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

Blaschke, Stefan J. ; Rautenberg, Nora ; Endepols, Heike ; Jendro, Aileen ; Konrad, Jens ; Vlachakis, Susan ; Wiedermann, Dirk ; Schroeter, Michael ; Hoffmann, Bernd and Merkel, Rudolf , et al. (2024) In International Journal of Molecular Sciences 25(9).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
blood–brain barrier, mice, mild traumatic brain injury, neuroinflammation, PET, repetitive concussion
in
International Journal of Molecular Sciences
volume
25
issue
9
article number
4837
publisher
MDPI AG
external identifiers
  • scopus:85192686568
  • pmid:38732053
ISSN
1661-6596
DOI
10.3390/ijms25094837
language
English
LU publication?
yes
id
db4c1add-ebcb-426a-ae89-1af06fc9777b
date added to LUP
2024-05-27 14:38:45
date last changed
2024-06-24 17:28:22
@article{db4c1add-ebcb-426a-ae89-1af06fc9777b,
  abstract     = {{<p>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 [<sup>18</sup>F]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, (R<sup>2</sup> = 0.29, p &lt; 0.01), even detectable by a significant increase in hippocampal uptake of [<sup>18</sup>F]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.</p>}},
  author       = {{Blaschke, Stefan J. and Rautenberg, Nora and Endepols, Heike and Jendro, Aileen and Konrad, Jens and Vlachakis, Susan and Wiedermann, Dirk and Schroeter, Michael and Hoffmann, Bernd and Merkel, Rudolf and Marklund, Niklas and Fink, Gereon R. and Rueger, Maria A.}},
  issn         = {{1661-6596}},
  keywords     = {{blood–brain barrier; mice; mild traumatic brain injury; neuroinflammation; PET; repetitive concussion}},
  language     = {{eng}},
  number       = {{9}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Early Blood–Brain Barrier Impairment as a Pathological Hallmark in a Novel Model of Closed-Head Concussive Brain Injury (CBI) in Mice}},
  url          = {{http://dx.doi.org/10.3390/ijms25094837}},
  doi          = {{10.3390/ijms25094837}},
  volume       = {{25}},
  year         = {{2024}},
}