The loading conditions used in some current in vivo and in vitro blast-induced neurotrauma models may not be representative of real-world blast conditions. To address these limitations, we developed ...a compressed-gas driven shock tube with different driven lengths that can generate Friedlander-type blasts. The shock tube can generate overpressures up to 650 kPa with durations between 0.3 and 1.1 ms using compressed helium driver gas, and peak overpressures up to 450 kPa with durations between 0.6 and 3 ms using compressed nitrogen. This device is used for short-duration blast overpressure loading for small animal in vivo injury models, and contrasts the more frequently used long duration/high impulse blast overpressures in the literature. We also developed a new apparatus that is used with the shock tube to recreate the in vivo intracranial overpressure response for loading in vitro culture preparations. The receiver device surrounds the culture with materials of similar impedance to facilitate the propagation of a single overpressure pulse through the tissue. This method prevents pressure waves reflecting off the tissue that can cause unrealistic deformation and injury. The receiver performance was characterized using the longest helium-driven shock tube, and produced in-fluid overpressures up to 1500 kPa at the location where a culture would be placed. This response was well correlated with the overpressure conditions from the shock tube (R(2) = 0.97). Finite element models of the shock tube and receiver were developed and validated to better elucidate the mechanics of this methodology. A demonstration exposing a culture to the loading conditions created by this system suggest tissue strains less than 5% for all pressure levels simulated, which was well below functional deficit thresholds for strain rates less than 50 s(-1). This novel system is not limited to a specific type of culture model and can be modified to reproduce more complex pressure pulses.
During development, half of brain white matter axons are maintained for growth, while the remainder undergo developmental axon degeneration. After traumatic brain injury (TBI), injured axons also ...appear to follow pathways leading to either degeneration or repair. These observations raise the intriguing, but unexamined possibility that TBI recapitulates developmental axonal programs. Here, we examined axonal changes in the developing brain in young rats and after TBI in adult rats. Multiple shared changes in axonal microtubule (MT) through tubulin post-translational modifications and MT associated proteins (MAPs), tau and MAP6, were found in both development and after TBI. Specifically, degenerating axons in both development and TBI underwent phosphorylation of tau and excessive tubulin tyrosination, suggesting MT instability and depolyermization. Conversely, nearby axons without degenerating morphologies, had increased MAP6 expression and maintenance of tubulin acetylation, suggesting enhanced MT stabilization, thereby supporting survival or repair. Quantitative proteomics revealed similar signaling pathways of axon degeneration and growth/repair, including protein clusters and networks. This comparison approach demonstrates how focused evaluation of developmental processes may provide insight into pathways initiated by TBI. In particular, the data suggest that TBI may reawaken dormant axonal programs that direct axons towards either degeneration or growth/repair, supporting further study in this area.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Apoptotic or necrotic cell death in the hippocampus is a major factor underlying the cognitive impairments following traumatic brain injury. In this study, we examined if traumatic mechanical injury ...would produce regional activation of calpain and caspase-3 in the in vitro hippocampus and studied how the mechanically induced activation of NR2A and NR2B containing
N-methyl-
d-aspartate receptors (NMDARs) affects the activation of these proteases following mechanical injury. Following a 75% stretch, significant levels of activated caspase-3 and calpain-mediated spectrin breakdown products were evident only in cells within the dentate gyrus, and little co-localization of the markers was identified within individual cells. After 100% stretch, only calpain activation was observed, localized to the CA3 subregion 24 h after stretch. At moderate injury levels, both caspase-3 and calpain activation was attenuated by blocking NR2B containing NMDARs prior to stretch or by blocking all NMDARs prior to stretch injury. Treatment with an NR2A selective NMDAR antagonist had little effect on either activated caspase-3 or Ab38 immunoreactivity following moderate injury but resulted in the appearance of activated caspase-3 in the dentate gyrus following severe mechanical stretch. Together, these studies suggest that the injury induced activation of NR2A containing NMDARs functions as a pro-survival signal, while the activation of NR2B containing NMDARs is a competing, anti-survival, signal following mechanical injury to the hippocampus.