Sex in Context: Limitations of Animal Studies for Addressing Human Sex/Gender Neurobehavioral Health Disparities

Abstract

Many brain and behavioral disorders differentially affect men and women.The new National Institutes of Health requirement to include both male and female animals in preclinical studies aims to address such health disparities, but we argue that the mandate is not the best solution to this problem. Sex differences are highly species-specific, tied to the mating system and social ecology of a given species or even strain of animal. In many cases, animals poorly replicate male-female differences in brain-related human diseases. Sex/gender disparities in human health have a strong sociocultural component that is intimately entangled with biological sex and challenging to model in animals. We support research that investigates sex-related variables in hypothesis-driven studies of animal brains and behavior. However, institutional policies that require sex analysis and give it special salience over other sources of biological variance can distort research. We caution that the costly imposition of sex analysis on nearly all animal research entrenches the presumption that human brain and behavioral differences are largely biological in origin and overlooks the potentially more powerful social, psychological, and cultural contributors to male-female neurobehavioral health gaps.

Similar reliability and equivalent performance of female and male mice in the open field and water‐maze place navigation task

“…Our study makes a strong case for the inclusion—together with male mice—of females without testing for estrous cycle in studies of spatial memory, anxiety‐related behavior, and locomotor activity with mouse models of nervous system disease. This will render studies more representative (Clayton, ; Miller et al, ; Shansky & Woolley, ) and provide opportunities to study sex‐specific aspects of disease, provided that they are biologically determined (Eliot & Richardson, ). Using only male mice will not make results more reliable.…”

“…This effect is particularly well known and reliable in tasks involving mental rotation of objects (Voyer, ; Voyer, Voyer, & Bryden, ), but a male advantage has also been observed repeatedly in studies involving navigation of a virtual water‐maze (Astur et al,; Astur, Purton, Zaniewski, Cimadevilla, & Markus, ; Astur, Tropp, Sava, Constable, & Markus, ; Korthauer, Nowak, Frahmand, & Driscoll, ; Newhouse, Newhouse, & Astur, ). Performance differences between women and men in spatial tasks may be strongly confounded with socialization and gender‐biased expectations (Eliot & Richardson, ; Estes & Felker, ), but the observation of congruent sex differences in water‐maze navigation between mice and human subjects is nevertheless remarkable.…”

Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential

“…In addition, girls and women are more likely to develop stress-related mental disorders. The origins of discrepancy between human and rodent studies are poorly understood, and have been the focus of excellent recent reviews (Eliot & Richardson, 2016). …”

Journal of neuroscience research policy on addressing sex as a biological variable: Comments, clarifications, and elaborations

“…Context and history is especially critical with respect to research with humans, and the need to reflect psychological and sociocultural factors should be an explicit consideration in research design and interpretation. Such issues have been addressed in published guidelines in neuroimaging research (Rippon et al, 2014) and, as a reflection of the timeliness of JNR's policy announcement, debated in a recent issue of the Journal of Neuroscience (Eliot and Richardson, 2016;Shanksy and Woolley, 2016).…”

“…Authors should be advised against the use of terms like 'profound,' 'fundamental,' and 'essential' in their titles and abstracts when the text reports findings of differences that are small and/or may only have been found in a minority of possible comparisons. Authors should also be encouraged to consider the appropriateness of-and evidence forinferences to function from structure (Fine, 2010) and the limits of generalizability between species (Eliot and Richardson, 2016). We acknowledge that such issues should generally be considered in the normal course of review, but note that such scientifically unjustified language and claims nonetheless occur in this research sphere (O'Connor and Joffe, 2014).…”