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Microglia processes associate with diffusely injured axons following mild traumatic brain injury in the micro pig.

Lafrenaye AD, Todani M, Walker SA, Povlishock JT - J Neuroinflammation (2015)

Bottom Line: Mild traumatic brain injury (mTBI) is an all too common occurrence that exacts significant personal and societal costs.The physical relationship between microglia and DAI, assessed via confocal 3D analysis, revealed a dramatic increase in the number of Iba-1+ microglial processes that contacted APP+ proximal axonal swellings compared to uninjured myelinated thalamic axons in sham animals.These findings transform our understanding of acute neuroinflammation following mTBI and may suggest its potential as a diagnostic and/or a therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, P.O. Box 980709, Richmond, VA, 23298, USA. forrestad@vcu.edu.

ABSTRACT

Background: Mild traumatic brain injury (mTBI) is an all too common occurrence that exacts significant personal and societal costs. The pathophysiology of mTBI is complex, with reports routinely correlating diffuse axonal injury (DAI) with prolonged morbidity. Progressive chronic neuroinflammation has also recently been correlated to morbidity, however, the potential association between neuroinflammatory microglia and DAI is not well understood. The majority of studies exploring neuroinflammatory responses to TBI have focused on more chronic phases of injury involving phagocytosis associated with Wallerian change. Little, however, is known regarding the neuroinflammatory response seen acutely following diffuse mTBI and its potential relationship to early DAI. Additionally, while inflammation is drastically different in rodents compared to humans, pigs and humans share very similar inflammatory profiles and responses.

Methods: In the current study, we employed a modified central fluid percussion model in micro pigs. Using this model of diffuse mTBI, paired with various immunohistological endpoints, we assessed the potential association between acute thalamic DAI and neuroinflammation 6 h following injury.

Results: Injured micro pigs displayed substantial axonal damage reflected in the presence of APP+ proximal axonal swellings, which were particularly prominent in the thalamus. In companion, the same thalamic sites displayed extensive neuroinflammation, which was observed using Iba-1 immunohistochemistry. The physical relationship between microglia and DAI, assessed via confocal 3D analysis, revealed a dramatic increase in the number of Iba-1+ microglial processes that contacted APP+ proximal axonal swellings compared to uninjured myelinated thalamic axons in sham animals.

Conclusions: In aggregate, these studies reveal acute microglial process convergence on proximal axonal swellings undergoing DAI, an interaction not previously recognized in the literature. These findings transform our understanding of acute neuroinflammation following mTBI and may suggest its potential as a diagnostic and/or a therapeutic target.

No MeSH data available.


Related in: MedlinePlus

Axonal injury is observed in various regions throughout the micro pig brain following cFPI. Representative photomicrographs of APP immunohistochemistry in regions of the micro pig brain that demonstrated DAI in animals sustaining cFPI. Images in the middle panel (b, f, i, l, o, r) are magnified regions indicated in the images of the left panel (a, e, h, k, n, q) and images in the right panel (c, g, j, m, p, s) are magnified regions indicated in the middle panel (b, f, i, l, o, r), respectively. Note that DAI within the thalamus and tectum was diffusely distributed throughout the domain, while DAI within the other regions was more localized. Also note that while not common, APP+ proximal axonal swellings in continuity with the neuronal soma (d) were observed in the thalamus. Scale bar in q: 200 μm; r and s: 100 μm; d: 50 μm
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Fig2: Axonal injury is observed in various regions throughout the micro pig brain following cFPI. Representative photomicrographs of APP immunohistochemistry in regions of the micro pig brain that demonstrated DAI in animals sustaining cFPI. Images in the middle panel (b, f, i, l, o, r) are magnified regions indicated in the images of the left panel (a, e, h, k, n, q) and images in the right panel (c, g, j, m, p, s) are magnified regions indicated in the middle panel (b, f, i, l, o, r), respectively. Note that DAI within the thalamus and tectum was diffusely distributed throughout the domain, while DAI within the other regions was more localized. Also note that while not common, APP+ proximal axonal swellings in continuity with the neuronal soma (d) were observed in the thalamus. Scale bar in q: 200 μm; r and s: 100 μm; d: 50 μm

Mentions: Since axonal injury is a pathological hallmark associated with much of the morbidity following TBI [10, 11, 14–18], the extent of DAI was qualitatively assessed in various regions of the micro pig brain 6 h following sham or cFPI. This time point was chosen, based on our initial observations in this model, which revealed robust DAI by 6-h post-injury in the micro pig brain (unpublished findings). Pronounced DAI, identified as APP+ proximal axonal swellings, indicative of impaired protein transport in the proximal axonal segment remaining attached to the neuronal soma following disconnection [53, 54, 58, 59], was observed in the thalamus, corpus callosum, fornix, tectum of the midbrain, cerebellum, and brainstem (Fig. 2). While, in some animals, other brain regions displayed more densely localized DAI, diffuse thalamic DAI was the most consistent finding across animals. As thalamic damage is also a common occurrence in human TBI [49–52], we concentrated our quantitative histological analysis on this anatomical region (one-way ANOVA F1,19 = 6.677, p = 0.018; sham n = 3, TBI n = 18; Fig. 3). Consistent with previous studies examining DAI via APP accumulation, no APP+ axonal swellings were observed in sham-injured micro pigs (Fig. 3a). Following cFPI, however, substantial APP+ proximal axonal swellings were apparent throughout the thalamic domain (Fig. 3). DAI within the micro pig thalamus appeared as large (~5 μm in diameter) APP+ spheroids diffusely distributed in patches throughout the dorsal-ventral and rostral-caudal extent of the thalamus.Fig. 2


Microglia processes associate with diffusely injured axons following mild traumatic brain injury in the micro pig.