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although hippocampal damage plays a key role in impairments after concussion, differences in hippocampal information processing during recovery are unknown. Micro-endoscopic calcium imaging was ...performed before and after primary blast injury in freely behaving mice in two environments: their familiar home cage and a novel open field. Results show that after concussion CA1 activity increased in the familiar environment in which animals were awake and mostly immobile but was unaltered in a novel environment which the animals actively and constantly explored. As awake immobility parallels cognitive rest, a common treatment for patients, the results imply that prolonged cognitive rest may unwittingly impede concussion recovery.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cytosolic PSD-95 interactor (cypin) regulates many aspects of neuronal development and function, ranging from dendritogenesis to synaptic protein localization. While it is known that removal of ...postsynaptic density protein-95 (PSD-95) from the postsynaptic density decreases synaptic N-methyl-D-aspartate (NMDA) receptors and that cypin overexpression protects neurons from NMDA-induced toxicity, little is known about cypin’s role in AMPA receptor clustering and function. Experimental work shows that cypin overexpression decreases PSD-95 levels in synaptosomes and the PSD, decreases PSD-95 clusters/μm
, and increases mEPSC frequency. Analysis of microelectrode array (MEA) data demonstrates that cypin or cypinΔPDZ overexpression increases sensitivity to CNQX (cyanquixaline) and AMPA receptor-mediated decreases in spike waveform properties. Network-level analysis of MEA data reveals that cypinΔPDZ overexpression causes networks to be resilient to CNQX-induced changes in local efficiency. Incorporating these findings into a computational model of a neural circuit demonstrates a role for AMPA receptors in cypin-promoted changes to networks and shows that cypin increases firing rate while changing network functional organization, suggesting cypin overexpression facilitates information relay but modifies how information is encoded among brain regions. Our data show that cypin promotes changes to AMPA receptor signaling independent of PSD-95 binding, shaping neural circuits and output to regions beyond the hippocampus.
We used lentivirus to overexpress cytosolic PSD-95 interactor (cypin) and a cypin mutant that cannot bind PSD-95 (cypinΔPDZ) to understand how cypin regulates synaptic signaling. Using biochemical and electrophysiological approaches, we show that cypin, but not the cypin mutant, regulates synaptic PSD-95 content. Surprisingly, cypin overexpression increases AMPA receptor function independent of its role in PSD-95 localization, while cypinΔPDZ overexpression causes networks to be resistant to CNQX-mediated changes to local efficiency. We then developed a computational model to account for the effects of cypin overexpression, finding that our simulated model also demonstrates a role for AMPA receptors in cypin-promoted changes to neural circuits. These results support a role for cypin in controlling synaptic function at synapses that is distinct from regulation of PSD-95 function.
Traumatic brain injury caused by explosive or blast events is currently divided into four phases: primary, secondary, tertiary, and quaternary blast injury. These phases of blast-induced traumatic ...brain injury (bTBI) are biomechanically distinct, and can be modeled in both in-vivo and in-vitro systems. The purpose of this review is to consider the mechanical phases of bTBI, how these phases are reproduced with in-vitro models, and to review findings from these models to assess how each phase of bTBI can be examined in more detail. Highlighted are some important gaps in the literature that may be addressed in the future to better identify the exact contributing mechanisms for bTBI. These in-vitro models, viewed in combination with in-vivo models and clinical studies, can be used to assess both the mechanisms and possible treatments for this type of trauma.
Animal models of traumatic brain injury Johnson, Victoria E; Meaney, David F; Cullen, D Kacy ...
Handbook of Clinical Neurology,
2015, Volume:
127
Journal Article
Peer reviewed
Open access
Traumatic brain injury (TBI) is a major health issue comprising a heterogeneous and complex array of pathologies. Over the last several decades, numerous animal models have been developed to address ...the diverse nature of human TBI. The clinical relevance of these models has been a major point of reflection given the poor translation of pharmacologic TBI interventions to the clinic. While previously characterized broadly as either focal or diffuse, this classification is falling out of favor with increased awareness of the overlap in pathologic outcomes between models and an emerging consensus that no one model is sufficient. Moreover, an appreciation of injury biomechanics is essential in recapitulating and interpreting the spectrum of TBI neuropathology observed in various established models of dynamic closed-head TBI. While these models have replicated many specific features of human TBI, an enhanced context with clinical relevancy will facilitate the further elucidation of the mechanisms and treatment of injury.
