PMID- 37907981 OWN - NLM STAT- MEDLINE DCOM- 20231102 LR - 20231103 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 20 IP - 1 DP - 2023 Oct 31 TI - Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats. PG - 250 LID - 10.1186/s12974-023-02916-5 [doi] LID - 250 AB - 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. CI - (c) 2023. The Author(s). FAU - Neale, Katie J AU - Neale KJ AD - Division of Medical Sciences, University of Victoria, Medical Sciences Building,3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada. FAU - Reid, Hannah M O AU - Reid HMO AD - Division of Medical Sciences, University of Victoria, Medical Sciences Building,3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada. FAU - Sousa, Barbara AU - Sousa B AD - Division of Medical Sciences, University of Victoria, Medical Sciences Building,3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada. FAU - McDonagh, Erin AU - McDonagh E AD - Division of Medical Sciences, University of Victoria, Medical Sciences Building,3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada. FAU - Morrison, Jamie AU - Morrison J AD - Division of Medical Sciences, University of Victoria, Medical Sciences Building,3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada. FAU - Shultz, Sandy AU - Shultz S AD - Division of Medical Sciences, University of Victoria, Medical Sciences Building,3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada. AD - Vancouver Island University, 900 Fifth Street, Nanaimo, BC, V9R 5S5, Canada. AD - Monash Trauma Group, Monash University, Melbourne, Australia. FAU - Eyolfson, Eric AU - Eyolfson E AD - Division of Medical Sciences, University of Victoria, Medical Sciences Building,3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada. FAU - Christie, Brian R AU - Christie BR AD - Division of Medical Sciences, University of Victoria, Medical Sciences Building,3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada. brain64@uvic.ca. AD - Institute for Aging and Life Long Health, University of Victoria, 3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada. brain64@uvic.ca. AD - Island Medical Program, Cellular and Physiological Sciences, University of British Columbia, 3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada. brain64@uvic.ca. AD - Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada. brain64@uvic.ca. LA - eng GR - FRN175402/CAPMC/CIHR/Canada GR - FRN175402/CAPMC/CIHR/Canada GR - FRN175402/CAPMC/CIHR/Canada PT - Journal Article DEP - 20231031 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - G34N38R2N1 (Bromodeoxyuridine) SB - IM MH - Humans MH - Rats MH - Female MH - Male MH - Animals MH - Child MH - *Brain Concussion/etiology MH - Bromodeoxyuridine MH - Rats, Long-Evans MH - *Head Injuries, Closed/complications MH - Cell Proliferation MH - Inflammation/complications PMC - PMC10617072 OTO - NOTNLM OT - Awake closed-head injury OT - Concussion OT - Dentate gyrus OT - Development OT - Microglia OT - Mild traumatic brain injury OT - Sub-granular zone OT - mTBI COIS- The authors declare no competing financial or personal interests. EDAT- 2023/11/01 06:43 MHDA- 2023/11/02 12:43 PMCR- 2023/10/31 CRDT- 2023/11/01 01:08 PHST- 2023/06/14 00:00 [received] PHST- 2023/09/29 00:00 [accepted] PHST- 2023/11/02 12:43 [medline] PHST- 2023/11/01 06:43 [pubmed] PHST- 2023/11/01 01:08 [entrez] PHST- 2023/10/31 00:00 [pmc-release] AID - 10.1186/s12974-023-02916-5 [pii] AID - 2916 [pii] AID - 10.1186/s12974-023-02916-5 [doi] PST - epublish SO - J Neuroinflammation. 2023 Oct 31;20(1):250. doi: 10.1186/s12974-023-02916-5.