Abstract
Traumatic brain injury (TBI) mechanism and severity are heterogenous clinically, resulting in a multitude of physical, cognitive, and behavioral deficits. Impact variability influences the origin, spread, and classification of molecular dysfunction which limits strategies for comprehensive clinical intervention. Indeed, there are currently no clinically approved therapeutics for treating the secondary consequences associated with TBI. Thus, examining pathophysiological changes from heterogeneous impacts is imperative for improving clinical translation and evaluating the efficacy of potential therapeutic strategies. Here we utilized TBI models that varied in both injury mechanism and severity including severe traditional controlled cortical impact (CCI), modified mild CCI (MTBI), and multiple severities of closed-head diffuse TBI (DTBI), and assessed pathophysiological changes. Severe CCI induced cortical lesions and necrosis, while both MTBI and DTBI lacked lesions or significant necrotic damage. Autophagy was activated in the ipsilateral cortex following CCI, but acutely impaired in the ipsilateral hippocampus. Additionally, autophagy was activated in the cortex following DTBI, and autophagic impairment was observed in either the cortex or hippocampus following impact from each DTBI severity. Thus, we provide evidence that autophagy is a therapeutic target for both mild and severe TBI. However, dramatic increases in necrosis following CCI may negatively impact the clinical translatability of therapeutics designed to treat acute dysfunction in TBI. Overall, these results provide evidence that injury sequalae affiliated with TBI heterogeneity is linked through autophagy activation and/or impaired autophagic flux. Thus, therapeutic strategies designed to intervene in autophagy may alleviate pathophysiological consequences, in addition to the cognitive and behavioral deficits observed in TBI.
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Data will be made available on request.
Abbreviations
- TBI:
-
Traumatic brain injury
- CCI:
-
Controlled cortical impact
- MTBI:
-
Modified mild CCI
- DTBI:
-
Closed-head diffuse TBI
- LMP:
-
Lysosomal membrane permeabilization
- SBDPs:
-
α-II Spectrin breakdown products
- TFEB:
-
Transcription factor EB
- LC3B:
-
Microtubule-associated protein 1A/1B light chain 3
- LAMP1:
-
Lysosomal-associated membrane protein 1
- SQSTM1:
-
Sequestosome1
- CA:
-
Cornu ammonis
- DG:
-
Dentate gyrus
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Acknowledgements
F.M.K. acknowledges support from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (R01NS109488). B.Z.M acknowledges support from the Molecular Mechanisms of Disease Training Program (T32 GM136593). We thank Jacob McNamara for assistance in performing Western blots.
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This research was funded by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (R01NS109488) and the National Institute of General Medical Sciences of the NIH (T32 GM136593).
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BZM and FMK were responsible for conceptualization. BZM was responsible for visualization and formal analysis. AT and BZM were responsible for methodology and investigation. HZ and SR were responsible for resources regarding DTBI mechanical characterization. SR, KME and FMK were responsible for supervision and FMK and BZM were responsible for funding acquisition. BZM was responsible for writing the original manuscript and all authors participated in review and editing of the final draft.
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All animal work reported here was approved by the Institutional Animal Care and Use Committee at the University of Nebraska – Lincoln under protocol number 2300.
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Communicated by Sreedharan Sajikumar.
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McDonald, B.Z., Tarudji, A.W., Zhang, H. et al. Traumatic brain injury heterogeneity affects cell death and autophagy. Exp Brain Res 242, 1645–1658 (2024). https://doi.org/10.1007/s00221-024-06856-1
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DOI: https://doi.org/10.1007/s00221-024-06856-1