IU Indianapolis ScholarWorks :: Browsing by Author "Shields, Christopher B."

Browsing by Author "Shields, Christopher B."

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A Compact Blast-Induced Traumatic Brain Injury Model in Mice
(Oxford University Press, 2016-02) Wang, Hongxing; Zhang, Yi Ping; Cai, Jun; Shields, Lisa B. E.; Tuchek, Chad A.; Shi, Riyi; Li, Jianan; Shields, Christopher B.; Xu, Xiao-Ming; Neurological Surgery, School of Medicine
Blast-induced traumatic brain injury (bTBI) is a common injury on the battlefield and often results in permanent cognitive and neurological abnormalities. We report a novel compact device that creates graded bTBI in mice. The injury severity can be controlled by precise pressures that mimic Friedlander shockwave curves. The mouse head was stabilized with a head fixator, and the body was protected with a metal shield; shockwave durations were 3 to 4 milliseconds. Reflective shockwave peak readings at the position of the mouse head were 12 6 2.6 psi, 50 6 20.3 psi, and 100 6 33.1 psi at 100, 200, and 250 psi predetermined driver chamber pressures, respectively. The bTBIs of 250 psi caused 80% mortality, which decreased to 27% with the metal shield. Brain and lung damage depended on the shockwave duration and amplitude. Cognitive deficits were assessed using the Morris water maze, Y-maze, and open-field tests. Pathological changes in the brain included disruption of the blood-brain barrier, multifocal neuronal and axonal degeneration, and reactive gliosis assessed by Evans Blue dye extravasation, silver and Fluoro-Jade B staining, and glial fibrillary acidic protein immunohistochemistry, respectively. Behavioral and pathological changes were injury severity-dependent. This mouse bTBI model may be useful for investigating injury mechanisms and therapeutic strategies associated with bTBI.
Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury
(Wiley, 2014-05) Liu, Nai-Kui; Deng, Ling-Xiao; Zhang, Yi Ping; Lu, Qing-Bo; Wang, Xiao-Fei; Hu, Jian-Guo; Oakes, Eddie; Bonventre, Joseph V.; Shields, Christopher B.; Xu, Xiao-Ming; Department of Medicine, IU School of Medicine
OBJECTIVE: The objective of this study was to investigate whether cytosolic phospholipase A2 (cPLA2 ), an important isoform of PLA2 that mediates the release of arachidonic acid, plays a role in the pathogenesis of spinal cord injury (SCI). METHODS: A combination of molecular, histological, immunohistochemical, and behavioral assessments were used to test whether blocking cPLA2 activation pharmacologically or genetically reduced cell death, protected spinal cord tissue, and improved behavioral recovery after a contusive SCI performed at the 10th thoracic level in adult mice. RESULTS: SCI significantly increased cPLA2 expression and activation. Activated cPLA2 was localized mainly in neurons and oligodendrocytes. Notably, the SCI-induced cPLA2 activation was mediated by the extracellular signal-regulated kinase signaling pathway. In vitro, activation of cPLA2 by ceramide-1-phosphate or A23187 induced spinal neuronal death, which was substantially reversed by arachidonyl trifluoromethyl ketone, a cPLA2 inhibitor. Remarkably, blocking cPLA2 pharmacologically at 30 minutes postinjury or genetically deleting cPLA2 in mice ameliorated motor deficits, and reduced cell loss and tissue damage after SCI. INTERPRETATION: cPLA2 may play a key role in the pathogenesis of SCI, at least in the C57BL/6 mouse, and as such could be an attractive therapeutic target for ameliorating secondary tissue damage and promoting recovery of function after SCI.
