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A Modified Repetitive Closed Head Injury Model Inducing Persistent Neuroinflammation and Functional Deficits Without

Lucia Fadon-Padilla1, Chengyan Chu1, Yajie Liang1

  • 1Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Journal of Neurotrauma
|October 31, 2025
PubMed
Summary

A new repetitive closed head injury (rCHI) model accurately mimics traumatic brain injury (TBI) features like BBB disruption and neuroinflammation in mice, offering a better platform for testing new TBI therapies.

Keywords:
MRIblood–brain barrierinflammationmodels of injurytraumatic brain injury

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Area of Science:

  • Neuroscience
  • Neurology
  • Biomedical Engineering

Background:

  • Traumatic brain injury (TBI) presents significant clinical challenges with limited treatment options.
  • Existing animal models often fail to accurately replicate human TBI pathophysiology.
  • Mild to moderate TBI is common, necessitating improved preclinical models for therapeutic development.

Purpose of the Study:

  • To introduce and validate a refined repetitive closed head injury (rCHI) model.
  • To assess the acute and chronic effects of varying injury severities in the rCHI model.
  • To establish a more relevant preclinical platform for evaluating TBI interventions.

Main Methods:

  • Developed a novel rCHI model using consecutive controlled impacts without craniotomy, comparing it with the closed head injury (CCI) model.
  • Evaluated injury severity using 1, 3, or 5 impacts in adult C57BL6/J mice.
  • Utilized MRI, immunofluorescence, qRT-PCR, and functional tests (beam walk, CatWalk, novel object recognition) to assess outcomes.

Main Results:

  • The rCHI model allowed precise impact application while preserving brain macrostructure.
  • Increased impact severity led to dose-dependent blood-brain barrier (BBB) disruption and significant neuroinflammation (microglia, astrocytes, inflammatory markers).
  • The 5-impact group exhibited sustained motor and cognitive deficits, with white matter alterations indicating progressive neurodegeneration.

Conclusions:

  • The refined rCHI model effectively replicates key TBI features including BBB dysfunction, chronic neuroinflammation, and functional impairments.
  • This model serves as a valuable platform for testing acute-phase interventions and neuroprotective strategies targeting inflammation and BBB integrity.
  • Injury severity is crucial in determining TBI outcomes, emphasizing the need for tailored therapeutic approaches.