A single closed head injury in male adult mice induces chronic, progressive white matter atrophy and increased phospho-tau expressing oligodendrocytes

Havlicek, David F.; Furhang, Rachel; Nikulina, Elena; Smith-Salzberg, Bayle; Lawless, Siobhán; Sevarin, Sasha A.; Mallaboeva, Sevara; Nayab, Fizza; Seifert, Alan C.; Crary, John F.; Bergold, Peter J.

doi:10.1016/j.expneurol.2022.114241

Cited by 6 publications

(6 citation statements)

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“…Radiological and histological assessment of animals utilized in this study demonstrate a single CHI acutely produces atrophy to cortical hindlimb/torso motor and sensory, retrosplenial, and association areas, corpus callosum, and thalamic nuclei in the ipsilesional hemisphere(Havlicek et al, 2023). At 180DPI, hyperphosphorylated tau containing oligodendrocytes increase in density ipsilesionally in corpus callosum and thalamic nuclei, followed by continued radiological atrophy in the contralesional corpus callosum(Havlicek et al, 2023). Decreased ability to recover from a foot-fault may increase absition without changing the number of foot-faults.…”

Section: Resultsmentioning

confidence: 89%

“…On complex wheel, however, this compensatory strategy disappears followed by a significant reduction in limb coordination. The development of simple wheel compensatory running strategy and drop in complex wheel limb coordination may suggest ongoing impairment resulting from progressive corpus callosum atrophy (Havlicek et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

“…This study uses a mouse closed head (CHI) model of TBI in which the freely moving head of the mouse is impacted with an electromagnetically controlled piston that produces a contusion of the motor, somatosensory, association, and visual cortices as well as producing diffuse acute and chronic gray and white matter injury (Grin'kina et al, 2016;Havlicek et al, 2023). Aged injured mice utilized in this study develop progressive contralesional white matter atrophy and increasing density of phospho-tau expressing oligodendrocytes in subcortical regions such as thalamus and corpus callosum (Havlicek et al, 2023). CHI produces transient motor deficits, but it remains unknown if these deficits either persist or become chronic.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of markerless limb tracking reveals chronic and progressive motor deficits after a single closed head injury in mice

Lawless

Havlicek

Kelley

et al. 2021

Preprint

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Background: Acute injury following brain trauma may evolve into a chronic and progressive disorder. Assessment of chronic consequences of TBI must distinguish between effects of age and injury. Methods: C57BL/6 mice receive single closed head injury (CHI) and are analyzed at 14DPI or 180DPI for cortical atrophy and 7DPI or 180DPI for behavioral outcomes. Results: CHI induces ipsilesional atrophy at 14DPI that increases 180 DPI due to an effect of age. On open field, injured mice develop a turn bias at 180DPI not present at 7DPI. On rotarod, injured mice have shorter latencies at 7DPI, but not at 180DPI due to worsening performance of aging uninjured mice. On beam walk, both groups at 180DPI more slowly traverse a 2cm and 1cm beam than at 7DPI. Foot-faults show no significant effects of age or injury. Limb position was assessed using DeeplabcutTM markerless tracking followed by computation of absition (integral of limb displacement over time) using custom Python scripts. On the 2cm beam, age increased absition in all limbs of uninjured mice and both forelimbs of injured mice. Injury increased left hindlimb absition at 7DPI. On the 1cm beam both forelimbs and the left hindlimb of injured mice at 180DPI have larger absition than uninjured mice at 180DPI or injured mice at 7DPI. These data suggest chronic and progressive motor deficits of injured mice at 180DPI. Conclusions: A single impact produces ipsilesional cortical atrophy and chronic and progressive motor deficits. Quantitative behavioral analysis reveals deficits not seen using standard outcomes.

