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Article

Early Blood–Brain Barrier Impairment as a Pathological Hallmark in a Novel Model of Closed-Head Concussive Brain Injury (CBI) in Mice

by
Stefan J. Blaschke
1,2,*,
Nora Rautenberg
1,2,
Heike Endepols
3,4,5,
Aileen Jendro
1,
Jens Konrad
6,
Susan Vlachakis
1,
Dirk Wiedermann
7,
Michael Schroeter
1,2,
Bernd Hoffmann
6,
Rudolf Merkel
6,
Niklas Marklund
8,
Gereon R. Fink
1,2 and
Maria A. Rueger
1,2
1
Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, 50923 Cologne, Germany
2
Cognitive Neuroscience Section, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, 52428 Juelich, Germany
3
Institute of Radiochemistry and Experimental Molecular Imaging, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany
4
Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
5
Nuclear Chemistry, Institute of Neuroscience and Medicine (INM-5), Research Centre Juelich, 52428 Juelich, Germany
6
Mechanobiology, Institute of Biological Information Processing (IBI-2), Research Centre Juelich, 52425 Juelich, Germany
7
Multimodal Imaging Group, Max Planck Institute for Metabolism Research, 50931 Cologne, Germany
8
Department of Clinical Sciences Lund, Neurosurgery, Lund University, 221 85 Lund, Sweden
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(9), 4837; https://doi.org/10.3390/ijms25094837
Submission received: 25 March 2024 / Revised: 25 April 2024 / Accepted: 26 April 2024 / Published: 29 April 2024
(This article belongs to the Special Issue Traumatic Brain Injury/Chronic Traumatic Encephalopathy as Cause of Alzheimer’s Disease: Physics and Molecular Biology in the Genesis of Neurodegeneration?)
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Abstract

Concussion, caused by a rotational acceleration/deceleration injury mild enough to avoid structural brain damage, is insufficiently captured in recent preclinical models, hampering the relation of pathophysiological findings on the cellular level to functional and behavioral deficits. We here describe a novel model of unrestrained, single vs. repetitive concussive brain injury (CBI) in male C56Bl/6j mice. Longitudinal behavioral assessments were conducted for up to seven days afterward, alongside the evaluation of structural cerebral integrity by in vivo magnetic resonance imaging (MRI, 9.4 T), and validated ex vivo by histology. Blood–brain barrier (BBB) integrity was analyzed by means of fluorescent dextran- as well as immunoglobulin G (IgG) extravasation, and neuroinflammatory processes were characterized both in vivo by positron emission tomography (PET) using [18F]DPA-714 and ex vivo using immunohistochemistry. While a single CBI resulted in a defined, subacute neuropsychiatric phenotype, longitudinal cognitive testing revealed a marked decrease in spatial cognition, most pronounced in mice subjected to CBI at high frequency (every 48 h). Functional deficits were correlated to a parallel disruption of the BBB, (R2 = 0.29, p < 0.01), even detectable by a significant increase in hippocampal uptake of [18F]DPA-714, which was not due to activation of microglia, as confirmed immunohistochemically. Featuring a mild but widespread disruption of the BBB without evidence of macroscopic damage, this model induces a characteristic neuro-psychiatric phenotype that correlates to the degree of BBB disruption. Based on these findings, the BBB may function as both a biomarker of CBI severity and as a potential treatment target to improve recovery from concussion.
Keywords: mild traumatic brain injury; mice; repetitive concussion; blood–brain barrier; neuroinflammation; PET mild traumatic brain injury; mice; repetitive concussion; blood–brain barrier; neuroinflammation; PET

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MDPI and ACS Style

Blaschke, S.J.; Rautenberg, N.; Endepols, H.; Jendro, A.; Konrad, J.; Vlachakis, S.; Wiedermann, D.; Schroeter, M.; Hoffmann, B.; Merkel, R.; et al. Early Blood–Brain Barrier Impairment as a Pathological Hallmark in a Novel Model of Closed-Head Concussive Brain Injury (CBI) in Mice. Int. J. Mol. Sci. 2024, 25, 4837. https://doi.org/10.3390/ijms25094837

AMA Style

Blaschke SJ, Rautenberg N, Endepols H, Jendro A, Konrad J, Vlachakis S, Wiedermann D, Schroeter M, Hoffmann B, Merkel R, et al. Early Blood–Brain Barrier Impairment as a Pathological Hallmark in a Novel Model of Closed-Head Concussive Brain Injury (CBI) in Mice. International Journal of Molecular Sciences. 2024; 25(9):4837. https://doi.org/10.3390/ijms25094837

Chicago/Turabian Style

Blaschke, Stefan J., Nora Rautenberg, Heike Endepols, Aileen Jendro, Jens Konrad, Susan Vlachakis, Dirk Wiedermann, Michael Schroeter, Bernd Hoffmann, Rudolf Merkel, and et al. 2024. "Early Blood–Brain Barrier Impairment as a Pathological Hallmark in a Novel Model of Closed-Head Concussive Brain Injury (CBI) in Mice" International Journal of Molecular Sciences 25, no. 9: 4837. https://doi.org/10.3390/ijms25094837

APA Style

Blaschke, S. J., Rautenberg, N., Endepols, H., Jendro, A., Konrad, J., Vlachakis, S., Wiedermann, D., Schroeter, M., Hoffmann, B., Merkel, R., Marklund, N., Fink, G. R., & Rueger, M. A. (2024). Early Blood–Brain Barrier Impairment as a Pathological Hallmark in a Novel Model of Closed-Head Concussive Brain Injury (CBI) in Mice. International Journal of Molecular Sciences, 25(9), 4837. https://doi.org/10.3390/ijms25094837

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