Unique from other brain disorders, traumatic brain injury (TBI) generally results from a discrete biomechanical event that induces rapid head movement. The large size and high organization of the ...human brain makes it particularly vulnerable to traumatic injury from rotational accelerations that can cause dynamic deformation of the brain tissue. Therefore, replicating the injury biomechanics of human TBI in animal models presents a substantial challenge, particularly with regard to addressing brain size and injury parameters. Here we present the historical development and use of a porcine model of head rotational acceleration. By scaling up the rotational forces to account for difference in brain mass between swine and humans, this model has been shown to produce the same tissue deformations and identical neuropathologies found in human TBI. The parameters of scaled rapid angular accelerations applied for the model reproduce inertial forces generated when the human head suddenly accelerates or decelerates in falls, collisions, or blunt impacts. The model uses custom-built linkage assemblies and a powerful linear actuator designed to produce purely impulsive non-impact head rotation in different angular planes at controlled rotational acceleration levels. Through a range of head rotational kinematics, this model can produce functional and neuropathological changes across the spectrum from concussion to severe TBI. Notably, however, the model is very difficult to employ, requiring a highly skilled team for medical management, biomechanics, neurological recovery, and specialized outcome measures including neuromonitoring, neurophysiology, neuroimaging, and neuropathology. Nonetheless, while challenging, this clinically relevant model has proven valuable for identifying mechanisms of acute and progressive neuropathologies as well as for the evaluation of noninvasive diagnostic techniques and potential neuroprotective treatments following TBI.
While individual susceptibility to traumatic brain injury (TBI) has been speculated, past work does not provide an analysis considering how physical features of an individual’s brain (e.g., brain ...size, shape), impact direction, and brain network features can holistically contribute to the risk of suffering a TBI from an impact. This work investigated each of these features simultaneously using computational modeling and analyses of simulated functional connectivity. Unlike the past studies that assess the severity of TBI based on the quantification of brain tissue damage (e.g., principal strain), we approached the brain as a complex network in which neuronal oscillations orchestrate to produce normal brain function (estimated by functional connectivity) and, to this end, both the anatomical damage location and its topological characteristics within the brain network contribute to the severity of brain function disruption and injury. To represent the variations in the population, we analyzed a publicly available database of brain imaging data and selected five distinct network architectures, seven different brain sizes, and three uniaxial head rotational conditions to study the consequences of 74 virtual impact scenarios. Results show impact direction produces the most significant change in connections across brain areas (structural connectome) and the functional coupling of activity across these brain areas (functional connectivity). Axial rotations were more injurious than those with sagittal and coronal rotations when the head kinematics were the same for each condition. When the impact direction was held constant, brain network architecture showed a significantly different vulnerability across axial and sagittal, but not coronal rotations. As expected, brain size significantly affected the expected change in structural and functional connectivity after impact. Together, these results provided groupings of predicted vulnerability to impact—a subgroup of male brain architectures exposed to axial impacts were most vulnerable, while a subgroup of female brain architectures was the most tolerant to the sagittal impacts studied. These findings lay essential groundwork for subject-specific analyses of concussion and provide invaluable guidance for designing personalized protection equipment.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Traumatic brain injury (TBI) induces cognitive deficits driven by neuroinflammation and cerebral edema. The commonly used atypical antipsychotic, quetiapine (QTP), has been recently shown to improve ...post-TBI outcomes. We hypothesized that QTP would thereby improve animal learning and memory 2 weeks after severe TBI.
CD1 male mice (n = 35) underwent severe TBI (controlled cortical impact, injury, I) or sham craniotomy (S), followed by BID saline (P, placebo) or QTP (10 or 20 mg/kg, IP) for 2 weeks. Animals underwent Morris Water Maze (MWM) exercises to gauge spatial learning and memory. The distance and time required for swimming animals to reach the platform area (Zone 5, Z5) located in quadrant 1 (Zone 1, Z1) was calculated from digital video recordings analyzed using Ethovision software. Animal bodyweights were recorded daily and on day 14, injured cerebral hemispheres were procured for edema determination (wet-to-dry ratio). Intergroup differences were evaluated with ANOVA/Bonferroni correction (p < 0.05).
On day 14, animal weight loss recovery was lowest in I + P compared to I + QTP20 and I + QTP10 (p ≤ 0.01 for either). Cerebral edema was greatest in I + P, and only significantly decreased in I + QTP20 (p < 0.05). Both QTP doses similarly improved spatial learning by significantly reducing latency time and travel distance to target zones (p < 0.05). In probe memory trials, only I + QTP20 and not I + QTP10 significantly favored animal reaching or crossing into target zones (p < 0.05).
Post-TBI QTP reduces brain edema and improves spatial learning and memory with a potential dose dependence impact benefiting memory up to 14 days. These data suggest an unanticipated QTP benefit following brain injury that should be specifically explored.
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