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Cellular Reactions and Behavioral Changes in Focal and Diffuse Traumatic Brain Injury: A Study in the Rat and Mouse
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic brain injury (TBI) is a severe condition and a major cause of death and disability. There is no pharmacological treatment available in clinical practice today and knowledge of brain injury mechanisms is of importance for development of neuroprotective drugs. The aims of the thesis were to get a better understanding of astrocyte reactions and immune responses, as well as behavioral changes after focal unilateral cortical contusion injury and diffuse bilateral central fluid percussion injury in rats and mice.

In the focal injury models, the astrocyte reactions were generally restricted to the ipsilateral hemisphere. After diffuse TBI, vimentin and glial fibrillary acidic protein (GFAP) positive reactive astrocytes were bilaterally expressed in brain regions even distant from the injury site, including regions where axonal injury was seen. Early after diffuse TBI, there was a robust immune response, including activation of macrophages/microglia (Mac-2+) and infiltration of neutrophils (GR-1+) and T-cells (CD3+).

In order to measure functional outcome, the recently established Multivariate Concentric Square Field™ (MCSF) test for complex behaviors, including risk taking and explorative strategies was used. The Morris water maze (MWM) was applied for testing learning and memory. The MCSF test revealed alterations in risk taking, risk assessment and exploratory behavior, in the mice subjected to focal injury whereas mice subjected to the diffuse injury showed a deviant stereotyped behavior. After focal injury mice showed a decreased ability to adapt to the arena in the second trial, when tested repeatedly in the MCSF test. Mice subjected to diffuse injury had an impaired memory but not learning, in the MWM test. Post-injury treatment with the anti-inflammatory anti-interleukin-1β (IgG2 a/k) antibody showed a positive effect on functional outcome in the diffuse injury model. Altogether, the results demonstrate that focal and diffuse TBI models produce differences in cellular reactions and behavioral outcome and that the immune response plays a key role in the pathology after brain injury. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 83 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 909
Keyword [en]
Traumatic brain injury, Astrocytes, Inflammatory response, Multivariate concentric square field test, Morris water maze, Exploratory behavior, Risk taking, Functional outcome.
National Category
Neurosciences
Research subject
Neurosurgery
Identifiers
URN: urn:nbn:se:uu:diva-177083ISBN: 978-91-554-8687-7 (print)OAI: oai:DiVA.org:uu-177083DiVA: diva2:617889
Public defence
2013-06-14, Hedstrandsalen, Akademiska sjukhuset, 75185, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2013-05-24 Created: 2012-07-03 Last updated: 2013-08-30
List of papers
1. Vimentin and GFAP responses in astrocytes after contusion trauma to the murine brain
Open this publication in new window or tab >>Vimentin and GFAP responses in astrocytes after contusion trauma to the murine brain
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2010 (English)In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 28, no 3, 311-321 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Astroglial responses after traumatic brain injury are difficult to detect with routine morphological methods. The aims for this study were to compare the temporal and spatial expression pattern of vimentin-and glial fibrillary acidic protein (GFAP) in a weight drop model of mild cerebral contusion injury in the rat. We also wanted to study the vimentin response with immunohistochemistry and vimentin mRNA RT-PCR analysis in severe cortical contusion injury produced by the controlled cortical impact in the mouse. Methods: Vimentin and GFAP immunohistochemistry (1day, 3 days and 7 days) combined with vimentin mRNA RT-PCR analysis (1 h, 4 h, 22 h, 3 days and 7 days) were used after experimental traumatic brain injury in the rat and mouse. Results: Increases in post-traumatic vimentin mRNA levels in the cortex and in the hippocampus appeared together with vimentin immunoreactivity in astrocytes in the perimeter of the cortical lesion, in the subcortical white matter and in the hippocampus starting at one day after severe trauma. GFAP immunostaining revealed hypertrophic astrocytes peaking at day 3 in the perifocal cortical region. There was no significant increase in GFAP immunoreactivity in the white matter in the rat. However, in the mouse there was a slight increase in the number of GFAP positive cells in this region, 3 days after trauma. Overall the pattern of vimentin immunoreactivity was very similar in the rat and mouse. Conclusions: Vimentin immunoreactivity was more sensitive than the GFAP staining method to demonstrate the distribution and time course of astrocyte reactions after a contusion injury, especially in the white matter distant from the cortical lesion.

