Research ReportA bilateral head injury that shows graded brain damage and behavioral deficits in adultmice
Highlights
► Reliable animal models are essential research tools. ► Developed a novel bilateral head injury model in mice. ► This model produced graded brain injury and long-lasting functional deficits. ► This may be a reliable model for assessments of therapeutic strategies forTBI.
Introduction
Traumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. In the United States alone, more than 1.7 million people suffer a TBI annually (Loane and Faden, 2010). Death and disability from TBI stem from two major mechanisms: a primary mechanical injury, and secondary injury driven by a complex interplay of multiple injury factors such as inflammatory mediators, free radicals, and glutamate excitotoxicity initiated by the primary injury (Loane and Faden, 2010, Marklund and Hillered, 2010). This cascade of secondary damage has been the focus of much research, but to date there are no pharmaceutical interventions with proven efficacy, and the complex relationships between various mediators are still poorly understood (Loane and Faden, 2010, Marklund and Hillered, 2010, Morales et al., 2005).
Animal models of TBI are critical to test novel hypotheses and therapeutic interventions. Unfortunately, due to the broad heterogeneity of TBI in humans, no single model has been able to reproduce the entire spectrum of these injuries (Marklund and Hillered, 2010, Morales et al., 2005). Dominant models currently used by investigators to examine focal injuries include the closed head injury (CHI), fluid percussion brain injury, and controlled cortical impact injury (CCI) models (Albert-Weissenberger and Siren, 2010, Morales et al., 2005). CHI is produced by weight-dropping and induces obvious brain damage and functional deficit (Chen et al., 1996, Shapira et al., 1988). However, the resulting force may cause skull fracture and high mortality. The CCI model utilizes a rigid, piston-like impactor to produce a graded TBI (Dixon et al., 1991, Smith et al., 1995). Because of the softness of the brain tissue, tip plunge imitates a penetration brain injury, and does not cause long-lasting motor functional deficits. In addition, moderate and severe CCIs often induce rupture of the dura. Breach of the dura mater would classify this injury as an open head TBI or penetrating TBI. Because transgenic and knockout mice are available, mouse TBI model becomes a preferred model for the study of cellular mechanisms. In this study, based on advantages of both CHI and CCI models, we developed a new CCI model, i.e. a bilateral head injury model by contusing a larger area of the cortex indirectly through a bone flap and preserving integrity of the dura. This developed new model produced graded brain injuries and severity-dependent functional deficits in mice. This model is a potentially useful and alternative one for selection of appropriate models for targeted investigation in the TBIfield.
Section snippets
Results
A total of 35 female C57/BL6 mice were used in this study. Five mice were excluded from the study before injury because their latency on day 5 during water maze training was greater than 50 s. The remaining 30 mice were randomly divided into four groups based on impact depth: sham (n=6), 0.5 mm (n=8), 1.0 mm (n=8) and 1.5 mm (n=8) from the surface of the skull. Over the course of the 4 week study period, 5 of the 8 mice impacted at a depth of 1.5 mm died. One mouse died within 1 day, two died within
Discussion
The CHI and CCI models of contusion brain injury are two of the most widely used models of TBI in neurotrauma research (Albert-Weissenberger and Siren, 2010, Morales et al., 2005). In this study, we modified the CCI method to produce a larger area of cortical impact through a bone flap on the target cortex. We take the advantage of the accuracy of site and depth of brain deformation produced by CCI but, at the same time, avoid shortcomings of the CCI model such as localized lesion, high
Traumatic brain injury
Female C57/BL6 mice (10 weeks, 20 g, Jackson Laboratory, Bar Harbor, Maine) were anesthetized with Avertin (2.5%, 0.2 ml/20 g) and placed in a stereotactic frame adapted for mice. A midline craniotomy (5 mm diameter) was performed extending 2 mm anteriorly and 3 mm posteriorly from the bregma, centered over the sagittal suture (Fig. 1A–C). The skull flap was left in place and stabilized with an adhesive, allowing for direct impact of the exposed skull without producing fractures. A bilateral cortical
Acknowledgments
This work was supported by Indiana Spinal Cord and Brain Injury Research Foundation and Mari Hulman George Endowment (XMX), and by the State of Indiana (ISDH, Grant # A70-2-079609 and A70-9-079138)(NKL).
