Abstract
The role of biological sex in short-term and long-term outcome after traumatic brain injury (TBI) remains controversial. The observation that exogenous female sex steroids (progesterone and estrogen) reduce brain injury coupled with a small number of clinical studies showing smaller injury in women suggest that sex steroids may play a role in outcome from TBI. We used the controlled cortical impact (CCI) model of TBI in mice to test the hypothesis that after CCI, female mice would demonstrate less injury than male mice, related to the protective role of endogenous steroids. Indeed, adult females exhibit histological protection (3.7 ± 0.5 mm3) compared to adult male mice (6.8 ± 0.6 mm3), and females that lacked sex steroids (ovex) showed increased injury compared to intact females. Consistent with histology, sensorimotor deficits measured as reduced contralateral limb use were most pronounced in male mice (31.9 ± 6.9% reduced limb use) compared to a 12.7 ± 3.8% reduction in female mice. Ovex mice exhibited behavioral deficits similar to males (31.5 ± 3.9% reduced limb use). Ovex females demonstrated increased microglial activation relative to intact females in both the peri-injury cortex and the reticular thalamic nucleus. Ovex females also demonstrated increased astrogliosis in comparison to both females and males in the peri-injury cortex. These data indicate that female sex steroids reduce brain sensitivity to TBI and that reduced acute neuroinflammation may contribute to the relative protection observed in females.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Acaz-Fonseca E, Duran JC, Carrero P, Garcia-Segura LM, Arevalo MA (2015) Sex differences in glia reactivity after cortical brain injury glia. https://doi.org/10.1002/glia.22867
Albrecht JS, McCunn M, Stein DM, Simoni-Wastila L, Smith GS (2016) Sex differences in mortality following isolated traumatic brain injury among older adults. The journal of trauma and acute care surgery 81(3):486–492. https://doi.org/10.1097/TA.0000000000001118
Allen D, Nakayama S, Kuroiwa M, Nakano T, Palmateer J, Kosaka Y, Ballesteros C, Watanabe M, Bond CT, Luján R, Maylie J, Adelman JP, Herson PS (2011) SK2 channels are neuroprotective for ischemia-induced neuronal cell death. J Cereb Blood Flow Metab 31(12):2302–2312. https://doi.org/10.1038/jcbfm.2011.90
Baum J, Entezami P, Shah K, Medhkour A (2016) Predictors of outcomes in traumatic brain injury. World neurosurgery 90:525–529. https://doi.org/10.1016/j.wneu.2015.12.012
Berry C, Ley EJ, Tillou A, Cryer G, Margulies DR, Salim A (2009) The effect of gender on patients with moderate to severe head injuries. J Trauma 67(5):950–953. https://doi.org/10.1097/TA.0b013e3181ba3354
Bland ST, Schallert T, Strong R, Aronowski J, Grotta JC, Feeney DM (2000) Early exclusive use of the affected forelimb after moderate transient focal ischemia in rats : functional and anatomic outcome. Stroke 31(5):1144–1152. https://doi.org/10.1161/01.STR.31.5.1144
Bramlett HM, Dietrich WD (2001) Neuropathological protection after traumatic brain injury in intact female rats versus males or ovariectomized females. J Neurotrauma 18(9):891–900. https://doi.org/10.1089/089771501750451811
Brotfain E, Gruenbaum SE, Boyko M, Kutz R, Zlotnik A, Klein M (2016) Neuroprotection by estrogen and progesterone in traumatic brain injury and spinal cord injury. Curr Neuropharmacol 14(6):641–653. https://doi.org/10.2174/1570159X14666160309123554
Bruce-Keller AJ, Dimayuga FO, Reed JL, Wang C, Angers R, Wilson ME, Dimayuga VM, Scheff SW (2007) Gender and estrogen manipulation do not affect traumatic brain injury in mice. J Neurotrauma 24(1):203–215. https://doi.org/10.1089/neu.2006.0163
Bruce-Keller AJ, Keeling JL, Keller JN, Huang FF, Camondola S, Mattson MP (2000) Antiinflammatory effects of estrogen on microglial activation. Endocrinology 141(10):3646–3656. https://doi.org/10.1210/endo.141.10.7693