Descending motor circuitry required for NT-3 mediated locomotor recovery after spinal cord injury in mice
(Nature Research, 2019-12-20) Han, Qi; Ordaz, Josue D.; Liu, Nai-Kui; Richardson, Zoe; Wu, Wei; Xia, Yongzhi; Qu, Wenrui; Wang, Ying; Dai, Heqiao; Zhang, Yi Ping; Shields, Christopher B.; Smith, George M.; Xu, Xiao-Ming; Neurological Surgery, School of Medicine
Locomotor function, mediated by lumbar neural circuitry, is modulated by descending spinal pathways. Spinal cord injury (SCI) interrupts descending projections and denervates lumbar motor neurons (MNs). We previously reported that retrogradely transported neurotrophin-3 (NT-3) to lumbar MNs attenuated SCI-induced lumbar MN dendritic atrophy and enabled functional recovery after a rostral thoracic contusion. Here we functionally dissected the role of descending neural pathways in response to NT-3-mediated recovery after a T9 contusive SCI in mice. We find that residual projections to lumbar MNs are required to produce leg movements after SCI. Next, we show that the spared descending propriospinal pathway, rather than other pathways (including the corticospinal, rubrospinal, serotonergic, and dopaminergic pathways), accounts for NT-3-enhanced recovery. Lastly, we show that NT-3 induced propriospino-MN circuit reorganization after the T9 contusion via promotion of dendritic regrowth rather than prevention of dendritic atrophy.
An In Vivo Duo-color Method for Imaging Vascular Dynamics Following Contusive Spinal Cord Injury
(Journal of Visualized Experiments, 2017-12-31) Chen, Chen; Zhang, Yi Ping; Sun, Yan; Xiong, Wenhui; Shields, Lisa B. E.; Shields, Christopher B.; Jin, Xiaoming; Xu, Xiao-Ming; Neurological Surgery, School of Medicine
Spinal cord injury (SCI) causes significant vascular disruption at the site of injury. Vascular pathology occurs immediately after SCI and continues throughout the acute injury phase. In fact, endothelial cells appear to be the first to die after a contusive SCI. The early vascular events, including increased permeability of the blood-spinal cord barrier (BSCB), induce vasogenic edema and contribute to detrimental secondary injury events caused by complex injury mechanisms. Targeting the vascular disruption, therefore, could be a key strategy to reduce secondary injury cascades that contribute to histological and functional impairments after SCI. Previous studies were mostly performed on postmortem samples and were unable to capture the dynamic changes of the vascular network. In this study, we have developed an in vivo duo-color two-photon imaging method to monitor acute vascular dynamic changes following contusive SCI. This approach allows detecting blood flow, vessel diameter, and other vascular pathologies at various sites of the same rat pre- and post-injury. Overall, this method provides an excellent venue for investigating vascular dynamics.
A Laser-Guided Spinal Cord Displacement Injury in Adult Mice
(Mary Ann Liebert, 2019-02-01) Wu, Xiangbing; Qu, Wenrui; Bakare, Adewale A.; Zhang, Yi Ping; Fry, Collin M.E.; Shields, Lisa B.E.; Shields, Christopher B.; Xu, Xiao-Ming; Medicine, School of Medicine
Mouse models are unique for studying molecular mechanisms of neurotrauma because of the availability of various genetic modified mouse lines. For spinal cord injury (SCI) research, producing an accurate injury is essential, but it is challenging because of the small size of the mouse cord and the inconsistency of injury production. The Louisville Injury System Apparatus (LISA) impactor has been shown to produce precise contusive SCI in adult rats. Here, we examined whether the LISA impactor could be used to create accurate and graded contusive SCIs in mice. Adult C57BL/6 mice received a T10 laminectomy followed by 0.2, 0.5, and 0.8 mm displacement injuries, guided by a laser, from the dorsal surface of the spinal cord using the LISA impactor. Basso Mouse Scale (BMS), grid-walking, TreadScan, and Hargreaves analyses were performed for up to 6 weeks post-injury. All mice were euthanized at the 7th week, and the spinal cords were collected for histological analysis. Our results showed that the LISA impactor produced accurate and consistent contusive SCIs corresponding to mild, moderate, and severe injuries to the cord. The degree of injury severities could be readily determined by the BMS locomotor, grid-walking, and TreadScan gait assessments. The cutaneous hyperalgesia threshold was also significantly increased as the injury severity increased. The terminal lesion area and the spared white matter of the injury epicenter were strongly correlated with the injury severities. We conclude that the LISA device, guided by a laser, can produce reliable graded contusive SCIs in mice, resulting in severity-dependent behavioral and histopathological deficits.
