Repeated mild traumatic brain injury produces neuroinflammation, anxiety-like behaviour and impaired spatial memory in mice

ABSTRACT

Primary Objective: Repeated traumatic brain injuries (rmTBI) are frequently associated with debilitating neuropsychiatric conditions such as cognitive impairment, mood disorders, and post-traumatic stress disorder. We tested the hypothesis that repeated mild traumatic brain injury impairs spatial memory and enhances anxiety-like behaviour.

Research Design: We used a between groups design using single (smTBI) or repeated (rmTBI) controlled cranial closed skull impacts to mice, compared to a control group.

Methods and Procedures: We assessed the effects of smTBI and rmTBI using measures of motor performance (Rotarod Test [RT]), anxiety-like behaviour (Elevated Plus Maze [EPM] and Open Field [OF] tests), and spatial memory (Morris Water Maze [MWM]) within 12 days of the final injury. In separate groups of mice, astrocytosis and microglial activation were assessed 24 hours after the final injury using GFAP and IBA-1 immunohistochemistry.

Main Outcomes and Results: RmTBI impaired spatial memory in the MWM and increased anxiety-like behaviour in the EPM and OFT. In addition, rmTBI elevated GFAP and IBA-1 immunohistochemistry throughout the mouse brain. RmTBI produced astrocytosis and microglial activation, and elicited impaired spatial memory and anxiety-like behaviour.

Conclusions: rmTBI produces acute cognitive and anxiety-like disturbances associated with inflammatory changes in brain regions involved in spatial memory and anxiety.

KEYWORDS:

• Animal model
• mild traumatic brain injury
• spatial memory
• anxiety
• chronic traumatic encephalopathy

Acknowledgments

John would like to dedicate this article to his wife Yulene Broussard.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

Funding

This work was supported by the Brain Injury Medicine Program; Beth K and Stuart C Yudofsky Division of Neuropsychiatry, Baylor College of Medicine [N/A];BCM IDDRC [U54HD083092];Brain Injury Medicine program; Beth K and Stuart C Yudofsky Division of Neuropsychiatry, Baylor College of Medicine [N/A];Unrestricted funds to AAP from the University of Iowa Carver College of Medicine [N/A];Anonymous donor to the Mary Alice Smith Fund for Neuropsychiatry Research to A.A.P. [N/A]; Michael E DeBakey VA Medical Center.

Additional information

Funding

This work was supported by the Brain Injury Medicine Program; Beth K and Stuart C Yudofsky Division of Neuropsychiatry, Baylor College of Medicine [N/A];BCM IDDRC [U54HD083092];Brain Injury Medicine program; Beth K and Stuart C Yudofsky Division of Neuropsychiatry, Baylor College of Medicine [N/A];Unrestricted funds to AAP from the University of Iowa Carver College of Medicine [N/A];Anonymous donor to the Mary Alice Smith Fund for Neuropsychiatry Research to A.A.P. [N/A];

Notes on contributors

John I Broussard

JIB performed the behavioural experiments and TBI procedures. LA & HDJC statistically analyzed the data and interpreted the results. TY and JKB conducted immunohistochemistry. JIB, RS, MCM, and RJ planned the behavioural experiments. AAP, DBA, and RJ planned additional immunohistochemistry experiments. CR provided laboratory space and MCM provided space and behavioural equipment. JIB, LA, and RJ wrote the manuscript with editorial assistance from AAP, RS, HDJC and DBA.