Buffo A, Rolando C, Ceruti S (2010) Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential. Biochem Pharmacol 79(2):77–89. https://doi.org/10.1016/j.bcp.2009.09.014
Chiu CC, Liao YE, Yang LY, Wang JY, Tweedie D, Karnati HK, Greig NH (2016) Neuroinflammation in animal models of traumatic brain injury. J Neurosci Methods 272:38–49. https://doi.org/10.1016/j.jneumeth.2016.06.018
Coimbra R, Hoyt DB, Potenza BM, Fortlage D, Hollingsworth-Fridlund P (2003) Does sexual dimorphism influence outcome of traumatic brain injury patients? The answer is no! J Trauma 54(4):689–700. https://doi.org/10.1097/01.TA.0000058314.31655.5F
Cutolo M, Sulli A, Seriolo B, Accardo S, Masi AT (1995) Estrogens, the immune response and autoimmunity. Clin Exp Rheumatol 13(2):217–226
Dams-O'Connor K, Spielman L, Singh A, Gordon WA, Lingsma HF, Maas AIR, Manley GT, Mukherjee P, Okonkwo DO, Puccio AM, Schnyer DM, Valadka AB, Yue JK, Yuh EL, Casey TRACKTBII, Cooper SR, Cheong M, Hricik AJ, Knight EE, Menon DK, Morabito DJ, Pacheco JL, Sinha TK, Vassar MJ (2013) The impact of previous traumatic brain injury on health and functioning: a TRACK-TBI study J Neurotrauma 30:2014–2020 doi:https://doi.org/10.1089/neu.2013.3049, 24
Davis DP, Douglas DJ, Smith W, Sise MJ, Vilke GM, Holbrook TL, Kennedy F, Eastman AB, Velky T, Hoyt DB (2006) Traumatic brain injury outcomes in pre- and post- menopausal females versus age-matched males. J Neurotrauma 23(2):140–148. https://doi.org/10.1089/neu.2006.23.140
Deng G, Orfila JE, Dietz RM, Moreno-Garcia M, Rodgers KM, Coultrap SJ, Quillinan N, Traystman RJ, Bayer KU, Herson PS (2017) Autonomous CaMKII activity as a drug target for histological and functional neuroprotection after resuscitation from cardiac arrest. Cell Rep 18(5):1109–1117. https://doi.org/10.1016/j.celrep.2017.01.011
Devitt R, Colantonio A, Dawson D, Teare G, Ratcliff G, Chase S (2006) Prediction of long-term occupational performance outcomes for adults after moderate to severe traumatic brain injury. Disabil Rehabil 28(9):547–559. https://doi.org/10.1080/00222930500219258
Farace E, Alves WM (2000) Do women fare worse: a metaanalysis of gender differences in traumatic brain injury outcome. J Neurosurg 93(4):539–545. https://doi.org/10.3171/jns.2000.93.4.0539
Finkelstein EA (2007) Corso PS, miller TR. Incidence and economic burden of injuries in the United States J Epidemiol Community Health 61:926–927
Groswasser Z, Cohen M (1998) Keren O. Female TBI patients recover better than males Brain injury : [BI] 12(9):805–808
Halassa MM, Acsady L (2016) Thalamic inhibition: diverse sources, diverse scales. Trends Neurosci 39(10):680–693. https://doi.org/10.1016/j.tins.2016.08.001
Hall ED, Gibson TR, Pavel KM (2005) Lack of a gender difference in post-traumatic neurodegeneration in the mouse controlled cortical impact injury model. J Neurotrauma 22(6):669–679. https://doi.org/10.1089/neu.2005.22.669
Herson PS, Koerner IP, Hurn PD (2009) Sex, sex steroids, and brain injury. SeminReprodMed 27:229–239
Hurn PD, Brass LM (2003) Estrogen and stroke: a balanced analysis. Stroke 34(2):338–341. https://doi.org/10.1161/01.STR.0000054051.88378.25
Huusko N, Pitkanen A (2014) Parvalbumin immunoreactivity and expression of GABAA receptor subunits in the thalamus after experimental TBI. Neuroscience 267:30–45. https://doi.org/10.1016/j.neuroscience.2014.02.026
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8(6):e1000412. https://doi.org/10.1371/journal.pbio.1000412
Kirkness CJ, Burr RL, Mitchell PH, Newell DW (2004) Is there a sex difference in the course following traumatic brain injury? Biological research for nursing 5(4):299–310. https://doi.org/10.1177/1099800404263050
Kraus JF, Peek-Asa C, McArthur D (2000) The independent effect of gender on outcomes following traumatic brain injury: a preliminary investigation Neurosurgical focus 8:e5