A Novel Vertebral Stabilization Method for Producing Contusive Spinal Cord Injury
(Jove, 2015-01) Walker, Melissa J.; Walker, Chandler L.; Zhang, Y. Ping; Shields, Lisa B. E.; Shields, Christopher B.; Xu, Xiao-Ming; Department of Anatomy & Cell Biology, IU School of Medicine
Clinically-relevant animal cervical spinal cord injury (SCI) models are essential for developing and testing potential therapies; however, producing reliable cervical SCI is difficult due to lack of satisfactory methods of vertebral stabilization. The conventional method to stabilize the spine is to suspend the rostral and caudal cervical spine via clamps attached to cervical spinous processes. However, this method of stabilization fails to prevent tissue yielding during the contusion as the cervical spinal processes are too short to be effectively secured by the clamps (Figure 1). Here we introduce a new method to completely stabilize the cervical vertebra at the same level of the impact injury. This method effectively minimizes movement of the spinal column at the site of impact, which greatly improves the production of consistent SCIs. We provide visual description of the equipment (Figure 2-4), methods, and a step-by-step protocol for the stabilization of the cervical 5 vertebra (C5) of adult rats, to perform laminectomy (Figure 5) and produce a contusive SCI thereafter. Although we only demonstrate a cervical hemi-contusion using the NYU/MASCIS impactor device, this vertebral stabilization technique can be applied to other regions of the spinal cord, or be adapted to other SCI devices. Improving spinal cord exposure and fixation through vertebral stabilization may be valuable for producing consistent and reliable injuries to the spinal cord. This vertebral stabilization method can also be used for stereotactic injections of cells and tracers, and for imaging using two-photon microscopy in various neurobiological studies.
Pathophysiological and behavioral deficits in developing mice following rotational acceleration-deceleration traumatic brain injury
(Company of Biologists:, 2018-01-30) Wang, Guoxiang; Zhang, Yi Ping; Gao, Zhongwen; Shields, Lisa B. E.; Li, Fang; Chu, Tianci; Lv, Huayi; Moriarty, Thomas; Xu, Xiao-Ming; Yang, Xiaoyu; Shields, Christopher B.; Cai, Jun; Neurological Surgery, School of Medicine
Abusive head trauma (AHT) is the leading cause of death from trauma in infants and young children. An AHT animal model was developed on 12-day-old mice subjected to 90° head extension-flexion sagittal shaking repeated 30, 60, 80 and 100 times. The mortality and time until return of consciousness were dependent on the number of repeats and severity of the injury. Following 60 episodes of repeated head shakings, the pups demonstrated apnea and/or bradycardia immediately after injury. Acute oxygen desaturation was observed by pulse oximetry during respiratory and cardiac suppression. The cerebral blood perfusion was assessed by laser speckle contrast analysis (LASCA) using a PeriCam PSI system. There was a severe reduction in cerebral blood perfusion immediately after the trauma that did not significantly improve within 24 h. The injured mice began to experience reversible sensorimotor function at 9 days postinjury (dpi), which had completely recovered at 28 dpi. However, cognitive deficits and anxiety-like behavior remained. Subdural/subarachnoid hemorrhage, damage to the brain-blood barrier and parenchymal edema were found in all pups subjected to 60 insults. Proinflammatory response and reactive gliosis were upregulated at 3 dpi. Degenerated neurons were found in the cerebral cortex and olfactory tubercles at 30 dpi. This mouse model of repetitive brain injury by rotational head acceleration-deceleration partially mimics the major pathophysiological and behavioral events that occur in children with AHT. The resultant hypoxia/ischemia suggests a potential mechanism underlying the secondary rotational acceleration-deceleration-induced brain injury in developing mice.
A Tissue Displacement-based Contusive Spinal Cord Injury Model in Mice
(JoVE, 2017-06-18) Wu, Xiangbing; Zhang, Yi Ping; Qu, Wenrui; Shields, Lisa B. E.; Shields, Christopher B.; Xu, Xiao-Ming; Neurological Surgery, School of Medicine
Producing a consistent and reproducible contusive spinal cord injury (SCI) is critical to minimizing behavioral and histological variabilities between experimental animals. Several contusive SCI models have been developed to produce injuries using different mechanisms. The severity of the SCI is based on the height that a given weight is dropped, the injury force, or the spinal cord displacement. In the current study, we introduce a novel mouse contusive SCI device, the Louisville Injury System Apparatus (LISA) impactor, which can create a displacement-based SCI with high injury velocity and accuracy. This system utilizes laser distance sensors combined with advanced software to produce graded and highly-reproducible injuries. We performed a contusive SCI at the 10th thoracic vertebral (T10) level in mice to demonstrate the step-by-step procedure. The model can also be applied to the cervical and lumbar spinal levels.
