Optimization of a translational murine model of closed-head traumatic brain injury

ABSTRACT

Traumatic brain injury (TBI) from closed-head trauma is a leading cause of disability, with limited effective interventions. Many TBI models impact brain parenchyma directly, and are limited by the fact that these forces do not recapitulate clinically relevant closed head injury. However, applying clinically relevant injury mechanics to the intact skull may lead to variability and as a result, preclinical modeling TBI remains a challenge. Current models often do not explore sex differences in TBI, which is critically important for translation to clinical practice. We systematically investigated sources of variability in a murine model of closed-head TBI and developed a framework to reduce variability across severity and sex. We manipulated pressure, dwell time, and displacement to determine effects on motor coordination, spatial learning, and neuronal damage in 10-week-old male and female mice. Increasing pressure beyond 70 psi had a ceiling effect on cellular and behavioral outcomes, while manipulating dwell time only affected behavioral performance. Increasing displacement precisely graded injury severity in both sexes across all outcomes. Physical signs of trauma occurred more frequently at higher displacements. Stratifying severity based on day-1 rotarod performance retained histological relationships and separated both sexes into injury severity cohorts with distinct patterns of behavioral recovery. Utilizing this stratification strategy, within-group rotarod variability over 6 days post-injury was reduced by 50%. These results have important implications for translational research in TBI and provide a framework for using this clinically relevant translational injury model in both male and female mice.

KEYWORDS:

• Tramatic Brain Injury (TBI)
• mouse model
• females
• optimization
• pneumatic piston
• closed skull injury

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability of statement

The datasets generated and analyzed during the current study are not publicly available due to research funded by a private corporation and material data agreement between the university and the funding grant, but are available from the corresponding author on reasonable request.

Authorship confirmation/contribution statement

B.M. was a project administration, writing and analysis of data and research. E.L. contributed to research methodology, investigation, data analysis, and writing of the manuscript. E.A. performed investigation and manuscript writing. B.M. was a project administration, writing and analysis of data. E.C. performed experimental investigation, data validation and review. VC performed data Investigation, and writing review. RG contributed to experimental investigation and writing review. TF performed experimental investigation and analysis, writing review & editing; BM was a project administration, performed experimental investigation, writing, review & editing of manuscript, also performed data curation, and formal analysis of data. DL contributed to methodology design, supervision of investigation, and review and editing of manuscript. BK conceptualization the study, was project administration, supervision, procured funding and supervised writing, review and editing of manuscript.

Ethical approval

Experimental research on vertebrates complied with institutional, national, and international guidelines. All procedures were approved by Duke University’s Institutional Animal Care and Use Committee. Duke University maintains an animal program that is registered and compliant with the USDA, and accredited with AAALAC, International. Recommended ARRIVE guidelines were used in design and reporting of all animal research.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/01616412.2024.2302261.

Additional information

Funding

Funding for a portion of this work was provided by Corticare Incorporated under a scientific research agreement.