New method to induce mild traumatic brain injury in rodents produces differential outcomes in female and male Sprague Dawley rats

Mild traumatic brain injury (mTBI) is an increasing public health concern as repetitive injuries can exacerbate existing neuropathology and result in increased neurologic deficits. In contrast to other models of repeated mTBI (rmTBI), our study focused on long-term white-matter abnormalities after bilateral mTBIs induced 7 days apart. A controlled cortical impact (CCI) was used to induce an initial mTBI to the right cortex of Single and rmTBI Sprague Dawley rats, followed by a second injury to the left cortex of rmTBI animals. Shams received only a craniectomy. Ex vivo diffusion tensor imaging (DTI), transmission electron microscopy (TEM), and histology were performed on the anterior corpus callosum at 60 days after injury. The rmTBI animals showed a significant bilateral increase in radial diffusivity (myelin), while only modest changes in axial diffusivity (axonal) were seen between the groups. Further, the rmTBI group showed an increased g-ratio and axon caliber in addition to myelin sheath abnormalities using TEM. Our DTI results indicate ongoing myelin changes, while the TEM data show continuing axonal changes at 60 days after rmTBI. These data suggest that bilateral rmTBI induced 7 days apart leads to progressive alterations in white matter that are not observed after a single mTBI.

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Examining the Progressive Behavior and Neuropathological Outcomes Associated with Chronic Repetitive Mild Traumatic Brain Injury in Rats

Cerebral Cortex Communications ◽

10.1093/texcom/tgaa002 ◽

2020 ◽

Vol 1 (1) ◽

Cited By ~ 2

Author(s):

Eric Eyolfson ◽

Glenn R Yamakawa ◽

Yannick Griep ◽

Reid Collins ◽

Thomas Carr ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Motor Behavior ◽

Functional Change ◽

Neurological Deficits ◽

Sprague Dawley ◽

Behavioral Impairment ◽

Motor Disturbance ◽

Ventricle Size

Abstract While the physical and behavioral symptomologies associated with a single mild traumatic brain injury (mTBI) are typically transient, repetitive mTBIs (RmTBI) have been associated with persisting neurological deficits. Therefore, this study examined the progressive changes in behavior and the neuropathological outcomes associated with chronic RmTBI through adolescence and adulthood in male and female Sprague Dawley rats. Rats experienced 2 mTBIs/week for 15 weeks and were periodically tested for changes in motor behavior, cognitive function, emotional disturbances, and aggression. Brain tissue was examined for neuropathological changes in ventricle size and presentation of Iba1 and GFAP. We did not see progressively worse behavioral impairments with the accumulation of injuries or time, but did find evidence for neurological and functional change (motor disturbance, reduced exploration, reduced aggression, alteration in depressive-like behavior, deficits in short-term working memory). Neuropathological assessment of RmTBI animals identified an increase in ventricle size, prolonged changes in GFAP, and sex differences in Iba1, in the corpus callosum, thalamus, and medial prefrontal cortex. Telomere length reduced exponentially as the injury load increased. Overall, chronic RmTBI did not result in accumulating behavioral impairment, and there is a need to further investigate progressive behavioral changes associated with repeated injuries in adolescence and young adulthood.

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Effect of Polyarginine Peptide R18D Following a Traumatic Brain Injury in Sprague-Dawley Rats

Current Therapeutic Research ◽

10.1016/j.curtheres.2020.100584 ◽

2020 ◽

Vol 92 ◽

pp. 100584

Author(s):

Li Shan Chiu ◽

Ryan S. Anderton ◽

Vince W. Clark ◽

Jane L. Cross ◽

Neville W. Knuckey ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Sprague Dawley ◽

Sprague Dawley Rats

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Progesterone and its Metabolite Allopregnanolone Differentially Regulate Hemostatic Proteins after Traumatic Brain Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.73 ◽

2008 ◽

Vol 28 (11) ◽

pp. 1786-1794 ◽

Cited By ~ 30

Author(s):

Jacob W VanLandingham ◽

Milos Cekic ◽

Sarah M Cutler ◽

Stuart W Hoffman ◽

Ebony R Washington ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Protein Expression ◽

Functional Outcomes ◽

Coagulation Factor ◽

Tissue Type ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Type Plasminogen Activator ◽

