The Importance of Inter-Species Variation in Traumatic Brain Injury-Induced Alterations of Microglial-Axonal Interactions

Interactions between microglia and neuronal components are important for normal CNS function. They are also associated with neuroinflammation and many pathological processes and several studies have explored these interactions in terms of phagocytic engulfment. Much progress has also been made in understanding the consequences of chronic neuroinflammatory changes following trauma. However, little is known about acute alterations to these physical non-phagocytic microglial-neuronal interactions following traumatic brain injury (TBI), and particularly to what degree these post-injury interactions may be influenced by the animal species utilized in pre-clinical models of TBI. To investigate these problems, we evaluated the physical interactions between microglia and injured axons acutely (6 h and 1 day) following central fluid percussion injury (cFPI) in both rats and micro pigs. The physical interactions between Iba-1+ microglia and either normal MBP+ myelinated fibers or APP+ injured axonal swellings in the thalamus were assessed following injury or sham via quantitative image analysis of 3D confocal micrographs. The results indicated that the physical interactions between microglia and injured axonal swellings decreased by nearly half in rats 6 h following cFPI but was consistent with sham control at 1 day post-cFPI. This reduction was also observed in non-injured intact fibers at both timepoints following TBI in the rat. Microglial process interactions with injured axons in the micro pig, however, increased nearly 2-fold compared to interactions with intact axonal segments 1 day post-cFPI. This study shows that the species utilized for in vivo pre-clinical studies influences the manner in which microglial-axonal interactions change following TBI. These species differences can be leveraged to further our understanding of the mechanisms involved in microglial process convergence and how these neuro-immune interactions alter the progression of axonal injury following TBI

Post-Injury Buprenorphine Administration Is Associated with Long-Term Region-Specific Glial Alterations in Rats Data

This is the Currated data published in the manuscript "Post-Injury Buprenorphine Administration is Associated with Long-Term Region-Specific Glial Alterations in Rats" Published in Parmaceutics on Sept. 28, 2022. https://www.mdpi.com/1999-4923/14/10/206

The Central Fluid Percussion Brain Injury in a Gyrencephalic Pig Brain: Scalable Diffuse Injury and Tissue Viability for Glial Cell Immunolabeling following Long-Term Refrigerated Storage data

This is the raw data generated in the study published in Biomedicines . 2023 Jun 10;11(6):1682. doi: 10.3390/biomedicines11061682

Bursting at the Seams: Molecular Mechanisms Mediating Astrocyte Swelling

Brain swelling is one of the most robust predictors of outcome following brain injury, including ischemic, traumatic, hemorrhagic, metabolic or other injury. Depending on the specific type of insult, brain swelling can arise from the combined space-occupying effects of extravasated blood, extracellular edema fluid, cellular swelling, vascular engorgement and hydrocephalus. Of these, arguably the least well appreciated is cellular swelling. Here, we explore current knowledge regarding swelling of astrocytes, the most abundant cell type in the brain, and the one most likely to contribute to pathological brain swelling. We review the major molecular mechanisms identified to date that contribute to or mitigate astrocyte swelling via ion transport, and we touch upon the implications of astrocyte swelling in health and disease

Microglial process convergence on axonal segments in health and disease

Microglia dynamically interact with neurons influencing the development, structure, and function of neuronal networks. Recent studies suggest microglia may also influence neuronal activity by physically interacting with axonal domains responsible for action potential initiation and propagation. However, the nature of these microglial process interactions is not well understood. Microglial-axonal contacts are present early in development and persist through adulthood, implicating microglial interactions in the regulation of axonal integrity in both the developing and mature central nervous system. Moreover, changes in microglial-axonal contact have been described in disease states such as multiple sclerosis (MS) and traumatic brain injury (TBI). Depending on the disease state, there are increased associations with specific axonal segments. In MS, there is enhanced contact with the axon initial segment and node of Ranvier, while, in TBI, microglia alter interactions with axons at the site of injury, as well as at the axon initial segment. In this article, we review the interactions of microglial processes with axonal segments, analyzing their associations with various axonal domains and how these interactions may differ between MS and TBI. Furthermore, we discuss potential functional consequences and molecular mechanisms of these interactions and how these may differ among various types of microglial-axonal interactions

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

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

Spatial Distribution of Neuropathology and Neuroinflammation Elucidate the Biomechanics of Fluid Percussion Injury

Diffuse brain injury is better described as multi-focal, where pathology can be found adjacent to seemingly uninjured neural tissue. In experimental diffuse brain injury, pathology and pathophysiology have been reported far more lateral than predicted by the impact site. We hypothesized that local thickening of the rodent skull at the temporal ridges serves to focus the intracranial mechanical forces experienced during brain injury and generate predictable pathology. We demonstrated local thickening of the skull at the temporal ridges using contour analysis on magnetic resonance imaging. After diffuse brain injury induced by midline fluid percussion injury (mFPI), pathological foci along the anterior-posterior length of cortex under the temporal ridges were evident acutely (1, 2, and 7 days) and chronically (28 days) post-injury by deposition of argyophilic reaction product. Area CA3 of the hippocampus and lateral nuclei of the thalamus showed pathological change, suggesting that mechanical forces to or from the temporal ridges shear subcortical regions. A proposed model of mFPI biomechanics suggests that injury force vectors reflect off the skull base and radiate toward the temporal ridge, thereby injuring ventral thalamus, dorsolateral hippocampus, and sensorimotor cortex. Surgically thinning the temporal ridge before injury reduced injury-induced inflammation in the sensorimotor cortex. These data build evidence for temporal ridges of the rodent skull to contribute to the observed pathology, whether by focusing extracranial forces to enter the cranium or intracranial forces to escape the cranium. Pre-clinical investigations can take advantage of the predicted pathology to explore injury mechanisms and treatment efficacy