Transhemispheric cortex remodeling promotes forelimb recovery after spinal cord injury
(American Society for Clinical Investigation, 2022-06-22) Wu, Wei; Nguyen, Tyler; Ordaz, Josue D.; Zhang, Yiping; Liu, Nai-Kui; Hu, Xinhua; Liu, Yuxiang; Ping, Xingjie; Han, Qi; Wu, Xiangbing; Qu, Wenrui; Gao, Sujuan; Shields, Christopher B.; Jin, Xiaoming; Xu, Xiao-Ming; Neurological Surgery, School of Medicine
Understanding the reorganization of neural circuits spared after spinal cord injury in the motor cortex and spinal cord would provide insights for developing therapeutics. Using optogenetic mapping, we demonstrated a transhemispheric recruitment of neural circuits in the contralateral cortical M1/M2 area to improve the impaired forelimb function after a cervical 5 right-sided hemisection in mice, a model mimicking the human Brown-Séquard syndrome. This cortical reorganization can be elicited by a selective cortical optogenetic neuromodulation paradigm. Areas of whisker, jaw, and neck, together with the rostral forelimb area, on the motor cortex ipsilateral to the lesion were engaged to control the ipsilesional forelimb in both stimulation and nonstimulation groups 8 weeks following injury. However, significant functional benefits were only seen in the stimulation group. Using anterograde tracing, we further revealed a robust sprouting of the intact corticospinal tract in the spinal cord of those animals receiving optogenetic stimulation. The intraspinal corticospinal axonal sprouting correlated with the forelimb functional recovery. Thus, specific neuromodulation of the cortical neural circuits induced massive neural reorganization both in the motor cortex and spinal cord, constructing an alternative motor pathway in restoring impaired forelimb function.
Transplantation of Ciliary Neurotrophic Factor-Expressing Adult Oligodendrocyte Precursor Cells Promotes Remyelination and Functional Recovery after SpinalCord Injury
(Society for Neuroscience, 2010-02-24) Cao, Qilin; He, Qian; Wang, Yaping; Cheng, Xiaoxin; Howard, Russell M.; Zhang, Yiping; DeVries, William H.; Shields, Christopher B.; Magnuson, David S. K.; Xu, Xiao-Ming; Kim, Dong H.; Whittemore, Scott R.; Neurological Surgery, School of Medicine
Demyelination contributes to the dysfunction after traumatic spinal cord injury (SCI). We explored whether the combination of neurotrophic factors and transplantation of adult rat spinal cord oligodendrocyte precursor cells (OPCs) could enhance remyelination and functional recovery after SCI. Ciliary neurotrophic factor (CNTF) was the most effective neurotrophic factor to promote oligodendrocyte (OL) differentiation and survival of OPCs in vitro. OPCs were infected with retroviruses expressing enhanced green fluorescent protein (EGFP) or CNTF and transplanted into the contused adult thoracic spinal cord 9 d after injury. Seven weeks after transplantation, the grafted OPCs survived and integrated into the injured spinal cord. The survival of grafted CNTF-OPCs increased fourfold compared with EGFP-OPCs. The grafted OPCs differentiated into adenomatus polyposis coli (APC+) OLs, and CNTF significantly increased the percentage of APC+ OLs from grafted OPCs. Immunofluorescent and immunoelectron microscopic analyses showed that the grafted OPCs formed central myelin sheaths around the axons in the injured spinal cord. The number of OL-remyelinated axons in ventrolateral funiculus (VLF) or lateral funiculus (LF) at the injured epicenter was significantly increased in animals that received CNTF-OPC grafts compared with all other groups. Importantly, 75% of rats receiving CNTF-OPC grafts recovered transcranial magnetic motor-evoked potential and magnetic interenlargement reflex responses, indicating that conduction through the demyelinated axons in VLF or LF, respectively, was partially restored. More importantly, recovery of hindlimb locomotor function was significantly enhanced in animals receiving grafts of CNTF-OPCs. Thus, combined treatment with OPC grafts expressing CNTF can enhance remyelination and facilitate functional recovery after traumatic SCI.

Browsing by Author "Shields, Christopher B."

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