Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats
Abstract Childhood represents a period of significant growth and maturation for the brain, and is also associated with a heightened risk for mild traumatic brain injuries (mTBI). There is also concern that repeated-mTBI (r-mTBI) may have a long-term impact on developmental trajectories. Using an awa...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02916-5 |
| _version_ | 1797636774235734016 |
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| author | Katie J. Neale Hannah M. O. Reid Barbara Sousa Erin McDonagh Jamie Morrison Sandy Shultz Eric Eyolfson Brian R. Christie |
| author_facet | Katie J. Neale Hannah M. O. Reid Barbara Sousa Erin McDonagh Jamie Morrison Sandy Shultz Eric Eyolfson Brian R. Christie |
| author_sort | Katie J. Neale |
| collection | DOAJ |
| description | Abstract Childhood represents a period of significant growth and maturation for the brain, and is also associated with a heightened risk for mild traumatic brain injuries (mTBI). There is also concern that repeated-mTBI (r-mTBI) may have a long-term impact on developmental trajectories. Using an awake closed head injury (ACHI) model, that uses rapid head acceleration to induce a mTBI, we investigated the acute effects of repeated-mTBI (r-mTBI) on neurological function and cellular proliferation in juvenile male and female Long-Evans rats. We found that r-mTBI did not lead to cumulative neurological deficits with the model. R-mTBI animals exhibited an increase in BrdU + (bromodeoxyuridine positive) cells in the dentate gyrus (DG), and that this increase was more robust in male animals. This increase was not sustained, and cell proliferation returning to normal by PID3. A greater increase in BrdU + cells was observed in the dorsal DG in both male and female r-mTBI animals at PID1. Using Ki-67 expression as an endogenous marker of cellular proliferation, a robust proliferative response following r-mTBI was observed in male animals at PID1 that persisted until PID3, and was not constrained to the DG alone. Triple labeling experiments (Iba1+, GFAP+, Brdu+) revealed that a high proportion of these proliferating cells were microglia/macrophages, indicating there was a heightened inflammatory response. Overall, these findings suggest that rapid head acceleration with the ACHI model produces an mTBI, but that the acute neurological deficits do not increase in severity with repeated administration. R-mTBI transiently increases cellular proliferation in the hippocampus, particularly in male animals, and the pattern of cell proliferation suggests that this represents a neuroinflammatory response that is focused around the mid-brain rather than peripheral cortical regions. These results add to growing literature indicating sex differences in proliferative and inflammatory responses between females and males. Targeting proliferation as a therapeutic avenue may help reduce the short term impact of r-mTBI, but there may be sex-specific considerations. |
| first_indexed | 2024-03-11T12:38:58Z |
| format | Article |
| id | doaj.art-b8085d1f6f5a4c10b9b8f54c794fcea8 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-11T12:38:58Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-b8085d1f6f5a4c10b9b8f54c794fcea82023-11-05T12:25:21ZengBMCJournal of Neuroinflammation1742-20942023-10-0120112010.1186/s12974-023-02916-5Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile ratsKatie J. Neale0Hannah M. O. Reid1Barbara Sousa2Erin McDonagh3Jamie Morrison4Sandy Shultz5Eric Eyolfson6Brian R. Christie7Division of Medical Sciences, University of VictoriaDivision of Medical Sciences, University of VictoriaDivision of Medical Sciences, University of VictoriaDivision of Medical Sciences, University of VictoriaDivision of Medical Sciences, University of VictoriaDivision of Medical Sciences, University of VictoriaDivision of Medical Sciences, University of VictoriaDivision of Medical Sciences, University of VictoriaAbstract Childhood represents a period of significant growth and maturation for the brain, and is also associated with a heightened risk for mild traumatic brain injuries (mTBI). There is also concern that repeated-mTBI (r-mTBI) may have a long-term impact on developmental trajectories. Using an awake closed head injury (ACHI) model, that uses rapid head acceleration to induce a mTBI, we investigated the acute effects of repeated-mTBI (r-mTBI) on neurological function and cellular proliferation in juvenile male and female Long-Evans rats. We found that r-mTBI did not lead to cumulative neurological deficits with the model. R-mTBI animals exhibited an increase in BrdU + (bromodeoxyuridine positive) cells in the dentate gyrus (DG), and that this increase was more robust in male animals. This increase was not sustained, and cell proliferation returning to normal by PID3. A greater increase in BrdU + cells was observed in the dorsal DG in both male and female r-mTBI animals at PID1. Using Ki-67 expression as an endogenous marker of cellular proliferation, a robust proliferative response following r-mTBI was observed in male animals at PID1 that persisted until PID3, and was not constrained to the DG alone. Triple labeling experiments (Iba1+, GFAP+, Brdu+) revealed that a high proportion of these proliferating cells were microglia/macrophages, indicating there was a heightened inflammatory response. Overall, these findings suggest that rapid head acceleration with the ACHI model produces an mTBI, but that the acute neurological deficits do not increase in severity with repeated administration. R-mTBI transiently increases cellular proliferation in the hippocampus, particularly in male animals, and the pattern of cell proliferation suggests that this represents a neuroinflammatory response that is focused around the mid-brain rather than peripheral cortical regions. These results add to growing literature indicating sex differences in proliferative and inflammatory responses between females and males. Targeting proliferation as a therapeutic avenue may help reduce the short term impact of r-mTBI, but there may be sex-specific considerations.https://doi.org/10.1186/s12974-023-02916-5ConcussionDentate gyrusAwake closed-head injuryMicrogliaSub-granular zoneDevelopment |
| spellingShingle | Katie J. Neale Hannah M. O. Reid Barbara Sousa Erin McDonagh Jamie Morrison Sandy Shultz Eric Eyolfson Brian R. Christie Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats Journal of Neuroinflammation Concussion Dentate gyrus Awake closed-head injury Microglia Sub-granular zone Development |
| title | Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats |
| title_full | Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats |
| title_fullStr | Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats |
| title_full_unstemmed | Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats |
| title_short | Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats |
| title_sort | repeated mild traumatic brain injury causes sex specific increases in cell proliferation and inflammation in juvenile rats |
| topic | Concussion Dentate gyrus Awake closed-head injury Microglia Sub-granular zone Development |
| url | https://doi.org/10.1186/s12974-023-02916-5 |
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