Endogenous Sex Steroids Dampen Neuroinflammation and Improve Outcome of Traumatic Brain Injury in Mice

  • Amy C. Clevenger
  • Hoon Kim
  • Ernesto Salcedo
  • Joan C. Yonchek
  • Krista M. Rodgers
  • James E. Orfila
  • Robert M. Dietz
  • Nidia Quillinan
  • Richard J. Traystman
  • Paco S. Herson


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.


Traumatic brain injury; sex differences Sex steroids Stereology Neuroinflammation 



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).

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Author Disclosure Statement



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Authors and Affiliations

  • Amy C. Clevenger
    • 1
  • Hoon Kim
    • 2
  • Ernesto Salcedo
    • 3
  • Joan C. Yonchek
    • 4
  • Krista M. Rodgers
    • 4
  • James E. Orfila
    • 4
  • Robert M. Dietz
    • 1
  • Nidia Quillinan
    • 4
  • Richard J. Traystman
    • 4
  • Paco S. Herson
    • 4
  1. 1.Department of Pediatrics, Children’s Hospital Colorado and University of Colorado DenverAuroraUSA
  2. 2.Department of Emergency Medicine, College of MedicineChungbuk National University HospitalCheongjuRepublic of Korea
  3. 3.Department of Cell and Developmental BiologyUniversity of Colorado DenverAuroraUSA
  4. 4.Department of AnesthesiologyUniversity of Colorado DenverAuroraUSA

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