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Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of markerless limb tracking reveals chronic and progressive motor deficits after a single closed head injury in mice

Lawless

Havlicek

Kelley

et al. 2021

Preprint

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“…Longer term analyses in wild-type mice reported similar findings with different single and repetitive models. White matter atrophy progressed from proximate to remote sites after a single TBI without detectable phosphorylated tau pathology in neurons [ 37 ]. Repetitive mild TBI resulted in corpus callosum atrophy, neuroinflammation and behavioral deficits with longer post-injury intervals of 6 and 12 months [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Neuronal tau pathology worsens late-phase white matter degeneration after traumatic brain injury in transgenic mice

Iacono

Perl

et al. 2023

Acta Neuropathol

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Traumatic brain injury (TBI) causes diffuse axonal injury which can produce chronic white matter pathology and subsequent post-traumatic neurodegeneration with poor patient outcomes. Tau modulates axon cytoskeletal functions and undergoes phosphorylation and mis-localization in neurodegenerative disorders. The effects of tau pathology on neurodegeneration after TBI are unclear. We used mice with neuronal expression of human mutant tau to examine effects of pathological tau on white matter pathology after TBI. Adult male and female hTau.P301S (Tg2541) transgenic and wild-type (Wt) mice received either moderate single TBI (s-TBI) or repetitive mild TBI (r-mTBI; once daily × 5), or sham procedures. Acutely, s-TBI produced more extensive axon damage in the corpus callosum (CC) as compared to r-mTBI. After s-TBI, significant CC thinning was present at 6 weeks and 4 months post-injury in Wt and transgenic mice, with homozygous tau expression producing additional pathology of late demyelination. In contrast, r-mTBI did not produce significant CC thinning except at the chronic time point of 4 months in homozygous mice, which exhibited significant CC atrophy (− 29.7%) with increased microgliosis. Serum neurofilament light quantification detected traumatic axonal injury at 1 day post-TBI in Wt and homozygous mice. At 4 months, high tau and neurofilament in homozygous mice implicated tau in chronic axon pathology. These findings did not have sex differences detected. Conclusions: Neuronal tau pathology differentially exacerbated CC pathology based on injury severity and chronicity. Ongoing CC atrophy from s-TBI became accompanied by late demyelination. Pathological tau significantly worsened CC atrophy during the chronic phase after r-mTBI.

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“…At the neuronal level, axonal injury from shearing forces and swelling following TBI may contribute to degenerative physiology [53]. White matter atrophy can occur in chronic post-injury pathology [54] and may be related to pTau [55]. Recent reports identify white matter loss as a key contributor to cognitive decline in healthy aging [56] and neurodegeneration [57].…”

Section: Linking Mtbi Sequelae To Dementia Riskmentioning

confidence: 99%

The Rehabilitation Potential of Neurostimulation for Mild Traumatic Brain Injury in Animal and Human Studies

McNerney,

Gurkoff,

Beard

et al. 2023

Brain Sciences

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Neurostimulation carries high therapeutic potential, accompanied by an excellent safety profile. In this review, we argue that an arena in which these tools could provide breakthrough benefits is traumatic brain injury (TBI). TBI is a major health problem worldwide, with the majority of cases identified as mild TBI (mTBI). MTBI is of concern because it is a modifiable risk factor for dementia. A major challenge in studying mTBI is its inherent heterogeneity across a large feature space (e.g., etiology, age of injury, sex, treatment, initial health status, etc.). Parallel lines of research in human and rodent mTBI can be collated to take advantage of the full suite of neuroscience tools, from neuroimaging (electroencephalography: EEG; functional magnetic resonance imaging: fMRI; diffusion tensor imaging: DTI) to biochemical assays. Despite these attractive components and the need for effective treatments, there are at least two major challenges to implementation. First, there is insufficient understanding of how neurostimulation alters neural mechanisms. Second, there is insufficient understanding of how mTBI alters neural function. The goal of this review is to assemble interrelated but disparate areas of research to identify important gaps in knowledge impeding the implementation of neurostimulation.

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A single closed head injury in male adult mice induces chronic, progressive white matter atrophy and increased phospho-tau expressing oligodendrocytes

Cited by 6 publications

References 63 publications

Analysis of markerless limb tracking reveals chronic and progressive motor deficits after a single closed head injury in mice

Analysis of markerless limb tracking reveals chronic and progressive motor deficits after a single closed head injury in mice

Neuronal tau pathology worsens late-phase white matter degeneration after traumatic brain injury in transgenic mice

The Rehabilitation Potential of Neurostimulation for Mild Traumatic Brain Injury in Animal and Human Studies

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