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Repetitive Model of Mild Traumatic Brain Injury Produces Cortical Abnormalities Detectable by Magnetic Resonance Diffusion Imaging, Histopathology, and Behavior

View Article: PubMed Central - PubMed

ABSTRACT

Noninvasive detection of mild traumatic brain injury (mTBI) is important for evaluating acute through chronic effects of head injuries, particularly after repetitive impacts. To better detect abnormalities from mTBI, we performed longitudinal studies (baseline, 3, 6, and 42 days) using magnetic resonance diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) in adult mice after repetitive mTBI (r-mTBI; daily × 5) or sham procedure. This r-mTBI produced righting reflex delay and was first characterized in the corpus callosum to demonstrate low levels of axon damage, astrogliosis, and microglial activation, without microhemorrhages. High-resolution DTI-DKI was then combined with post-imaging pathological validation along with behavioral assessments targeted for the impact regions. In the corpus callosum, only DTI fractional anisotropy at 42 days showed significant change post-injury. Conversely, cortical regions under the impact site (M1–M2, anterior cingulate) had reduced axial diffusivity (AD) at all time points with a corresponding increase in axial kurtosis (Ka) at 6 days. Post-imaging neuropathology showed microglial activation in both the corpus callosum and cortex at 42 days after r-mTBI. Increased cortical microglial activation correlated with decreased cortical AD after r-mTBI (r = −0.853; n = 5). Using Thy1-YFP-16 mice to fluorescently label neuronal cell bodies and processes revealed low levels of axon damage in the cortex after r-mTBI. Finally, r-mTBI produced social deficits consistent with the function of this anterior cingulate region of cortex. Overall, vulnerability of cortical regions is demonstrated after mild repetitive injury, with underlying differences of DTI and DKI, microglial activation, and behavioral deficits.

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r-mTBI results in social deficits. Mice were assessed for motor and social behavior related to functions of cortical regions under the impact site at bregma and corresponding areas of the corpus callosum. (A and B) The motor task used a running wheel sequence as shown by the pattern of wheel rungs (A) across a 3-week time line. Mice were first provided training wheels (TW; regular rung pattern) to stabilize baseline running behavior for 1 week preceding r-sham/r-mTBI (days −7 to 0). After r-sham/r-mTBI, mice were provided complex wheels (CW; nonuniform rung spacing) for 1 week (days 0–7). Mice must learn to adapt to the complex rung pattern to master this motor skill. The second week (days 8–14) on the complex wheels assesses the velocity plateau as a measure of bilateral sensorimotor coordination. The cohorts (n = 12 per condition) did not show differences in any phase on the training or complex wheel after r-mTBI (B). (C) A three-chamber sociability test was used to test social behavior at 3 weeks after r-mTBI. The r-sham mice spent the majority of time interacting with the carrier containing a stranger mouse rather than the empty carrier. The r-mTBI mice showed a significant reduction in social approach behaviors. The r-mTBI mice spent less time interacting with the unfamiliar mouse, as compared to the behavior of r-sham. Values are mean ± standard error of the mean; n = 12; ***p < 0.001. Max, maximum; r-mTBI, repetitive mild traumatic brain injury; r-sham, repetitive sham.
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f10: r-mTBI results in social deficits. Mice were assessed for motor and social behavior related to functions of cortical regions under the impact site at bregma and corresponding areas of the corpus callosum. (A and B) The motor task used a running wheel sequence as shown by the pattern of wheel rungs (A) across a 3-week time line. Mice were first provided training wheels (TW; regular rung pattern) to stabilize baseline running behavior for 1 week preceding r-sham/r-mTBI (days −7 to 0). After r-sham/r-mTBI, mice were provided complex wheels (CW; nonuniform rung spacing) for 1 week (days 0–7). Mice must learn to adapt to the complex rung pattern to master this motor skill. The second week (days 8–14) on the complex wheels assesses the velocity plateau as a measure of bilateral sensorimotor coordination. The cohorts (n = 12 per condition) did not show differences in any phase on the training or complex wheel after r-mTBI (B). (C) A three-chamber sociability test was used to test social behavior at 3 weeks after r-mTBI. The r-sham mice spent the majority of time interacting with the carrier containing a stranger mouse rather than the empty carrier. The r-mTBI mice showed a significant reduction in social approach behaviors. The r-mTBI mice spent less time interacting with the unfamiliar mouse, as compared to the behavior of r-sham. Values are mean ± standard error of the mean; n = 12; ***p < 0.001. Max, maximum; r-mTBI, repetitive mild traumatic brain injury; r-sham, repetitive sham.

