Murine Model of Controlled Cortical Impact for the Induction of Traumatic Brain Injury

Schwulst, Steven J.; Islam, Mecca B.A.R.

doi:10.3791/60027

Cited by 12 publications

(9 citation statements)

References 19 publications

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“…TBI or sham injury was induced via controlled cortical impact (CCI), as previously published by our laboratory (22). Animals were anesthetized with 50 mg/kg Kataset Ketamine (Fort Dodge, IA) and 2.5 mg/kg xylazine (AnaSed; Shenandoah, IA) via intraperitoneal injection.…”

Section: Methodsmentioning

confidence: 99%

Microglia and Infiltrating T-Cells Adopt Long-Term, Age-Specific, Transcriptional Changes After Traumatic Brain Injury in Mice

Chen

Islam

Ford

et al. 2022

Shock

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Aged traumatic brain injury (TBI) patients suffer increased mortality and long-term neurocognitive and neuropsychiatric morbidity compared with younger patients. Microglia, the resident innate immune cells of the brain, are complicit in both. We hypothesized that aged microglia would fail to return to a homeostatic state after TBI and adopt a long-term injury-associated state within aged brains compared with young brains after TBI. Young and aged male C57BL/6 mice underwent TBI via controlled cortical impact versus sham injury and were sacrificed 4 months post-TBI. We used single-cell RNA sequencing to examine age-associated cellular responses after TBI. Brains were harvested, and CD45+ cells were isolated via fluorescence-activated cell sorting. cDNA libraries were prepared using the 10x Genomics Chromium Single Cell 3′ Reagent Kit, followed by sequencing on a HiSeq 4,000 instrument and computational analyses. Post-injury, aged mice demonstrated a disparate microglial gene signature and an increase in infiltrating T cells compared with young adult mice. Notably, aged mice post-injury had a subpopulation of age-specific, immune-inflammatory microglia resembling the gene profile of neurodegenerative disease-associated microglia with enriched pathways involved in leukocyte recruitment and brain-derived neurotrophic factor signaling. Meanwhile, post-injury, aged mice demonstrated heterogeneous T-cell infiltration with gene profiles corresponding to CD8 effector memory, CD8 naive-like, CD8 early active T cells, and Th1 cells with enriched pathways, such as macromolecule synthesis. Taken together, our data showed that the aged brain had an age-specific gene signature change in both T-cell infiltrates and microglia, which may contribute to its increased vulnerability to TBI and the long-term sequelae of TBI.

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Section: Methodsmentioning

confidence: 99%

Microglia and Infiltrating T-Cells Adopt Long-Term, Age-Specific, Transcriptional Changes After Traumatic Brain Injury in Mice

Chen

Islam

Ford

et al. 2022

Shock

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“…However, differing opinions do exist in the field. Schwulst and Islam believed that the sham‐injury group should not undergo craniotomy (Schwulst & Islam, 2019). This ongoing disagreement can potentially be solved by more careful experimental designs, for example, by incorporating “sham” procedures that can distinguish among sham, experimentally injured, and healthy animals (Cole et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Progranulin deficiency promotes persistent neuroinflammation and causes regional pathology in the hippocampus following traumatic brain injury

Zheng

Wang

et al. 2022

Glia

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Traumatic brain injury (TBI) can be progressive and can lead to the development of a long‐term complication termed chronic traumatic encephalopathy. The mechanisms underlying the progressive changes are still unknown; however, studies have suggested that microglia‐mediated neuroinflammation in response to TBI may play a fundamental role. This study aimed to determine whether progranulin (PGRN), a major modulator of microglial activity, plays a role in the progressive damage following TBI. PGRN‐deficient and wild‐type mice were subjected to controlled cortical impact and were observed neuropathologically after 3 days, 7 days, and 5 months. Compared to sham and wild‐type mice, the PGRN‐deficient mice showed overall stronger microgliosis and astrocytosis. The astrocytosis involved broader areas than the microgliosis and was more prominent in the basal ganglia, hippocampus, and internal capsule in PGRN‐deficient mice. Ongoing neuronal death was uniquely observed in the hippocampal CA3 region of PGRN‐deficient mice at 5 months after TBI, accompanying the regional chronic microgliosis and astrocytosis involving the CA3 commissural pathway. In addition, there was M1 microglial polarization in the pericontusional area with activated TLR4/MyD88/NF‐κB signaling; however, the hippocampus showed only mild M1 polarization 7 days after TBI. Lastly, Morris water maze tests showed PGRN‐deficient mice had poorer spatial learning and memory 5 months after TBI than wild‐type or sham mice. The data indicated the PGRN deficiency caused TBI progression by promoting persistent microgliosis with microglial polarization and astrocytosis, as well as regional pathology in the hippocampus. The study suggests that PGRN should be evaluated as a potential therapy for TBI.

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“…Regarding surgical methods in the sham group, a previous paper reported that craniotomy should not be performed because of the brain damage caused by the vibration and heat of the drill or deviation of operation [ 51 ]. In this study, we adopted a non-craniotomy method to avoid brain and meninx damage, considering that six times more mice would be sacrificed than usual because we pooled the meninges of six mice per sample.…”

Section: Discussionmentioning

confidence: 99%

Gene expression in meningeal lymphatic endothelial cells following traumatic brain injury in mice

2022

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Meningeal lymphatic vessels transport both the cerebrospinal fluid and interstitial fluid to the deep cervical lymph nodes. Traumatic brain injury (TBI) is accompanied by meningeal injury. We hypothesized that the TBI-induced meningeal injury would damage lymphatic vessels and affect brain function. We observed altered gene expression in meningeal lymphatic endothelial cells (LECs) in a mouse model of TBI. Through flow cytometry–based cell sorting, meningeal LECs were obtained from a mouse model of controlled cortical impact 3 days after TBI. Microarray analysis, real-time polymerase chain reaction assays, and enzyme-linked immunosorbent assays were performed to determine mRNA and protein expression levels in meningeal LECs. The number of meningeal LECs was significantly lower in the injury group than in the sham group 3 days after TBI. Additionally, the mRNA expression of lymphatic vessel endothelial hyaluronan receptor 1 (a specific marker of lymphatic vessels) in meningeal LECs was significantly lower in the injury group than in the sham group. The mRNA and protein expression of FMS-like tyrosine kinase 4 and neuropilin 2 (markers of lymphangiogenesis) in meningeal LECs was significantly higher in the injury group than in the sham group. Our findings indicate that TBI is associated with the impairment of meningeal LECs and meningeal lymphangiogenesis, which implicates lymphatic vessel injury in the pathogenesis of this condition.

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Murine Model of Controlled Cortical Impact for the Induction of Traumatic Brain Injury

Cited by 12 publications

References 19 publications

Microglia and Infiltrating T-Cells Adopt Long-Term, Age-Specific, Transcriptional Changes After Traumatic Brain Injury in Mice

Microglia and Infiltrating T-Cells Adopt Long-Term, Age-Specific, Transcriptional Changes After Traumatic Brain Injury in Mice

Progranulin deficiency promotes persistent neuroinflammation and causes regional pathology in the hippocampus following traumatic brain injury

Gene expression in meningeal lymphatic endothelial cells following traumatic brain injury in mice

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