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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.

No MeSH data available.


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Tau pathology is not observed after r-mTBI. Immunohistochemistry for phosphorylated serine 396 tau shows a lack of immunolabeling in the cortex of mice perfused post-imaging at 6 weeks after r-mTBI (A). In contrast, the positive control P301S human tau tissues show high levels of phosphorylated serine 396 tau in cortical neurons (B). Scale bar = 100 μm. r-mTBI, repetitive mild traumatic brain injury.
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f7: Tau pathology is not observed after r-mTBI. Immunohistochemistry for phosphorylated serine 396 tau shows a lack of immunolabeling in the cortex of mice perfused post-imaging at 6 weeks after r-mTBI (A). In contrast, the positive control P301S human tau tissues show high levels of phosphorylated serine 396 tau in cortical neurons (B). Scale bar = 100 μm. r-mTBI, repetitive mild traumatic brain injury.

Mentions: Further analysis of tau pathology was performed in the post-imaging 6-week cohort as a potential feature that may produce cortical changes after repetitive injury (Fig. 7). However, immunoreactivity for phosphorylated tau epitopes was not detected in r-mTBI mice using a pSer396 antibody (Fig. 7A) or AT8 antibody (data not shown). The sham condition also did not exhibit immunoreactivity for phosphorylated tau (data not shown). P301S human tau mice were used as a positive control using the same immunohistochemical protocols and showed clear tau pathology in cortical neurons for both pSer396 (Fig. 7B) and AT8 (data not shown).


Repetitive Model of Mild Traumatic Brain Injury Produces Cortical Abnormalities Detectable by Magnetic Resonance Diffusion Imaging, Histopathology, and Behavior
Tau pathology is not observed after r-mTBI. Immunohistochemistry for phosphorylated serine 396 tau shows a lack of immunolabeling in the cortex of mice perfused post-imaging at 6 weeks after r-mTBI (A). In contrast, the positive control P301S human tau tissues show high levels of phosphorylated serine 396 tau in cortical neurons (B). Scale bar = 100 μm. r-mTBI, repetitive mild traumatic brain injury.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5385606&req=5

f7: Tau pathology is not observed after r-mTBI. Immunohistochemistry for phosphorylated serine 396 tau shows a lack of immunolabeling in the cortex of mice perfused post-imaging at 6 weeks after r-mTBI (A). In contrast, the positive control P301S human tau tissues show high levels of phosphorylated serine 396 tau in cortical neurons (B). Scale bar = 100 μm. r-mTBI, repetitive mild traumatic brain injury.
Mentions: Further analysis of tau pathology was performed in the post-imaging 6-week cohort as a potential feature that may produce cortical changes after repetitive injury (Fig. 7). However, immunoreactivity for phosphorylated tau epitopes was not detected in r-mTBI mice using a pSer396 antibody (Fig. 7A) or AT8 antibody (data not shown). The sham condition also did not exhibit immunoreactivity for phosphorylated tau (data not shown). P301S human tau mice were used as a positive control using the same immunohistochemical protocols and showed clear tau pathology in cortical neurons for both pSer396 (Fig. 7B) and AT8 (data not shown).

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.

No MeSH data available.


Related in: MedlinePlus