References (24)
A consideration of neural counting methods
Trends. Neurosci.
(1992)- et al.
Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies
Trends Pharmacol. Sci.
(2010) - et al.
Experimental models of traumatic brain injury: do we really need to build a better mousetrap?
Neuroscience
(2005) - et al.
Administration of adenosine receptor agonists or antagonists after controlled cortical impact in mice: effects on function and histopathology
Brain Res.
(2002) - et al.
Continuous nicotinamide administration improves behavioral recovery and reduces lesion size following bilateral frontal controlled cortical impact injury
Behav. Brain Res.
(2011) - et al.
Genetic disruption of cyclooxygenase-2 does not improve histological or behavioral outcome after traumatic brain injury in mice
J. Neurosci. Res.
(2008) - et al.
Experimental traumatic brain injury
Exp. Transl. Stroke Med.
(2010) - et al.
The adhesive removal test: a sensitive method to assess sensorimotor deficits in mice
Nat. Protoc.
(2009) - et al.
An experimental model of closed head injury in mice: pathophysiology, histopathology, and cognitive deficits
J. Neurotrauma
(1996) - et al.
A controlled cortical impact model of traumatic brain injury in the rat
J. Neurosci. Methods
(1991)
Acute etomidate treatment reduces cognitive deficits and histopathology in rats with traumatic brain injury
Crit. Care Med.
Sustained sensory/motor and cognitive deficits with neuronal apoptosis following controlled cortical impact brain injury in the mouse
J. Neurotrauma
Cited by (15)
Repeated mild traumatic brain injuries impair visual discrimination learning in adolescent mice
2020, Neurobiology of Learning and MemoryCitation Excerpt :However, the role of SDs in mTBI pathology and cognitive dysfunction remains unclear. The lack of gross motor dysfunction supports that even our RmTBI injury is milder in comparison to other models that typically produce robust motor deficits, as well as gross tissue damage (Liu, 2013; Peterson, Maass, Anderson, Anderson, & Hoane, 2015; Shear, 2010; Yang, Gangidine, Pritts, Goodman, & Lentsch, 2013). Our previous study reported no significant motor deficits following a single injury (Pacheco, 2019).
Criteria to define mild, moderate, and severe traumatic brain injury in the mouse controlled cortical impact model
2018, Experimental NeurologyCitation Excerpt :A 0.6 mm difference in cortical depression can result in a substantial alteration in injury as demonstrated by previous studies examining the impact of 0.5 mm injury parameter differences. Specifically, there were substantial differences in hippocampal volumetric tissue loss when comparing cortical depth values differing by only 0.5 mm (Liu et al., 2013). The zero-point was defined in <10% of the examined articles (8 out of 58 studies).
Applications of the Morris water maze in translational traumatic brain injury research
2018, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Overall, the adjustments made in these models have allowed researchers to control the severity of injury and monitor changes in cognitive functioning (Briones, 2015). Utilizing animal models of TBI, a plethora of studies have documented that the level of cognitive impairment is proportionate to the severity of the injury (Brody et al., 2007; Budde et al., 2013; DeFord et al., 2002; Fox et al., 1998; Liu et al., 2013; Washington et al., 2012; Zhao et al., 2012; Zohar et al., 2011). Specifically, increasing the impact depth (Washington et al., 2012), the impact velocity (Zhao et al., 2012), and the weight drop mass (Beaumont et al., 1999; DeFord et al., 2002) all led to increased injury severity and cognitive dysfunction.