Article

Concussive Brain Trauma in the Mouse Results in Acute Cognitive Deficits and Sustained Impairment of Axonal Function

Program in Neuroscience, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA.
Journal of neurotrauma (Impact Factor: 3.71). 02/2011; 28(4):547-63. DOI: 10.1089/neu.2010.1729
Source: PubMed

ABSTRACT

Concussive brain injury (CBI) accounts for approximately 75% of all brain-injured people in the United States each year and is particularly prevalent in contact sports. Concussion is the mildest form of diffuse traumatic brain injury (TBI) and results in transient cognitive dysfunction, the neuropathologic basis for which is traumatic axonal injury (TAI). To evaluate the structural and functional changes associated with concussion-induced cognitive deficits, adult mice were subjected to an impact on the intact skull over the midline suture that resulted in a brief apneic period and loss of the righting reflex. Closed head injury also resulted in an increase in the wet weight:dry weight ratio in the cortex suggestive of edema in the first 24 h, and the appearance of Fluoro-Jade-B-labeled degenerating neurons in the cortex and dentate gyrus of the hippocampus within the first 3 days post-injury. Compared to sham-injured mice, brain-injured mice exhibited significant deficits in spatial acquisition and working memory as measured using the Morris water maze over the first 3 days (p<0.001), but not after the fourth day post-injury. At 1 and 3 days post-injury, intra-axonal accumulation of amyloid precursor protein in the corpus callosum and cingulum was accompanied by neurofilament dephosphorylation, impaired transport of Fluoro-Gold and synaptophysin, and deficits in axonal conductance. Importantly, deficits in retrograde transport and in action potential of myelinated axons continued to be observed until 14 days post-injury, at which time axonal degeneration was apparent. These data suggest that despite recovery from acute cognitive deficits, concussive brain trauma leads to axonal degeneration and a sustained perturbation of axonal function.

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Available from: Ann Mae Dileonardi, Jan 20, 2015
    • "In healthy neurons, phosphorylated NFs are primarily limited to the axonal compartment, but transection leads to aberrant accumulation in the soma (Klosen et al., 1990; Mansour et al., 1989). Additionally, axonal injury due to brain trauma results in dephosphorylation of NFs within the axon (Creed et al., 2011). These phenomena suggest reorganization of NF phosphorylation after injury, with phosphorylated NF becoming more prominent in the soma, and non-phosphorylated NF in the axon. "
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    • "Furthermore , DiLeonardi et al. (2009) showed in the same model that APP and RM014 labeled the same anatomical distribution at six and 24 h after injury, but labeling was never directly colocalised, suggesting that NF compaction and transport failure are discrete forms of axonal injury. Although NF compaction and impaired axonal transport are largely distinct (DiLeonardi et al., 2009), these pathological features occur in the same tracts after injury (Creed et al., 2011). More recently, a study of the spatial distribution of NF compaction and impaired axonal transport in the corpus callosum and pyramidal tracts after TBI demonstrated that impaired transport is the prevalent injury phenotype in white matter tracts at 24 h post-injury (Kallakuri et al., 2012). "
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    • "Synaptophysin, a major synaptic vesicle membrane protein, is transported along the axon in an anterograde manner comparable with APP transport (Koo et al., 1990;Okada et al., 1995). Axonal transport disturbances and axon transection lead to accumulation of synaptophysin in spheroid formations similar to the typical axonal swelling as shown by APP staining (Katsuse et al., 2003;Creed et al., 2011;Schirmer et al., 2012). In our study, synaptophysin-positive axons were found in the corpus callosum after 5 weeks of cuprizone feeding (Fig. 6). "
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Questions & Answers about this publication

  • Vigneswaran Veeramuthu added an answer in Demyelination:
    How soon can the demyelinating process start in mild traumatic brain injury?

    Traumatic brain injury, even in its mildest form, is known to result in degenerative processes including demyelination and dysmyelination of the axons over time. The shearing and tearing of the axons (primary injury) due to the acceleration and deceleration force of high velocity impact would also normally trigger off the secondary injury cascades. This includes the synaptic deregulation, cell death and axonal degeneration.  

    But how quickly does these processes start (especially the demyelination of the axons) in patients with mild TBI? I am of the opinion that it will take at least a few days or weeks before such degenerative process starts. What are your thoughts?

    Vigneswaran Veeramuthu

    Chandramouli Balasubramaniam, if I understood you correctly , I believe you do concur that demyelination does not start in the early stages (acute) of mild neurotrauma. It is usually the other processes that kicks in including increased vascular permeability, edema, derangement of blood brain barrier homeostasis, neuroinflammation (astrogliosis/ microgliosis), glial scarring.  Did I get you right?

    Besides Kossman et al, I believe there are few others who have suggested that the demyelinating process in mild TBI does not start at least until some later stages (Ref 1-4).

    In our current work, we found similar results (hopefully accepted for publication in coming months). Through cutting age DTI post scan processing methods (combination of ROI and TBSS), we found interesting patterns of change in the DTI parameters which are better explained by vasogenic and cytotoxic edema and as well as astrogliosis than the demyelination (the scans were acquired at 10 hours post trauma on average).

    1. Creed et al 2011 https://www.researchgate.net/publication/49815588_Concussive_brain_trauma_in_the_mouse_results_in_acute_cognitive_deficits_and_sustained_impairment_of_axonal_function

    2. Staal and Vickers, 2011 http://www.ncbi.nlm.nih.gov/pubmed/21235329

    3. Bramlett and Dietrich, 2002 http://www.ncbi.nlm.nih.gov/pubmed/12012093

    4. Liu et al, 2006 http://www.ncbi.nlm.nih.gov/pubmed/16893416

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      [Show abstract] [Hide abstract]
      ABSTRACT: Concussive brain injury (CBI) accounts for approximately 75% of all brain-injured people in the United States each year and is particularly prevalent in contact sports. Concussion is the mildest form of diffuse traumatic brain injury (TBI) and results in transient cognitive dysfunction, the neuropathologic basis for which is traumatic axonal injury (TAI). To evaluate the structural and functional changes associated with concussion-induced cognitive deficits, adult mice were subjected to an impact on the intact skull over the midline suture that resulted in a brief apneic period and loss of the righting reflex. Closed head injury also resulted in an increase in the wet weight:dry weight ratio in the cortex suggestive of edema in the first 24 h, and the appearance of Fluoro-Jade-B-labeled degenerating neurons in the cortex and dentate gyrus of the hippocampus within the first 3 days post-injury. Compared to sham-injured mice, brain-injured mice exhibited significant deficits in spatial acquisition and working memory as measured using the Morris water maze over the first 3 days (p<0.001), but not after the fourth day post-injury. At 1 and 3 days post-injury, intra-axonal accumulation of amyloid precursor protein in the corpus callosum and cingulum was accompanied by neurofilament dephosphorylation, impaired transport of Fluoro-Gold and synaptophysin, and deficits in axonal conductance. Importantly, deficits in retrograde transport and in action potential of myelinated axons continued to be observed until 14 days post-injury, at which time axonal degeneration was apparent. These data suggest that despite recovery from acute cognitive deficits, concussive brain trauma leads to axonal degeneration and a sustained perturbation of axonal function.
      Full-text · Article · Feb 2011 · Journal of neurotrauma