Coagulation Protein

Our laboratory has shown in numerous experiments that the neurosteroids progesterone (PROG) and allopregnanolone (ALLO) improve molecular and functional outcomes after traumatic brain injury (TBI). As coagulopathy is an important contributor to the secondary destruction of nervous tissue, we hypothesized that PROG and ALLO administration may also have a beneficial effect on coagulation protein expression after TBI. Adult male Sprague—Dawley rats were given bilateral contusions of the medial frontal cortex followed by treatments with PROG (16 mg/kg), ALLO (8 mg/kg), or vehicle (22.5% hydroxypropyl-β-cyclodextrin). Controls received no injury or injections. Progesterone generally maintained procoagulant (thrombin, fibrinogen, and coagulation factor XIII), whereas ALLO increased anticoagulant protein expression (tissue-type plasminogen activator, tPA). In addition, PROG significantly increased the ratio of tPA bound to neuroserpin, a serine protease inhibitor that can reduce the activity of tPA. Our findings suggest that in a model of TBI, where blood loss may exacerbate injury, it may be preferable to treat patients with PROG, whereas it might be more appropriate to use ALLO as a treatment for thrombotic stroke, where a reduction in coagulation would be more beneficial.

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Determining Sex-based Differences in Inflammatory Response in an Experimental Traumatic Brain Injury Model

10.21203/rs.3.rs-563986/v1 ◽

2021 ◽

Author(s):

Michael Collins Scott ◽

Karthik Prabhakara ◽

Andrew J. Walters ◽

Scott D. Olson ◽

Charles S. Cox

Keyword(s):

Traumatic Brain Injury ◽

Flow Cytometry ◽

Brain Injury ◽

Rodent Model ◽

Sprague Dawley ◽

Male And Female ◽

Cytokine Analysis ◽

Sprague Dawley Rats ◽

Significant Difference ◽

Bbb Permeability

Abstract Introduction: Traumatic brain injury is a leading cause of injury-related death and morbidity. Despite multiple clinical and pre-clinical studies, sex-based differences in blunt TBI outcomes based remain unclear. Our accepted rodent model of blunt traumatic brain injury was used to identify differences in the pathological features of blunt TBI. Methods: Male and female Sprague-Dawley rats were subjected to either controlled-cortical impact (CCI) or sham injury; brain tissue was harvested at different time intervals depending on the specific study. Blood-brain barrier (BBB) analysis was performed using Alexa Fluor 680 dye. Microglia and splenocytes were characterized with traditional flow cytometry; microglia markers such as CD45, P2Y12, CD32, and CD163 were analyzed with t-distributed stochastic neighbor embedding (t-SNE). Flow cytometry was used to study tissue cytokine levels, and supplemented with ELISAs of TNF-⍺, IL-17, and IL-1β of the ipsilateral hemisphere tissue were performed. Results: CCI groups had an increase in BBB permeability in both sexes. There was significant difference in the integrated density value of BBB permeability between the male CCI group and the female CCI group (female CCI mean = 3.08 x 108 ± 2.83 x 107, male CCI mean = 2.20 x 108 ± 4.05 x 106, p = 0.0210), but otherwise no differences were observed. Traditional flow cytometry did not distinguish any sex-based difference in regards to splenocyte cell population after CCI. t-SNE did not reveal any significant difference between the male and female injury groups in the activation of microglia. Cytokine analysis after injury by flow cytometry and ELISA did not reveal any significant differences between sex. Conclusion: In our rodent model of blunt traumatic brain injury, sex-based differences in pathology and neuroinflammation are limited, and only noted in one specific analysis of BBB permeability.

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Downregulation of microRNA-9-5p promotes synaptic remodeling in the chronic phase after traumatic brain injury

Cell Death and Disease ◽

10.1038/s41419-020-03329-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jingchuan Wu ◽

Hui Li ◽

Junchi He ◽

Xiaocui Tian ◽

Shuilian Luo ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neurovascular Unit ◽

Chronic Phase ◽

Synaptic Proteins ◽

Luciferase Reporter ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Brain Tissues