Keyword
Traumatic brain injury, rat, mouse, astrocytes, gliosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-136066 (URN)10.3233/RNN-2010-0529 (DOI)000278442500002 ()
Available from: 2010-12-10 Created: 2010-12-09 Last updated: 2017-12-11Bibliographically approved
2. The Multivariate Concentric Square Field Test Reveals Behavioral Profiles of Risk Taking, Exploration, and Cognitive Impairment in Mice Subjected to Traumatic Brain Injury
Open this publication in new window or tab >>The Multivariate Concentric Square Field Test Reveals Behavioral Profiles of Risk Taking, Exploration, and Cognitive Impairment in Mice Subjected to Traumatic Brain Injury
2010 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 27, no 9, 1643-1655 p.Article in journal (Refereed) Published
Abstract [en]

There is a need for more efficient tests to evaluate functional outcome following experimental traumatic brain injury (TBI), reflecting deficits in cognitive, sensory, and motor functions that are seen in TBI patients. The Multivariate Concentric Square Field (TM) (MCSF) test is a relatively new behavioral model that measures exploration, risk taking, risk assessment, and shelter seeking, all of which are evolutionarily-conserved strategies for survival. The multivariate design enables scoring of different functional domains in a single test situation, with a free choice of optional environmental settings. Furthermore, repeated trials permits cognitive effects to be measured. In the present study, 11 anesthetized C57BL6 mice received controlled cortical injury (CCI) (0.5mm and 3.3 m/sec) over the right parietal cerebral cortex or sham surgery (n - 12). Naive mice (n 12) not subjected to any surgical procedure were also included. The animals were evaluated in the MCSF test at 2 and 7 days post-surgery, and behavioral profiles were analyzed. The results revealed differences in risk taking and explorative behavior between the sham animals and the animals subjected to trauma. Animals subjected to trauma were characterized by taking more risks and had a higher level of exploration activity, but they sought less shelter. Repeated exposure to the MCSF caused a general decrease in activity in the naive and sham group, while a more specific behavioral impairment was seen in injured mice, suggesting cognitive dysfunction. We submit that the MCSF test is a useful complementary tool for functional outcome evaluation in experimental TBI.

Keyword
cognition, functional outcome, mouse, Multivariate Concentric Square Field Test, traumatic brain injury
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-134829 (URN)10.1089/neu.2009.0953 (DOI)000281796500011 ()
Available from: 2010-12-02 Created: 2010-12-01 Last updated: 2017-12-12Bibliographically approved
3. Traumatic axonal injury in the mouse is accompanied by a dynamic inflammatory response, astroglial reactivity and complex behavioral changes
Open this publication in new window or tab >>Traumatic axonal injury in the mouse is accompanied by a dynamic inflammatory response, astroglial reactivity and complex behavioral changes
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2013 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 10, no 1, 44- p.Article in journal (Refereed) Published
Abstract [en]

Background

Diffuse traumatic axonal injury (TAI), a common consequence of traumatic brain injury, is associated with high morbidity and mortality. Inflammatory processes may play an important role in the pathophysiology of TAI. In the murine central fluid percussion injury (cFPI) TAI model, the neuroinflammatory and astroglial response and behavioral changes are unknown.

Methods

Twenty cFPI-injured and nine sham-injured mice were used, and the neuroinflammatory and astroglial response was evaluated by immunohistochemistry at 1, 3 and 7 days post-injury. The multivariate concentric square field test (MCSF) was used to compare complex behavioral changes in mice subjected to cFPI (n = 16) or sham injury (n = 10). Data was analyzed using non-parametric statistics and principal component analysis (MCSF data).

Results

At all post-injury time points, beta-amyloid precursor protein (beta-APP) immunoreactivity revealed widespread bilateral axonal injury and IgG immunostaining showed increased blood--brain barrier permeability. Using vimentin and glial fibrillary acidic protein (GFAP) immunohistochemistry, glial cell reactivity was observed in cortical regions and important white matter tracts peaking at three days post-injury. Only vimentin was increased post-injury in the internal capsule and only GFAP in the thalamus. Compared to sham-injured controls, an increased number of activated microglia (MAC-2), infiltrating neutrophils (GR-1) and T-cells (CD3) appearing one day after TAI (P<0.05 for all cell types) was observed in subcortical white matter. In the MCSF, the behavioral patterns including general activity and exploratory behavior differed between cFPI mice and sham-injured controls.

Conclusions

Traumatic axonal injury in mice resulted in marked bilateral astroglial and neuroinflammatory responses and complex behavioral changes. The cFPI model in mice appears suitable for the study of injury mechanisms, including neuroinflammation, and the development of treatments targeting traumatic axonal injury.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-198322 (URN)10.1186/1742-2094-10-44 (DOI)000318852600001 ()
Available from: 2013-04-11 Created: 2013-04-11 Last updated: 2017-12-06Bibliographically approved
4. Functional outcome after diffuse traumatic axonal injury in mice is improved by post-injury neutralization of interleukin-1ß
Open this publication in new window or tab >>Functional outcome after diffuse traumatic axonal injury in mice is improved by post-injury neutralization of interleukin-1ß
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-198738 (URN)
Available from: 2013-04-23 Created: 2013-04-23 Last updated: 2014-01-02

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