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Brain-on-a-chip microsystem for investigating traumatic brain injury: Axon diameter and mitochondrial membrane changes play a significant role in axonal response to strain injuries.

ABSTRACT: Diffuse axonal injury (DAI) is a devastating consequence of traumatic brain injury, resulting in significant axon and neuronal degeneration. Currently, therapeutic options are limited. Using our brain-on-a-chip device, we evaluated axonal responses to DAI. We observed that axonal diameter plays a significant role in response to strain injury, which correlated to delayed elasticity and inversely correlated to axonal beading and axonal degeneration. When changes in mitochondrial membrane potential (MMP) were monitored an applied strain injury threshold was noted, below which delayed hyperpolarization was observed and above which immediate depolarization occurred. When the NHE-1 inhibitor EIPA was administered before injury, inhibition in both hyperpolarization and depolarization occurred along with axonal degeneration. Therefore, axonal diameter plays a significant role in strain injury and our brain-on-a-chip technology can be used both to understand the biochemical consequences of DAI and screen for potential therapeutic agents.

SUBMITTER: Dolle JP

PROVIDER: S-EPMC4120884 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Brain-on-a-chip microsystem for investigating traumatic brain injury: Axon diameter and mitochondrial membrane changes play a significant role in axonal response to strain injuries.

Dollé Jean-Pierre JP Morrison Barclay B Schloss Rene S RS Yarmush Martin L ML

Technology 20140601 2

Diffuse axonal injury (DAI) is a devastating consequence of traumatic brain injury, resulting in significant axon and neuronal degeneration. Currently, therapeutic options are limited. Using our brain-on-a-chip device, we evaluated axonal responses to DAI. We observed that axonal diameter plays a significant role in response to strain injury, which correlated to delayed elasticity and inversely correlated to axonal beading and axonal degeneration. When changes in mitochondrial membrane potential ...[more]

PMID: 25101309

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Project description:Neurodevelopment, plasticity, and cognition are integral with functional directional transport in neuronal axons that occurs along a unique network of discontinuous polar microtubule (MT) bundles. Axonopathies are caused by brain trauma and genetic diseases that perturb or disrupt the axon MT infrastructure and, with it, the dynamic interplay of motor proteins and cargo essential for axonal maintenance and neuronal signaling. The inability to visualize and quantify normal and altered nanoscale spatio-temporal dynamic transport events prevents a full mechanistic understanding of injury, disease progression, and recovery. To address this gap, we generated DyNAMO, a Dynamic Nanoscale Axonal MT Organization model, which is a biologically realistic theoretical axon framework. We use DyNAMO to experimentally simulate multi-kinesin traffic response to focused or distributed tractable injury parameters, which are MT network perturbations affecting MT lengths and multi-MT staggering. We track kinesins with different motility and processivity, as well as their influx rates, in-transit dissociation and reassociation from inter-MT reservoirs, progression, and quantify and spatially represent motor output ratios. DyNAMO demonstrates, in detail, the complex interplay of mixed motor types, crowding, kinesin off/on dissociation and reassociation, and injury consequences of forced intermingling. Stalled forward progression with different injury states is seen as persistent dynamicity of kinesins transiting between MTs and inter-MT reservoirs. DyNAMO analysis provides novel insights and quantification of axonal injury scenarios, including local injury-affected ATP levels, as well as relates these to influences on signaling outputs, including patterns of gating, waves, and pattern switching. The DyNAMO model significantly expands the network of heuristic and mathematical analysis of neuronal functions relevant to axonopathies, diagnostics, and treatment strategies.

Dataset Information

Brain-on-a-chip microsystem for investigating traumatic brain injury: Axon diameter and mitochondrial membrane changes play a significant role in axonal response to strain injuries.

Publications

Brain-on-a-chip microsystem for investigating traumatic brain injury: Axon diameter and mitochondrial membrane changes play a significant role in axonal response to strain injuries.

Similar Datasets

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