Experimental models of traumatic brain injury: do we really need to build a better mousetrap?
ABSTRACT Approximately 4000 human beings experience a traumatic brain injury each day in the United States ranging in severity from mild to fatal. Improvements in initial management, surgical treatment, and neurointensive care have resulted in a better prognosis for traumatic brain injury patients but, to date, there is no available pharmaceutical treatment with proven efficacy, and prevention is the major protective strategy. Many patients are left with disabling changes in cognition, motor function, and personality. Over the past two decades, a number of experimental laboratories have attempted to develop novel and innovative ways to replicate, in animal models, the different aspects of this heterogenous clinical paradigm to better understand and treat patients after traumatic brain injury. Although several clinically-relevant but different experimental models have been developed to reproduce specific characteristics of human traumatic brain injury, its heterogeneity does not allow one single model to reproduce the entire spectrum of events that may occur. The use of these models has resulted in an increased understanding of the pathophysiology of traumatic brain injury, including changes in molecular and cellular pathways and neurobehavioral outcomes. This review provides an up-to-date and critical analysis of the existing models of traumatic brain injury with a view toward guiding and improving future research endeavors.
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ABSTRACT: Glia of the central nervous system (CNS) help to maintain homeostasis in the brain and support efficient neuronal function. Microglia are innate immune cells of the brain that mediate responses to pathogens and injury. They have key roles in phagocytic clearing, surveying the local microenvironment and propagating inflammatory signals. An interruption in homeostasis induces a cascade of conserved adaptive responses in glia. This response involves biochemical, physiological and morphological changes and is associated with the production of cytokines and secondary mediators that influence synaptic plasticity, cognition and behavior. This reorganization of host priorities represents a beneficial response that is normally adaptive but may become maladaptive when the profile of microglia is compromised. For instance, microglia can develop a primed or pro-inflammatory mRNA, protein and morphological profile with aging, traumatic brain injury and neurodegenerative disease. As a result, primed microglia exhibit an exaggerated inflammatory response to secondary and sub-threshold challenges. Consequences of exaggerated inflammatory responses by microglia include the development of cognitive deficits, impaired synaptic plasticity and accelerated neurodegeneration. Moreover, impairments in regulatory systems in these circumstances may make microglia more resistant to negative feedback and important functions of glia can become compromised and dysfunctional. Overall, the purpose of this review is to discuss key concepts of microglial priming and immune-reactivity in the context of aging, traumatic CNS injury and neurodegenerative disease. Copyright © 2014. Published by Elsevier Ltd.Neuropharmacology 11/2014; 96. DOI:10.1016/j.neuropharm.2014.10.028
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ABSTRACT: Purpose: Despite advances towards potential clinically viable therapies there has been only limited success in improving functional recovery following traumatic brain injury (TBI). In rats, exposure to an enriched environment (EE) improves learning and fosters motor skill development. Induced pluripotent stem cells (iPSC) have been shown to survive transplantation and influence the recovery process. The current study evaluated EE and iPSC as a polytherapy for remediating cognitive deficits following medial frontal cortex (mFC) controlled cortical impact (CCI) injury. Methods: Sixty adult male rats received a midline mFC CCI or sham injury and were randomly placed in either EE or standard environment (SE). Seven days post-injury rats received bilateral transplantation of iPSCs or media. Behavioral measures were conducted throughout the remainder of the study. Following behavioral analysis, brains were extracted and prepared for histological analysis. Results: Open-field data revealed that combined therapy resulted in typical Sham/EE activity rearing patterns by the conclusion of the study. On the Vermicelli Handling task, rats with EE/iPSC polytherapy performed better than media-treated rats. Furthermore, rats treated with polytherapy performed equivalently to Sham/EE rats on the Morris water maze. Proficiency on the Rotarod was consistently better in EE when compared to SE counterparts. Confocal microscopy confirmed that iPSCs survived and migrated away from the transplantation site. Conclusions: Overall, EE or iPSC therapy improved cognition and motor performance, however, full cognitive restoration was seen only with the EE/iPSC treatment. These data suggest that EE/iPSC therapy should be explored as a potential, clinically relevant, treatment for TBI.Restorative neurology and neuroscience 07/2014; 32(5). DOI:10.3233/RNN-140408
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ABSTRACT: Due to the marked heterogeneity of human traumatic brain injury (TBI), none of the available animal model can reproduce the entire spectrum of TBI, especially mild focal TBI. This study was designed to develop a modified TBI weight drop model for induction of focal mild cerebral injury. New method: A stereotaxic coupled weight drop device was designed. Principle arm of device carries up to 500g weights which their force was conveyed to animal skull through a thin nail like metal tip. To determine the optimal configuration of the device to induce mild TBI, six different trials were designed. The optimal configuration of the instrument was used for evaluation of behavioral, histopathological and molecular changes of mild TBI.Journal of Neuroscience Methods 06/2014; 233. DOI:10.1016/j.jneumeth.2014.05.035