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Minocycline plus N-acetylcysteine improve chronic and progressive structural and functional deficits following a single TBI in male mice
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Bergold, Peter
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Spring 2025
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2025-04-07
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Lawless_Thesis_Defense.pdf
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Abstract
Traumatic brain injury (TBI) is the leading cause of death and disability above
any other trauma. The high prevalence of later life degenerative outcomes strongly
suggests a single TBI can develop into a progressive neurodegenerative disorder.
Clinical TBI may produce chronic deficits in limb coordination, and gait that is
associated with corpus callosum damage. Detection of chronic motor deficits after TBI
may be obscured by effects of aging or the development of compensatory motor
strategies. Chronic motor deficits are poorly studied in rodent TBI models. The murine
closed head injury (CHI) model produces diffuse, chronic white matter injury that may
underlie chronic white matter dysfunction and motor deficits. DeepLabCutTM markerless
limb tracking provided the data for novel assessments of limb function on beam walk
and simple-complex wheel. Injured mice on beam walk do not differ from sham mice on time to traverse or foot fault number. Novel assay beam walk absition integrates time
and extent of all foot faults during a beam walk trial. Injured mice have chronic absition
deficits that are blocked by dosing of minocycline and N-acetylcysteine beginning 12
hours post injury (MN12). Absition deficits do not appear until 90 DPI and worsen at
180 DPI suggesting chronic and progressive motor decline. Speed is a standard
method to assess performance on simple-complex wheel. Novel assays show that at
14 DPI, MN12 improves limb coordination to prevent an injury dependent decline in
running speed. Ex-vivo T2 and diffusion-tensor MRI studies show that MN12 prevents
most progressive gray and white matter atrophy in motor structures and improves
bilateral white matter integrity. MN12 increases inflammatory cell density in corpus
callosum after CHI. This increased inflammatory response is likely beneficial since
MN12 improves callosal structure and function. Evoked compound action potentials (CAP) assess corpus callosum function from 3 to 180-days post injury (DPI). CHI
acutely decreases CAP amplitudes that recover by 90 DPI and further increase at 180
DPI. Changes in CAP amplitude are blocked by MN12. CHI mice have chronic corpus
callosum dysfunction that coincide with motor deficits. Analysis using DeepLabCutTM
limb tracking reveals chronic deficits and compensatory motor strategies not seen with
standard outcomes. These observations support the central hypothesis of this thesis:
MINO plus NAC improves injury-dependent deficits in white matter histology,
structure, and function with a favorable therapeutic time window in male mice, as
well as the aim to test if MINO plus NAC reduce structural and functional deficits
in white matter after a single CHI in male mice. The results of these experiments
provide important information about the chronic phase of TBI in addition to developing novel methods to assay the onset, persistence, and progression of injury-dependent
changes in the CHI mouse model of TBI.
Citation
Lawless, S. (2025). Minocycline plus N-acetylcysteine improve chronic and progressive structural and functional deficits following a single TBI in male mice [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. http://hdl.handle.net/20.500.12648/16549