Lafrenaye AD, Todani M, Walker SA, Povlishock JT - J Neuroinflammation (2015)

Axonal injury is observed in various regions throughout the micro pig brain following cFPI. Representative photomicrographs of APP immunohistochemistry in regions of the micro pig brain that demonstrated DAI in animals sustaining cFPI. Images in the middle panel (b, f, i, l, o, r) are magnified regions indicated in the images of the left panel (a, e, h, k, n, q) and images in the right panel (c, g, j, m, p, s) are magnified regions indicated in the middle panel (b, f, i, l, o, r), respectively. Note that DAI within the thalamus and tectum was diffusely distributed throughout the domain, while DAI within the other regions was more localized. Also note that while not common, APP+ proximal axonal swellings in continuity with the neuronal soma (d) were observed in the thalamus. Scale bar in q: 200 μm; r and s: 100 μm; d: 50 μm
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Fig2: Axonal injury is observed in various regions throughout the micro pig brain following cFPI. Representative photomicrographs of APP immunohistochemistry in regions of the micro pig brain that demonstrated DAI in animals sustaining cFPI. Images in the middle panel (b, f, i, l, o, r) are magnified regions indicated in the images of the left panel (a, e, h, k, n, q) and images in the right panel (c, g, j, m, p, s) are magnified regions indicated in the middle panel (b, f, i, l, o, r), respectively. Note that DAI within the thalamus and tectum was diffusely distributed throughout the domain, while DAI within the other regions was more localized. Also note that while not common, APP+ proximal axonal swellings in continuity with the neuronal soma (d) were observed in the thalamus. Scale bar in q: 200 μm; r and s: 100 μm; d: 50 μm
Mentions: Since axonal injury is a pathological hallmark associated with much of the morbidity following TBI [10, 11, 14–18], the extent of DAI was qualitatively assessed in various regions of the micro pig brain 6 h following sham or cFPI. This time point was chosen, based on our initial observations in this model, which revealed robust DAI by 6-h post-injury in the micro pig brain (unpublished findings). Pronounced DAI, identified as APP+ proximal axonal swellings, indicative of impaired protein transport in the proximal axonal segment remaining attached to the neuronal soma following disconnection [53, 54, 58, 59], was observed in the thalamus, corpus callosum, fornix, tectum of the midbrain, cerebellum, and brainstem (Fig. 2). While, in some animals, other brain regions displayed more densely localized DAI, diffuse thalamic DAI was the most consistent finding across animals. As thalamic damage is also a common occurrence in human TBI [49–52], we concentrated our quantitative histological analysis on this anatomical region (one-way ANOVA F1,19 = 6.677, p = 0.018; sham n = 3, TBI n = 18; Fig. 3). Consistent with previous studies examining DAI via APP accumulation, no APP+ axonal swellings were observed in sham-injured micro pigs (Fig. 3a). Following cFPI, however, substantial APP+ proximal axonal swellings were apparent throughout the thalamic domain (Fig. 3). DAI within the micro pig thalamus appeared as large (~5 μm in diameter) APP+ spheroids diffusely distributed in patches throughout the dorsal-ventral and rostral-caudal extent of the thalamus.Fig. 2

Bottom Line: Mild traumatic brain injury (mTBI) is an all too common occurrence that exacts significant personal and societal costs.The physical relationship between microglia and DAI, assessed via confocal 3D analysis, revealed a dramatic increase in the number of Iba-1+ microglial processes that contacted APP+ proximal axonal swellings compared to uninjured myelinated thalamic axons in sham animals.These findings transform our understanding of acute neuroinflammation following mTBI and may suggest its potential as a diagnostic and/or a therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, P.O. Box 980709, Richmond, VA, 23298, USA. forrestad@vcu.edu.

ABSTRACT

Background: Mild traumatic brain injury (mTBI) is an all too common occurrence that exacts significant personal and societal costs. The pathophysiology of mTBI is complex, with reports routinely correlating diffuse axonal injury (DAI) with prolonged morbidity. Progressive chronic neuroinflammation has also recently been correlated to morbidity, however, the potential association between neuroinflammatory microglia and DAI is not well understood. The majority of studies exploring neuroinflammatory responses to TBI have focused on more chronic phases of injury involving phagocytosis associated with Wallerian change. Little, however, is known regarding the neuroinflammatory response seen acutely following diffuse mTBI and its potential relationship to early DAI. Additionally, while inflammation is drastically different in rodents compared to humans, pigs and humans share very similar inflammatory profiles and responses.

Methods: In the current study, we employed a modified central fluid percussion model in micro pigs. Using this model of diffuse mTBI, paired with various immunohistological endpoints, we assessed the potential association between acute thalamic DAI and neuroinflammation 6 h following injury.

Results: Injured micro pigs displayed substantial axonal damage reflected in the presence of APP+ proximal axonal swellings, which were particularly prominent in the thalamus. In companion, the same thalamic sites displayed extensive neuroinflammation, which was observed using Iba-1 immunohistochemistry. The physical relationship between microglia and DAI, assessed via confocal 3D analysis, revealed a dramatic increase in the number of Iba-1+ microglial processes that contacted APP+ proximal axonal swellings compared to uninjured myelinated thalamic axons in sham animals.

Conclusions: In aggregate, these studies reveal acute microglial process convergence on proximal axonal swellings undergoing DAI, an interaction not previously recognized in the literature. These findings transform our understanding of acute neuroinflammation following mTBI and may suggest its potential as a diagnostic and/or a therapeutic target.

No MeSH data available.


Related in: MedlinePlus