Mentions: Finally, behavioral assessments were targeted to the MRI ROIs to detect potential functional deficits in r-mTBI mice. The corpus callosum overlying the lateral ventricles is associated with motor skill learning that can be assessed using a running wheel with irregularly spaced rungs.43 Over a 3-week period, the r-mTBI mice appeared similar to r-sham mice in mastering the complex running-wheel task (Fig. 10A,B). The medial cortical region under the impact site used in this r-mTBI model includes the anterior cingulate cortex, which is considered a hub of social behaviors.51 A three-chamber social apparatus was used to compare the time each mouse spent interacting with an empty carrier or with a stranger mouse inside the carrier (Fig. 10C). The r-sham mice showed the normal preference to spend time interacting with the stranger mouse (Fig. 10C). The interaction time decreased from 190.3 ± 13.8 sec in r-sham mice to 127.9 ± 13.5 sec in r-mTBI mice (Fig. 10C), indicating impaired social approach behavior after r-mTBI. A cohort of mice subjected to the s-mTBI model that produces more-extensive damage in the corpus callosum than the cortex (Supplementary Figs. 2 and 3) (see online supplementary material at http://www.liebertpub.com) did not result in behavioral changes in either wheel running or social interaction (Supplementary Fig. 6) (see online supplementary material at http://www.liebertpub.com) and serves as a negative control comparison. Overall, the r-mTBI impairment on social behavior supports the interpretation that r-mTBI induces significant cortical changes.


Repetitive Model of Mild Traumatic Brain Injury Produces Cortical Abnormalities Detectable by Magnetic Resonance Diffusion Imaging, Histopathology, and Behavior
r-mTBI results in social deficits. Mice were assessed for motor and social behavior related to functions of cortical regions under the impact site at bregma and corresponding areas of the corpus callosum. (A and B) The motor task used a running wheel sequence as shown by the pattern of wheel rungs (A) across a 3-week time line. Mice were first provided training wheels (TW; regular rung pattern) to stabilize baseline running behavior for 1 week preceding r-sham/r-mTBI (days −7 to 0). After r-sham/r-mTBI, mice were provided complex wheels (CW; nonuniform rung spacing) for 1 week (days 0–7). Mice must learn to adapt to the complex rung pattern to master this motor skill. The second week (days 8–14) on the complex wheels assesses the velocity plateau as a measure of bilateral sensorimotor coordination. The cohorts (n = 12 per condition) did not show differences in any phase on the training or complex wheel after r-mTBI (B). (C) A three-chamber sociability test was used to test social behavior at 3 weeks after r-mTBI. The r-sham mice spent the majority of time interacting with the carrier containing a stranger mouse rather than the empty carrier. The r-mTBI mice showed a significant reduction in social approach behaviors. The r-mTBI mice spent less time interacting with the unfamiliar mouse, as compared to the behavior of r-sham. Values are mean ± standard error of the mean; n = 12; ***p < 0.001. Max, maximum; r-mTBI, repetitive mild traumatic brain injury; r-sham, repetitive sham.
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Related In: Results  -  Collection

