasks in the chronic phase revealed that mild FPI led to long-term memory deficits, as assessed by the object recognition task, while the surgical procedure itself resulted in short-term spatial memory deficits, as evaluated by the Y-maze task. Conversely, working memory remained unaffected in the water maze task. Collectively, these findings provide a nuanced characterization of behavioral deficits induced by mild FPI.

Fecal microbial transplantation limits neural injury severity and functional deficits in a pediatric piglet traumatic brain injury model.

Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. Due to bidirectional communication between the brain and gut microbial population, introduction of key gut bacteria may mitigate critical TBI-induced secondary injury cascades, thus lessening neural damage and improving functional outcomes. The objective of this study was to determine the efficacy of a daily fecal microbial transplant (FMT) to alleviate neural injury severity, prevent gut dysbiosis, and improve functional recovery post TBI in a translational pediatric piglet model. Male piglets at 4-weeks of age were randomly assigned to Sham + saline, TBI + saline, or TBI + FMT treatment groups. A moderate/severe TBI was induced by controlled cortical impact and Sham pigs underwent craniectomy surgery only. FMT or saline were administered by oral gavage daily for 7 days. MRI was performed 1 day (1D) and 7 days (7D) post TBI. Fecal and cecal samples were collected for 16S rRNA gene sequencing. Ipsilateral brain and ileum tissue samples were collected for histological assessment. Gait and behavior testing were conducted at multiple timepoints. MRI showed that FMT treated animals demonstrated decreased lesion volume and hemorrhage volume at 7D post TBI as compared to 1D post TBI. Histological analysis revealed improved neuron and oligodendrocyte survival and restored ileum tissue morphology at 7D post TBI in FMT treated animals. Microbiome analysis indicated decreased dysbiosis in FMT treated animals with an increase in multiple probiotic Lactobacilli species, associated with anti-inflammatory therapeutic effects, in the cecum of the FMT treated animals, while non-treated TBI animals showed an increase in pathogenic bacteria, associated with inflammation and disease such in feces. FMT mediated enhanced cellular and tissue recovery resulted in improved motor function including stride and step length and voluntary motor activity in FMT treated animals. Here we report for the first time in a highly translatable pediatric piglet TBI model, the potential of FMT treatment to significantly limit cellular and tissue damage leading to improved functional outcomes following a TBI.

Oxygen saturation profile in traumatic brain injury animal model after propofol administration.

Traumatic brain injury (TBI) is a traumatic that often leads to death due to untreatable cerebral hypoxia, indicated by oxygen saturation of <90%. Cerebral hypoxia is rarely monitored and thereby often overlooked as a cause of mortality and monitoring oxygen saturation is an accurate method to detect the condition. Propofol, an anesthetic agent, is commonly used in the management of TBI; however, its effect on brain tissue and cerebral hypoxia in TBI cases is not well understood. The aim of this study was to evaluate the profile of oxygen saturation in TBI animal model after propofol administration. A laboratory experimental study was conducted, involving 18 male Rattus novergicus rats (aged 4-8 weeks with weight between 150-200 grams) divided into three different treatment groups (non-TBI, TBI without propofol, and TBI with propofol). Oxygen saturation was measured regularly from day 1 to day 8 using pulse oximetry. The oxygen saturation percentages were compared between the TBI rats with and without propofol administration using independent Student t-rest. The results revealed significant reductions of oxygen saturation levels of animals within propofol-treated TBI group compared to that of the untreated-TBI group (p<0.05), with the average oxygen saturation ranging from 80.8%±6.96% vs 86.8%±5.48%. This finding suggests a reducing effect of propofol administration on oxygen saturation levels in rats with TBI and this potentially causes cerebral hypoxia.

Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury

Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Seizures and cortical spreading depolarization (CSD) are metabolically demanding processes that may worsen secondary brain injury. Metabolic stress has been associated with mitochondrial dysfunction, including impaired calcium homeostasis, reduced ATP production, and elevated ROS production. However, the association between mitochondrial impairment and vascular function after TBI is poorly understood. Here, we explored this association using a rodent closed head injury model. CSD is associated with neurobehavioral decline after TBI. Craniotomy was performed to elicit CSD via electrical stimulation or to induce seizures via 4-aminopyridine application. We measured vascular dysfunction following CSDs and seizures in TBI animals using laser doppler flowmetry. We observed a more profound reduction in local cortical blood flow in TBI animals compared to healthy controls. CSD resulted in mitochondrial dysfunction and pathological signs of increased oxidative stress adjacent to the vasculature. We explored these findings further using electron microscopy and found that TBI and CSDs resulted in vascular morphological changes and mitochondrial cristae damage in astrocytes, pericytes and endothelial cells. Overall, we provide evidence that CSDs induce mitochondrial dysfunction, impaired cortical blood flow, and neurobehavioral deficits in the setting of TBI.