Lozano D, Gonzales-Portillo GS, Acosta S, de la Pena I, Tajiri N, Kaneko Y, Borlongan CV (2015) Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatr Dis Treat 11:97–106. https://doi.org/10.2147/NDT.S65815
Maghool F, Khaksari M, Siahposht Khachki A (2013) Differences in brain edema and intracranial pressure following traumatic brain injury across the estrous cycle: involvement of female sex steroid hormones. Brain Res 1497:61–72. https://doi.org/10.1016/j.brainres.2012.12.014
Moore DW, Ashman TA, Cantor JB, Krinick RJ, Spielman LA (2010) Does gender influence cognitive outcome after traumatic brain injury? Neuropsychological rehabilitation 20(3):340–354. https://doi.org/10.1080/09602010903250928
Mushkudiani NA, Engel DC, Steyerberg EW, Butcher I, Lu J, Marmarou A, Slieker F, McHugh GS, Murray GD, Maas AIR (2007) Prognostic value of demographic characteristics in traumatic brain injury: results from the IMPACT study. J Neurotrauma 24(2):259–269. https://doi.org/10.1089/neu.2006.0028
Ng I, Lee KK, Lim JH, Wong HB, Yan XY (2006) Investigating gender differences in outcome following severe traumatic brain injury in a predominantly Asian population. Br J Neurosurg 20(2):73–78. https://doi.org/10.1080/02688690600682259
Nortje J, Menon DK (2004) Traumatic brain injury: physiology, mechanisms, and outcome. Curr Opin Neurol 17(6):711–718. https://doi.org/10.1097/00019052-200412000-00011
O'Connor CA, Cernak I, Vink R (2003) Interaction between anesthesia, gender, and functional outcome task following diffuse traumatic brain injury in rats. J Neurotrauma 20(6):533–541. https://doi.org/10.1089/089771503767168465
Ottochian M, Salim A, Berry C, Chan LS, Wilson MT, Margulies DR (2009) Severe traumatic brain injury: is there a gender difference in mortality? Am J Surg 197(2):155–158. https://doi.org/10.1016/j.amjsurg.2008.09.008
Parent A, Hazrati LN (1995) Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop brain research. Brain Res Rev 20(1):91–127. https://doi.org/10.1016/0165-0173(94)00007-C
Ponsford JL, Myles PS, Cooper DJ, Mcdermott FT, Murray LJ, Laidlaw J, Cooper G, Tremayne AB, Bernard SA (2008) Gender differences in outcome in patients with hypotension and severe traumatic brain injury. Injury 39(1):67–76. https://doi.org/10.1016/j.injury.2007.08.028
Renner C et al (2012) The influence of gender on the injury severity, course and outcome of traumatic brain injury brain injury : [BI] 26:1360-1371. https://doi.org/10.3109/02699052.2012.667592
Roof RL, Duvdevani R, Stein DG (1993) Gender influences outcome of brain injury: progesterone plays a protective role. Brain Res 607(1-2):333–336. https://doi.org/10.1016/0006-8993(93)91526-X
Roof RL, Hall ED (2000a) Estrogen-related gender difference in survival rate and cortical blood flow after impact-acceleration head injury in rats. J Neurotrauma 17(12):1155–1169. https://doi.org/10.1089/neu.2000.17.1155
Roof RL, Hall ED (2000b) Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. JNeurotrauma 17(5):367–388. https://doi.org/10.1089/neu.2000.17.367
Sarajuuri JM, Kaipio ML, Koskinen SK, Niemela MR, Servo AR, Vilkki JS (2005) Outcome of a comprehensive neurorehabilitation program for patients with traumatic brain injury. Arch Phys Med Rehabil 86(12):2296–2302. https://doi.org/10.1016/j.apmr.2005.06.018
Scholten AC, Haagsma JA, Andriessen TM, Vos PE, Steyerberg EW, van Beeck EF, Polinder S (2015) Health-related quality of life after mild, moderate and severe traumatic brain injury: patterns and predictors of suboptimal functioning during the first year after injury. Injury 46(4):616–624. https://doi.org/10.1016/j.injury.2014.10.064
Semple BD, Dixit S, Shultz SR, Boon WC, O'Brien TJ (2017) Sex-dependent changes in neuronal morphology and psychosocial behaviors after pediatric brain injury. Behav Brain Res 319:48–62. https://doi.org/10.1016/j.bbr.2016.10.045
