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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

Microglia processes appear to preferentially contact TBI-induced proximal axonal swellings. Representative 3D reconstructions of MBP+ myelinated axons (red) or APP+ axonal swellings (green) and Iba-1+ microglia (white) in sham-injured (a) or central fluid percussion injured (b) thalami. c Bar graph depicting the average number of Iba-1+ microglial processes contacting either MBP+ myelinated fibers in the sham animals or APP+ axonal swellings in injured animals. Graph depicts the mean ± standard error of the mean. *p < 0.05. Scale bar: 5 μm
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Fig7: Microglia processes appear to preferentially contact TBI-induced proximal axonal swellings. Representative 3D reconstructions of MBP+ myelinated axons (red) or APP+ axonal swellings (green) and Iba-1+ microglia (white) in sham-injured (a) or central fluid percussion injured (b) thalami. c Bar graph depicting the average number of Iba-1+ microglial processes contacting either MBP+ myelinated fibers in the sham animals or APP+ axonal swellings in injured animals. Graph depicts the mean ± standard error of the mean. *p < 0.05. Scale bar: 5 μm

Mentions: To investigate the possibility that activated microglial processes converge on proximal axonal swellings sustaining mTBI-induced DAI in the micro pig thalamus, the number of microglia processes that contacted APP+ axonal swellings in injured animals or normal myelinated axons in sham animals was assessed (Mann–Whitney U test p = 0.018; sham n = 60 axonal segments, TBI n = 60 axonal swellings). Following sham injury, microglia processes made contact with myelinated axons, however, these contacts were sparse (Fig. 7a) and primarily consisted of microglia processes passing by and/or crossing over myelinated axons (sham = 63.39 % of total contacts, TBI = 25.23 % of total contacts). This is shown in more detail in an additional movie file (Additional file 1). Conversely, nearly double the number of microglia processes contacted APP+ proximal axonal swellings following diffuse mTBI (Fig. 7). The majority of these contacts were bulbous end processes (TBI = 58.16 % of total contacts, sham = 36.61 % of total contacts) as apposed to processes passing over axons, which were common in the sham. An additional movie file represents these finding in more detail (Additional file 2). The percentage of microglial processes that appeared to cradle or “cup” the axon were also increased when contacting APP+ swellings compared to sham myelinated axons (TBI = 16.60 % of total contacts, sham = 6.09 % of total contacts).Fig. 7


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)

Microglia processes appear to preferentially contact TBI-induced proximal axonal swellings. Representative 3D reconstructions of MBP+ myelinated axons (red) or APP+ axonal swellings (green) and Iba-1+ microglia (white) in sham-injured (a) or central fluid percussion injured (b) thalami. c Bar graph depicting the average number of Iba-1+ microglial processes contacting either MBP+ myelinated fibers in the sham animals or APP+ axonal swellings in injured animals. Graph depicts the mean ± standard error of the mean. *p < 0.05. Scale bar: 5 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4595283&req=5

Fig7: Microglia processes appear to preferentially contact TBI-induced proximal axonal swellings. Representative 3D reconstructions of MBP+ myelinated axons (red) or APP+ axonal swellings (green) and Iba-1+ microglia (white) in sham-injured (a) or central fluid percussion injured (b) thalami. c Bar graph depicting the average number of Iba-1+ microglial processes contacting either MBP+ myelinated fibers in the sham animals or APP+ axonal swellings in injured animals. Graph depicts the mean ± standard error of the mean. *p < 0.05. Scale bar: 5 μm
Mentions: To investigate the possibility that activated microglial processes converge on proximal axonal swellings sustaining mTBI-induced DAI in the micro pig thalamus, the number of microglia processes that contacted APP+ axonal swellings in injured animals or normal myelinated axons in sham animals was assessed (Mann–Whitney U test p = 0.018; sham n = 60 axonal segments, TBI n = 60 axonal swellings). Following sham injury, microglia processes made contact with myelinated axons, however, these contacts were sparse (Fig. 7a) and primarily consisted of microglia processes passing by and/or crossing over myelinated axons (sham = 63.39 % of total contacts, TBI = 25.23 % of total contacts). This is shown in more detail in an additional movie file (Additional file 1). Conversely, nearly double the number of microglia processes contacted APP+ proximal axonal swellings following diffuse mTBI (Fig. 7). The majority of these contacts were bulbous end processes (TBI = 58.16 % of total contacts, sham = 36.61 % of total contacts) as apposed to processes passing over axons, which were common in the sham. An additional movie file represents these finding in more detail (Additional file 2). The percentage of microglial processes that appeared to cradle or “cup” the axon were also increased when contacting APP+ swellings compared to sham myelinated axons (TBI = 16.60 % of total contacts, sham = 6.09 % of total contacts).Fig. 7

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