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f10: r-mTBI results in social deficits. Mice were assessed for motor and social behavior related to functions of cortical regions under the impact site at bregma and corresponding areas of the corpus callosum. (A and B) The motor task used a running wheel sequence as shown by the pattern of wheel rungs (A) across a 3-week time line. Mice were first provided training wheels (TW; regular rung pattern) to stabilize baseline running behavior for 1 week preceding r-sham/r-mTBI (days −7 to 0). After r-sham/r-mTBI, mice were provided complex wheels (CW; nonuniform rung spacing) for 1 week (days 0–7). Mice must learn to adapt to the complex rung pattern to master this motor skill. The second week (days 8–14) on the complex wheels assesses the velocity plateau as a measure of bilateral sensorimotor coordination. The cohorts (n = 12 per condition) did not show differences in any phase on the training or complex wheel after r-mTBI (B). (C) A three-chamber sociability test was used to test social behavior at 3 weeks after r-mTBI. The r-sham mice spent the majority of time interacting with the carrier containing a stranger mouse rather than the empty carrier. The r-mTBI mice showed a significant reduction in social approach behaviors. The r-mTBI mice spent less time interacting with the unfamiliar mouse, as compared to the behavior of r-sham. Values are mean ± standard error of the mean; n = 12; ***p < 0.001. Max, maximum; r-mTBI, repetitive mild traumatic brain injury; r-sham, repetitive sham.
Mentions: Finally, behavioral assessments were targeted to the MRI ROIs to detect potential functional deficits in r-mTBI mice. The corpus callosum overlying the lateral ventricles is associated with motor skill learning that can be assessed using a running wheel with irregularly spaced rungs.43 Over a 3-week period, the r-mTBI mice appeared similar to r-sham mice in mastering the complex running-wheel task (Fig. 10A,B). The medial cortical region under the impact site used in this r-mTBI model includes the anterior cingulate cortex, which is considered a hub of social behaviors.51 A three-chamber social apparatus was used to compare the time each mouse spent interacting with an empty carrier or with a stranger mouse inside the carrier (Fig. 10C). The r-sham mice showed the normal preference to spend time interacting with the stranger mouse (Fig. 10C). The interaction time decreased from 190.3 ± 13.8 sec in r-sham mice to 127.9 ± 13.5 sec in r-mTBI mice (Fig. 10C), indicating impaired social approach behavior after r-mTBI. A cohort of mice subjected to the s-mTBI model that produces more-extensive damage in the corpus callosum than the cortex (Supplementary Figs. 2 and 3) (see online supplementary material at http://www.liebertpub.com) did not result in behavioral changes in either wheel running or social interaction (Supplementary Fig. 6) (see online supplementary material at http://www.liebertpub.com) and serves as a negative control comparison. Overall, the r-mTBI impairment on social behavior supports the interpretation that r-mTBI induces significant cortical changes.

View Article: PubMed Central - PubMed

ABSTRACT

Noninvasive detection of mild traumatic brain injury (mTBI) is important for evaluating acute through chronic effects of head injuries, particularly after repetitive impacts. To better detect abnormalities from mTBI, we performed longitudinal studies (baseline, 3, 6, and 42 days) using magnetic resonance diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) in adult mice after repetitive mTBI (r-mTBI; daily&thinsp;&times;&thinsp;5) or sham procedure. This r-mTBI produced righting reflex delay and was first characterized in the corpus callosum to demonstrate low levels of axon damage, astrogliosis, and microglial activation, without microhemorrhages. High-resolution DTI-DKI was then combined with post-imaging pathological validation along with behavioral assessments targeted for the impact regions. In the corpus callosum, only DTI fractional anisotropy at 42 days showed significant change post-injury. Conversely, cortical regions under the impact site (M1&ndash;M2, anterior cingulate) had reduced axial diffusivity (AD) at all time points with a corresponding increase in axial kurtosis (Ka) at 6 days. Post-imaging neuropathology showed microglial activation in both the corpus callosum and cortex at 42 days after r-mTBI. Increased cortical microglial activation correlated with decreased cortical AD after r-mTBI (r&thinsp;=&thinsp;&minus;0.853; n&thinsp;=&thinsp;5). Using Thy1-YFP-16 mice to fluorescently label neuronal cell bodies and processes revealed low levels of axon damage in the cortex after r-mTBI. Finally, r-mTBI produced social deficits consistent with the function of this anterior cingulate region of cortex. Overall, vulnerability of cortical regions is demonstrated after mild repetitive injury, with underlying differences of DTI and DKI, microglial activation, and behavioral deficits.

No MeSH data available.


Related in: MedlinePlus