Shimizu K, Quillinan N, Orfila JE, Herson PS (2016) Sirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels experimental neurology 275 Pt 1:78-83. https://doi.org/10.1016/j.expneurol.2015.10.014
Slewa-Younan S, Green AM, Baguley IJ, Gurka JA, Marosszeky JE (2004) Sex differences in injury severity and outcome measures after traumatic brain injury. Arch Phys Med Rehabil 85(3):376–379. https://doi.org/10.1016/j.apmr.2003.05.007
Slewa-Younan S, van den Berg S, Baguley IJ, Nott M, Cameron ID (2008) Towards an understanding of sex differences in functional outcome following moderate to severe traumatic brain injury: a systematic review. J Neurol Neurosurg Psychiatry 79(11):1197–1201. https://doi.org/10.1136/jnnp.2008.147983
Stein DG (2011) Is progesterone a worthy candidate as a novel therapy for traumatic brain injury? Dialogues Clin Neurosci 13(3):352–359
Suzuki T, Bramlett HM, Dietrich WD (2003) The importance of gender on the beneficial effects of posttraumatic hypothermia. Exp Neurol 184(2):1017–1026. https://doi.org/10.1016/S0014-4886(03)00389-3
Taylor CA, Bell JM, Breiding MJ, Xu L (2017) Traumatic brain injury-related emergency department visits, hospitalizations, and deaths - United States, 2007 and 2013. MMWR Surveill Summ 66(9):1–16. https://doi.org/10.15585/mmwr.ss6609a1
Tsushima WT, Lum M (2009) Geling O. Sex differences in the long-term neuropsychological outcome of mild traumatic brain injury Brain injury : [BI] 23(10):809–814. https://doi.org/10.1080/02699050903200530
Tucker LB, Burke JF, Fu AH, McCabe JT (2017) Neuropsychiatric symptom modeling in male and female C57BL/6J mice after experimental traumatic brain injury. J Neurotrauma 34(4):890–905. https://doi.org/10.1089/neu.2016.4508
Tucker LB, Fu AH, McCabe JT (2016) Performance of male and female C57BL/6J mice on motor and cognitive tasks commonly used in pre-clinical traumatic brain injury research. J Neurotrauma 33(9):880–894. https://doi.org/10.1089/neu.2015.3977
Villapol S, Loane DJ, Burns MP (2017) Sexual dimorphism in the inflammatory response to traumatic brain injury. Glia 65(9):1423–1438. https://doi.org/10.1002/glia.23171
Wagner AK, Willard LA, Kline AE, Wenger MK, Bolinger BD, Ren D, Zafonte RD, Dixon CE (2004) Evaluation of estrous cycle stage and gender on behavioral outcome after experimental traumatic brain injury. Brain Res 998(1):113–121. https://doi.org/10.1016/j.brainres.2003.11.027
Whelan-Goodinson R, Ponsford JL, Schonberger M, Johnston L (2010) Predictors of psychiatric disorders following traumatic brain injury. J Head Trauma Rehabil 25(5):320–329. https://doi.org/10.1097/HTR.0b013e3181c8f8e7
Xing G, Carlton J, Jiang X, Wen J, Jia M, Li H (2014) Differential expression of brain cannabinoid receptors between repeatedly stressed males and females may play a role in age and gender-related difference in traumatic brain injury: implications from animal studies. Front Neurol 5:161. https://doi.org/10.3389/fneur.2014.00161
Xiong Y, Mahmood A, Lu D, Qu C, Goussev A, Schallert T, Chopp M (2007) Role of gender in outcome after traumatic brain injury and therapeutic effect of erythropoietin in mice. Brain Res 1185:301–312. https://doi.org/10.1016/j.brainres.2007.09.052
Acknowledgements
We would like to acknowledge Frank Strnad, who completed a portion of the animal perfusions post-injury. We would also like to acknowledge Myriam Moreno Garcia who managed the animal colonies. Funding provided by National Institutes of Health, R01NS046072 (RJT) and R01NS092645 (PSH).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Author Disclosure Statement
None.
Rights and permissions
About this article
Cite this article
Clevenger, A.C., Kim, H., Salcedo, E. et al. Endogenous Sex Steroids Dampen Neuroinflammation and Improve Outcome of Traumatic Brain Injury in Mice. J Mol Neurosci 64, 410–420 (2018). https://doi.org/10.1007/s12031-018-1038-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-018-1038-x