Sex as a Biological Variable in Preclinical Modeling of Blast-Related Traumatic Brain Injury

Abstract

Approaches to furthering our understanding of the bioeffects, behavioral changes, and treatment options following exposure to blast are a worldwide priority. Of particular need is a more concerted effort to employ animal models to determine possible sex differences, which have been reported in the clinical literature. In this review, clinical and preclinical reports concerning blast injury effects are summarized in relation to sex as a biological variable (SABV). The review outlines approaches that explore the pertinent role of sex chromosomes and gonadal steroids for delineating sex as a biological independent variable. Next, underlying biological factors that need exploration for blast effects in light of SABV are outlined, including pituitary, autonomic, vascular, and inflammation factors that all have evidence as having important SABV relevance. A major second consideration for the study of SABV and preclinical blast effects is the notable lack of consistent model design-a wide range of devices have been employed with questionable relevance to real-life scenarios-as well as poor standardization for reporting of blast parameters. Hence, the review also provides current views regarding optimal design of shock tubes for approaching the problem of primary blast effects and sex differences and outlines a plan for the regularization of reporting. Standardization and clear description of blast parameters will provide greater comparability across models, as well as unify consensus for important sex difference bioeffects.

Measuring Anxiety-Like Behaviors in Rodent Models of Traumatic Brain Injury

“…Although CCI and FPI have remained popular, in recent years attention has turned to less invasive and more clinically relevant "closed-head" models that produce a concussive, more diffuse injury, with or without acceleration/deceleration and rotational components (Bodnar et al, 2019;McNamara et al, 2020). Also of growing interest are animal models of blast overpressure (Skotak et al, 2019;McCabe and Tucker, 2020), as TBI from blast has been the signature wound from military conflicts for the past 20 years.…”

Hippocampal-Dependent Cognitive Dysfunction following Repeated Diffuse Rotational Brain Injury in Male and Female Mice

“…[94][95][96][97][98] Experimental approaches to the exploration of sex as a biological variable (SABV) in neurotrauma research were recently reviewed, and include methods such as monitoring the estrous cycle of female animals, performing gonadectomies with and without hormone replacement, and employment of the four core mouse genotype model. 99 Some of these procedures were performed in valuable earlier studies using classical TBI models such as CCI, FPI, and weightdrop, [100][101][102][103] but are lacking in present experiments in models growing in popularity such as CBI, blast, and CHIMERA. Consideration of SABV, including the effects of sex steroids, their receptors, and other influences such as epigenetics will increase our understanding of the biological underpinnings of behavioral differences between males and females following injury.…”

Limbic Responses Following Shock Wave Exposure in Male and Female Mice

“…Results from behavioral tests can depend on the animal strain and sex ( McCabe and Tucker, 2020 ). Overall, female rodents exhibit more activity compared to males during behavioral tasks and this inherent difference can make data interpretation challenging ( Tucker et al, 2016 , 2017 ).…”