AbstractThe level of microRNA-9-5p (miRNA-9-5p) in brain tissues is significantly changed in the chronic phase after traumatic brain injury (TBI). However, the effect of miRNA-9-5p on brain function after TBI has not been elucidated. In this study, we used a controlled cortical impact (CCI) model to induce TBI in Sprague–Dawley rats. Brain microvascular endothelial cells (BMECs), astrocytes, and neurons were extracted from immature Sprague–Dawley rats and cocultured to reconstruct the neurovascular unit (NVU) in vitro. The results showed that downregulation of miRNA-9-5p in the chronic phase contributed to neurological function recovery by promoting astrocyte proliferation and increasing the release of astrocyte-derived neurotrophic factors around injured brain tissues after TBI. A dual-luciferase reporter assay validated that miRNA-9-5p was a post-transcriptional modulator of thrombospondin 2 (Thbs-2), and downregulation of miRNA-9-5p promoted Thbs-2 expression in astrocytes. Furthermore, we verified that Thbs-2 can promote Notch pathway activation by directly binding to Jagged and Notch. Through in vitro experiments, we found that the expression of synaptic proteins and the number of synaptic bodies were increased in neurons in the NVU, which was constructed using astrocytes pretreated with miRNA-9-5p inhibitor. Moreover, we also found that downregulation of miRNA-9-5p promoted Thbs-2 expression in astrocytes, which activated the Notch/cylindromatosis/transforming growth factor-β-activated kinase 1 pathway in neurons and promoted the expression of synaptic proteins, including post-synaptic density protein 95 and synaptotagmin. Based on these results, miRNA-9-5p may be a new promising prognostic marker and treatment target for TBI.

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A simple rat model of mild traumatic brain injury: device to reproduce anatomical and neurological changes of mild traumatic brain injury

10.7287/peerj.preprints.2037 ◽

2016 ◽

Author(s):

Ho Jeong Kim ◽

Soo Jeong Han

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Water Pressure ◽

Brain Mri ◽

Free Fall ◽

Absolute Number ◽

Grid Floor ◽

Sprague Dawley ◽

The Brain

Mild traumatic brain injury typically involves temporary impairment of neurological function. Previous studies used the water pressure or rotational injury for designing the device to make a rat mild traumatic brain injury model. The objective of this study was to make a simple model of mild traumatic brain injury in rat. The device consisted of a free-fall impactor that was targeted onto the rat skull. The weight (175g) was freely dropped 30cm to rat’s skull bregma. We installed a safety device made of acrylic panel. To confirm a mild traumatic brain injury in 36 Sprague–Dawley rats, we performed the brain magnetic resonance image(MRI) within 24 hours after injury. We evaluated behavior and chemical changes in rats before and after mild traumatic brain injury. The brain MRI did not show high or low signal intensity in 34 rats. The mobility on grid floor was decreased after mild traumatic brain injury. Absolute number of foot-fault and foot-fault ratio were decreased after mild traumatic brain. But the difference of ratio was lesser than absolute number of foot-fault. These results show that the device is capable of reproducing mild traumatic brain injury in rat. Our device can reduce the potential to cause brain hemorrhage and reflect the mechanism of real mild traumatic brain injury compared with existing methods and behaviors. This model can be useful in exploring physiology and management of mild traumatic brain injury.

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A simple rat model of mild traumatic brain injury: a device to reproduce anatomical and neurological changes of mild traumatic brain injury

PeerJ ◽

10.7717/peerj.2818 ◽

2017 ◽

Vol 5 ◽

pp. e2818 ◽

Cited By ~ 4

Author(s):

Ho Jeong Kim ◽

Soo Jeong Han

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Water Pressure ◽

Brain Mri ◽

Free Fall ◽

Absolute Number ◽

Grid Floor ◽

Sprague Dawley ◽

The Brain

Mild traumatic brain injury typically involves temporary impairment of neurological function. Previous studies used water pressure or rotational injury for designing the device to make a rat a mild traumatic brain injury model. The objective of this study was to make a simple model of causing mild traumatic brain injury in rats. The device consisted of a free-fall impactor that was targeted onto the rat skull. The weight (175 g) was freely dropped 30 cm to rat’s skull bregma. We installed a safety device made of acrylic panel. To confirm a mild traumatic brain injury in 36 Sprague-Dawley rats, we performed magnetic resonance imaging (MRI) of the brain within 24 h after injury. We evaluated behavior and chemical changes in rats before and after mild traumatic brain injury. The brain MRI did not show high or low signal intensity in 34 rats. The mobility on grid floor was decreased after mild traumatic brain injury. The absolute number of foot-fault and foot-fault ratio were decreased after mild traumatic brain injury. However, the difference of the ratio was a less than absolute number of foot-fault. These results show that the device is capable of reproducing mild traumatic brain injury in rats. Our device can reduce the potential to cause brain hemorrhage and reflect the mechanism of real mild traumatic brain injury compared with existing methods and behaviors. This model can be useful in exploring physiology and management of mild traumatic brain injury.

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