Sex differences in cued fear responses and parvalbumin cell density in the hippocampus following repetitive concussive brain injuries in C57BL/6J mice

PLoS One. 2019 Sep 5;14(9):e0222153. doi: 10.1371/journal.pone.0222153. eCollection 2019.


There is strong evidence to suggest a link between repeated head trauma and cognitive and emotional disorders, and Repetitive concussive brain injuries (rCBI) may also be a risk factor for depression and anxiety disorders. Animal models of brain injury afford the opportunity for controlled study of the effects of injury on functional outcomes. In this study, male and cycling female C57BL/6J mice sustained rCBI (3x) at 24-hr intervals and were tested in a context and cued fear conditioning paradigm, open field (OF), elevated zero maze and tail suspension test. All mice with rCBI showed less freezing behavior than sham control mice during the fear conditioning context test. Injured male, but not female mice also froze less in response to the auditory cue (tone). Injured mice were hyperactive in an OF environment and spent more time in the open quadrants of the elevated zero maze, suggesting decreased anxiety, but there were no differences between injured mice and sham-controls in depressive-like activity on the tail suspension test. Pathologically, injured mice showed increased astrogliosis in the injured cortex and white matter tracts (optic tracts and corpus callosum). There were no changes in the number of parvalbumin-positive interneurons in the cortex or amygdala, but injured male mice had fewer parvalbumin-positive neurons in the hippocampus. Parvalbumin-reactive interneurons of the hippocampus have been previously demonstrated to be involved in hippocampal-cortical interactions required for memory consolidation, and it is possible memory changes in the fear-conditioning paradigm following rCBI are the result of more subtle imbalances in excitation and inhibition both within the amygdala and hippocampus, and between more widespread brain regions that are injured following a diffuse brain injury.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anxiety / etiology
  • Anxiety / pathology*
  • Behavior, Animal
  • Brain Concussion / complications*
  • Brain Concussion / psychology
  • Cell Count
  • Cues*
  • Depression / etiology
  • Depression / pathology*
  • Fear / psychology*
  • Female
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Parvalbumins / metabolism*
  • Sex Factors


  • Parvalbumins

Grant support

This work was supported by The Center for Neuroscience and Regenerative Medicine (Department of Defense); Award recipient: JM; Grant number: 310185-6.01-65310; Funder website: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.