A mouse model of sensorimotor controlled cortical impact: Characterization using longitudinal magnetic resonance imaging, behavioral assessments and histology

Onyszchuk, Gregory; Al-Hafez, Baraa; He, Ye; Bilgen, Mehmet; Berman, Nancy E.J.; Brooks, William M.

doi:10.1016/j.jneumeth.2006.09.007

Cited by 93 publications

(80 citation statements)

References 20 publications

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“…Grid walk. The grid-walk apparatus consisted of an elevated 1.1-cm wire grid that was 20 ϫ 35 cm, adapted from Onyszchuk et al (19). Animals were recorded with a digital video camera for 5 min while walking on the grid at 10 weeks post-STZ injection.…”

Section: Methodsmentioning

confidence: 99%

Abnormal Muscle Spindle Innervation and Large-Fiber Neuropathy in Diabetic Mice

et al. 2008

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OBJECTIVE-Large-fiber diabetic polyneuropathy (DPN) leads to balance and gait abnormalities, placing patients at risk for falls. Large sensory axons innervating muscle spindles provide feedback for balance and gait and, when damaged, can cause altered sensorimotor function. This study aimed to determine whether symptoms of large-fiber DPN in type 1 and type 2 diabetic mouse models are related to alterations in muscle spindle innervation. In addition, diabetic mice were treated with insulin to assess whether sensorimotor and spindle deficits were reversible.RESEARCH DESIGN AND METHODS-Behavioral assessments were performed in untreated and treated streptozotocin (STZ)-injected C57BL/6 mice to quantitate diabetes-induced deficits in balance and gait. Quantification of Ia axon innervation of spindles was carried out using immunohistochemistry and confocal microscopy on STZ-injected C57BL/6 and db/db mice.RESULTS-STZ-injected C57BL/6 mice displayed significant and progressive sensorimotor dysfunction. Analysis of Ia innervation patterns of diabetic C57BL/6 spindles revealed a range of abnormalities suggestive of Ia axon degeneration and/or regeneration. The multiple abnormal Ia fiber morphologies resulted in substantial variability in axonal width and inter-rotational distance (IRD). Likewise, db/db mice displayed significant variability in their IRDs compared with db ϩ mice, suggesting that damage to Ia axons occurs in both type 1 and type 2 diabetes models. Insulin treatment improved behavioral deficits and restored Ia fiber innervation in comparison with nondiabetic mice.CONCLUSIONS-Similar to small fibers, Ia axons are vulnerable to diabetes, and their damage may contribute to balance and gait deficits. In addition, these studies provide a novel method to assay therapeutic interventions designed for diabetes-induced large-fiber dysfunction. Diabetes 57:1693-1701, 2008 E stimates from the Centers for Disease Control and Prevention suggest that 60 -70% of diabetic patients develop neuropathy. In addition, diabetes is the leading cause of neuropathy in the U.S. and Western countries (1). Sensorimotor diabetic polyneuropathy (DPN) affects both large and small sensory afferent nerve fibers. The majority of research focuses on small-fiber neuropathy leading to increased or decreased pain and temperature sensations (2-5). Consequently, there is a shortage of animal model research exploring large-fiber DPN, which can cause deficits in lower-limb proprioception, decreased tactile sensitivity and vibration sense, and incoordination due to balance abnormalities (1,6).The sensorimotor deficits resulting from large-fiber DPN, while sometimes subtle in nature, can lead to significant impairment. Numerous human studies report that patients with DPN are at increased risk for falls due to decreased postural control, altered gait and balance, and increased body sway (7-9). The underlying neurologic mechanisms involved in large-fiber DPN remain poorly understood. It has been hypothesized that large-fiber DPN instability could be ca...

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Section: Methodsmentioning

confidence: 99%

Abnormal Muscle Spindle Innervation and Large-Fiber Neuropathy in Diabetic Mice

et al. 2008

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“…18 Following anaesthesia with 2,2 tribromoethanol (0.5 mg/kg) WT mice were placed in a stereotaxic frame (Kopf, Tujunga, CA). A surgical incision was made, the skull was exposed and a 3-mm diameter circular craniotomy was performed with a burr drill over the left parietal cortex, with the centre at coordinates AP ¼ À2.0, ML ¼ þ 2.0 from bregma.…”

