Negative Impact of Female Sex on Outcomes from Repetitive Mild Traumatic Brain Injury in hTau Mice Is Age Dependent: A Chronic Effects of Neurotrauma Consortium Study.

Scott A Ferguson,Fiona Crawford,Benoit C Mouzon,Alexander Morin,Gogce Crynen,Elliott J Mufson,Benjamin Carper,Cillian Lynch,Gayle Bieler,Carlyn Lungmus,William Stewart,Michael Mullan

doi:10.3389/fnagi.2017.00416

Abstract

Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative diseases after TBI it is important to understand how these factors influence the outcome from TBI. This study examined the neurobehavioral and neuropathological effects of age and sex on the outcome 15 days following repetitive mild traumatic brain injury (r-mTBI) in mice transgenic for human tau (hTau). These mice express the six human isoforms of tau but do not express endogenous murine tau and they develop tau pathology and memory impairment in an age-dependent manner. After 5 mild impacts, aged female mice showed motor impairments that were absent in aged male mice, as well as younger animals. Conversely, aged female sham mice outperformed all other groups of aged mice in a Barnes maze spatial memory test. Pathologically, increases in IBA-1 and GFAP staining typically seen in this model of r-mTBI showed the expected increases with both injury and age, but phosphorylated tau stained with CP13 in the hippocampus (reduced in female sham mice compared to males) and PHF1 in the cortex (reduced in female TBI mice compared to male TBI mice) showed the only histological signs of sex-dependent differences in these mice.

Highlights

Traumatic brain injury (TBI) contributes to in excess of 2.5 million emergency department visits a year in the United States (CDC), with a 70% increase in attendances from 2001 to 2010 (Faul et al, 2010)
The probe trial analysis of the average time to reach the target zone, revealed that the performance of the young repetitive mild traumatic brain injury (r-mTBI) mice was markedly impaired compared to the sham group when data are combined across sexes (Figure 2, p < 0.02)
We have examined the effect of sex on neurobehavioral and pathological outcomes in young and aged human tau (hTau) mouse after repetitive mild TBI

Summary

Introduction

In a meta-analysis of the influence of sex on TBI it was reported that, compared to men, women display worse outcomes from TBI across multiple measures, including mortality, days of post-traumatic amnesia, memory impairment, and insomnia (Farace and Alves, 2000), with one study of 306 individuals with a history of moderate to severe TBI documenting an increased incidence of self-reported headaches, dizziness, and depression in women with a history of TBI (Colantonio et al, 2010). Despite this bias, there has been limited enquiry into the influence of sex on acute or long-term consequences of TBI.

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Results

Conclusion