Due to their viscoelastic nature, white matter axons are susceptible to damage by high strain rates produced during traumatic brain injury (TBI). Indeed, diffuse axonal injury (DAI) is one of the most common features of TBI, characterized by the hallmark pathological profiles of axonal bulbs at disconnected terminal ends of axons and periodic swellings along axons, known as "varicosities." Although transport interruption underlies axonal bulb formation, it is unclear how varicosities arise, with multiple sites accumulating transported materials along one axon. Recently, axonal microtubules have been found to physically break during dynamic stretch injury of cortical axons in vitro. Here, the same in vitro model was used in parallel with histopathological analyses of human brains acquired acutely following TBI to examine the potential role of mechanical microtubule damage in varicosity formation post-trauma. Transmission electron microscopy (TEM) following in vitro stretch injury revealed periodic breaks of individual microtubules along axons that regionally corresponded with undulations in axon morphology. However, typically less than a third of microtubules were broken in any region of an axon. Within hours, these sites of microtubule breaks evolved into periodic swellings. This suggests axonal transport may be halted along one broken microtubule, yet can proceed through the same region via other intact microtubules. Similar axonal undulations and varicosities were observed following TBI in humans, suggesting primary microtubule failure may also be a feature of DAI. These data indicate a novel mechanism of mechanical microtubule damage leading to partial transport interruption and varicosity formation in traumatic axonal injury.
"Recent studies have suggested that tensile strain can modify patterns of axonal transport. While theoretical and experimental evidence suggests that high strain rates fracture microtubules, thus resulting in transport failure (Ahmadzadeh et al., 2014; Tang- Schomer et al., 2010; Tang-Schomer et al., 2012), lower, physiological levels of stretch are not necessarily detrimental for axonal transport. Specifically, mitochondrial velocity and transport frequency in stretch-grown axons appear unaffected for strains b24% (Loverde et al., 2011). "
"In vitro axonal stretch injury with subsequent transmission electron microscopy has demonstrated that microtubule breakage occurs in abnormally convoluted axons post-injury (Tang-Schomer et al., 2012). Interestingly, these breakage points corresponded to the varicosities that develop 3 h after injury (Tang-Schomer et al., 2012), providing evidence that microtubule disruption precedes swelling development. Measurement of this phenomenon immunohistochemically has been achieved using antibodies to the APP (Blumbergs et al., 1994), as it is a fast anterograde axonal transport product that rapidly accumulates at sites of transport disruption (Saatman et al., 2003). "
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a range of forms of neural damage, which culminate in mortality or impart mild to significant neurological disability. In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes. The neurofilament triplet proteins are key structural cytoskeletal elements, which may also be important contributors to the tensile strength of axons. This has significant implications with respect to how axons may respond to TBI. It is not known, however, whether neurofilament compaction and the cytoskeletal changes that evolve following axonal injury represent a component of a protective mechanism following damage, or whether they serve to augment degeneration and progression to secondary axotomy. Here we review the structure and role of neurofilament proteins in normal neuronal function. We also discuss the processes that characterize DAI and the resultant alterations in neurofilaments, highlighting potential clues to a possible protective or degenerative influence of specific neurofilament alterations within injured neurons. The potential utility of neurofilament assays as biomarkers for axonal injury is also discussed. Insights into the complex alterations in neurofilaments will contribute to future efforts in developing therapeutic strategies to prevent, ameliorate or reverse neuronal degeneration in the central nervous system (CNS) following traumatic injury.
"Recently, a long-length (2 mm) axon tract culture system (Tang- Schomer et al., 2010) was established as an in vitro model for studying diffuse axonal injury after brain trauma. This model allows for examination of dynamic changes of axons (Tang-Schomer et al., 2010) and dendrites (Monnerie et al., 2010), such as mechanical injury-induced undulations and beading, that are similar to the pathological presentations of patient brains (Tang-Schomer et al., 2012). An earlier version of compartmentalized cultures, in which axons grew as 2 mm-wide networks, was used to identify sodium channel cleavage as a potential molecular mechanism for brain trauma-related functional deficits (Iwata et al., 2004; Yuen et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: The cortical circuitry in the brain consists of structurally and functionally distinct neuronal assemblies with reciprocal axon connections. To generate cell culture-based systems that emulate axon tract systems of an in vivo neural network, we developed a living neural circuit consisting of compartmentalized neuronal populations connected by arrays of two millimeter-long axon tracts that are integrated on a planar multi-electrode array (MEA). The millimeter-scale node-to-node separation allows for pharmacological and electrophysiological manipulations to simultaneously target multiple neuronal populations. The results show controlled selectivity of dye absorption by neurons in different compartments. MEA-transmitted electrical stimulation of targeted neurons shows ∼46% increase of intracellular calcium levels with 20Hz stimulation, but ∼22% decrease with 2k Hz stimulation. The unique feature of long distance axons promotes in vivo-like fasciculation. These axon tracts are determined to be inhibitory afferents by showing increased action potential firing of downstream node upon selective application of γ-aminobutyric acid (GABA) to the upstream node. Together, this model demonstrates integrated capabilities for assessing multiple endpoints including axon tract tracing, calcium influx, network architecture and activities. This system can be used as a multi-functional platform for studying axon tract-associated CNS disorders in vitro, such as diffuse axonal injury after brain trauma.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.