Section: Controlled Cortical Impact (Cci) Model Of Traumatic Brain Inmentioning

confidence: 99%

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

Sashindranath

Samson

Downes

et al. 2011

Laboratory Investigation

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Tissue-type plasminogen activator (tPA) is a major protease of the central nervous system. Most studies to date have used in situ-or gel-based zymographic assays to monitor in vivo changes in neural tPA activity. In this study, we demonstrate that the amidolytic assay can be adapted to accurately detect changes in net tPA activity in mouse brain tissues. Using the amidolytic assay, we examined differences in net tPA activity in the cerebral cortex, sub-cortical structures and cerebellum in wildtype (WT) and tPA À/À mice, and in transgenic mice selectively overexpressing tPA in neurons. In addition, we assessed changes in endogenous net tPA activity in WT mice following morphine administration, epileptic seizures, traumatic brain injury and ischaemic stroke-neurological settings in which tPA has a known functional role. Under these conditions, acute and compartment-specific regulation of tPA activity was observed. tPA also participates in various forms of chronic neurodegeneration. Accordingly, we assessed tPA activity levels in mouse models of Alzheimer's disease (AD) and spinocerebellar ataxia type-1 (SCA1). Decreased tPA activity was detected in the cortex and subcortex of AD mice, whereas increased tPA activity was found in the cerebellum of SCA1 mice. These findings extend the existing hypotheses that low tPA activity promotes AD, whereas increased tPA activity contributes to cerebellar degeneration. Collectively, our results exemplify the utility of the amidolytic assay and emphasise tPA as a complex mediator of brain function and dysfunction. On the basis of this evidence, we propose that alterations in tPA activity levels could be used as a biomarker for perturbations in brain homeostasis.

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“…The MRI scan data were used for two purposes: (1) to provide gross anatomical inspection of the brain to qualitatively demonstrate lesion size and location (and to verify no obvious structural damage in the sham and naïve conditions) and (2) to quantitatively estimate total lesion volume, which typically overestimates histologically verified volume by about 25% (Nishi, et al, 2007;Onyszchuk, et al, 2007). Analysis techniques were adapted from methods originally developed to determine lesion and total brain volumes in human TBI subjects (Hopkins, et al, 1997;Wilde, et al, 2005).…”

Section: Lesion Assessment By Mrimentioning

confidence: 99%

Traumatic brain injury during development reduces minimal clonic seizure thresholds at maturity

et al. 2008

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Post-traumatic seizures affect 12 -35% of children after traumatic brain injury (TBI) and are associated with worse cognitive and functional outcome, even after adjustment for severity of injury. Unfortunately, experimental models of pediatric post-traumatic epilepsy are lacking, and pathogenesis remains poorly understood. We have applied a standard model of TBI in immature rats to determine the effect of TBI on electroconvulsive seizure thresholds later in life.Male rats underwent controlled cortical impact to left parietal cortex on post-natal day (PND) 16-18. Hindbrain, forebrain, and limbic seizure thresholds were assessed, respectively, by tonic hindlimb extension (THE), minimal clonic, and partial psychomotor seizure responses during adolescence and at maturity (PND 60 -63). Post-traumatic seizure thresholds were compared to those obtained in age-and litter-matched sham craniotomy and naïve controls.TBI during immaturity had no clear effect on THE seizure thresholds. In contrast, TBI lowered minimal clonic seizure thresholds at maturity (p < 0.05 vs. sham or naïve rats), but not during adolescence. Consequently, minimal clonic seizure thresholds increased with age for sham and naïve rats but remained similar for TBI rats during adolescence and at maturity. TBI also tended to lower partial psychomotor seizure thresholds, which were determined only during adolescence (p < 0.1 vs. naive).Controlled cortical impact causes both focal cortical injury at the site of impact and ipsilateral hippocampal neuronal death. Since minimal clonic seizures are mediated by the forebrain, partial psychomotor seizures by the limbic system, and THE seizures by the brainstem, the observed pattern of changes in post-traumatic seizure thresholds is not surprising. The apparent age-dependent effects of TBI, however, are unexpected and likely due to a combination of attenuated maturational increases

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A mouse model of sensorimotor controlled cortical impact: Characterization using longitudinal magnetic resonance imaging, behavioral assessments and histology

Cited by 93 publications

References 20 publications

Abnormal Muscle Spindle Innervation and Large-Fiber Neuropathy in Diabetic Mice

Abnormal Muscle Spindle Innervation and Large-Fiber Neuropathy in Diabetic Mice

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

Traumatic brain injury during development reduces minimal clonic seizure thresholds at maturity

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