Sex bias in neuroscience and biomedical research

Robert Wood Johnson Health & Society Scholar at University of California, San Francisco, CA, USA.
Neuroscience & Biobehavioral Reviews (Impact Factor: 8.8). 01/2011; 35(3):565-72. DOI: 10.1016/j.neubiorev.2010.07.002
Source: PubMed


Female mammals have long been neglected in biomedical research. The NIH mandated enrollment of women in human clinical trials in 1993, but no similar initiatives exist to foster research on female animals. We reviewed sex bias in research on mammals in 10 biological fields for 2009 and their historical precedents. Male bias was evident in 8 disciplines and most prominent in neuroscience, with single-sex studies of male animals outnumbering those of females 5.5 to 1. In the past half-century, male bias in non-human studies has increased while declining in human studies. Studies of both sexes frequently fail to analyze results by sex. Underrepresentation of females in animal models of disease is also commonplace, and our understanding of female biology is compromised by these deficiencies. The majority of articles in several journals are conducted on rats and mice to the exclusion of other useful animal models. The belief that non-human female mammals are intrinsically more variable than males and too troublesome for routine inclusion in research protocols is without foundation. We recommend that when only one sex is studied, this should be indicated in article titles, and that funding agencies favor proposals that investigate both sexes and analyze data by sex.

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    • "uch of our understanding of the neurobiological basis of psychiatric disorders, such as post-traumatic stress disorder and depression, is based on studies that involve rodents. However, although post-traumatic stress disorder and depression occur more frequently in women (Kessler et al., 2012), most preclinical studies in this area have been conducted on male rodents (Beery and Zucker, 2011). This means many of the tests that researchers use to measure fear, anxiety and depressive-like behavior have been validated in male rodents, but not in female rodents (Kokras and Dalla, 2014). "
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    ABSTRACT: Male and female rats respond to a fearful experience in different ways, but this was not previously taken into account in research into psychiatric disorders.
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    • "Whereas, past Framework Programmes focused on promoting gender equality as a way of addressing the issue of women's underrepresentation in science, technology, engineering and mathematics fields (STEM), the new approach responds to the persuasive evidence showing widespread gender bias in science knowledge and science practice, and its effects on quality of research outcomes for women and men. In short, science today has more evidence for men than for women because historically researchers tended primarily to use male subjects in experimental studies[9]; often also failing to disaggregate results by sex, even when both sexes were used[10]; and omitting to report the subjects' sex[11]. This means that research outcomes can be poorer for women than for men, and, therefore, this suggest that innovation outcomes may be affected in the same way[12]. "

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    • "Moreover, the male GR DBHCre mutants not only did not exhibit changes in basal behavior but were resistant to chronic restraint stress, which clearly indicates the gender-dependent response to this particular mutation. The gender differences in our model are particularly interesting because depression is more prevalent in women (Seedat et al., 2009), and this issue has not been properly addressed in most descriptions of transgenic and pharmacological models of this illness (Beery and Zucker, 2011; Kreiner et al., 2013). Interestingly, several studies performed with transgenic mouse models with differences in male and female behavioral responses have reported gender-specific differences in depressive-like behavior after modification of the serotonergic system (Bhatnagar et al., 2004; Jones and Lucki, 2005), HPA axis elements (Chen et al., 2006; Solomon et al., 2012) and BDNF expression (Monteggia et al., 2007). "
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    ABSTRACT: Recently, we have demonstrated that conditional inactivation of glucocorticoid receptors (GRs) in the noradrenergic system, may evoke depressive-like behavior in female but not male mutant mice (GR(DBHCre) mice). The aim of the current study was to dissect how selective ablation of glucocorticoid signaling in the noradrenergic system influences the previously reported depressive-like phenotype and whether it might be linked to neurotrophic alterations or secondary changes in the serotonergic system. We demonstrated that selective depletion of GRs enhances brain derived neurotrophic factor (BDNF) expression in female but not male GR(DBHCre) mice on both the mRNA and protein levels. The possible impact of the mutation on brain noradrenergic and serotonergic systems was addressed by investigating the tissue neurotransmitter levels under basal conditions and after acute restraint stress. The findings indicated a stress-provoked differential response in tissue noradrenaline content in the GR(DBHCre) female but not male mutant mice. An analogous gender-specific effect was identified in the diminished content of 5-hydroxyindoleacetic acid, the main metabolite of serotonin, in the prefrontal cortex, which suggests down-regulation of this monoamine system in female GR(DBHCre) mice. The lack of GR also resulted in an up-regulation of alpha2-adrenergic receptor (α2-AR) density in the female but not male mutants in the locus coeruleus. We have also confirmed the utility of the investigated model in pharmacological studies, which demonstrates that the depressive-like phenotype of GR(DBHCre) female mice can be reversed by antidepressant treatment with desipramine or fluoxetine, with the latter drug evoking more pronounced effects. Overall, our study validates the use of female GR(DBHCre) mice as an interesting and novel genetic tool for the investigation of the cross-connected mechanisms of depression that is not only based on behavioral phenotypes.
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