Lost in translational biology: Understanding sex differences to inform studies of diseases of the nervous system.

Female and male humans are different. As simple and obvious as that statement is, in biomedical research there has been an historical tendency to either not consider sex at all or to only use males in clinical and in preclinical model system studies. The result is a large volume of research that reflects the average biology and pathology of males even though we know that disease risk, presentation, and response to therapies can be different between females and males. This is true, albeit to differing degrees, for virtually all neurological and psychiatric diseases. However, the days of ignoring sex as a biological variable are over - both because of the realization that genetic sex impacts brain function, and because of the 2014 mandate by the U.S. National Institutes of Health that requires that "sex as a biological variable" be addressed in each grant application. This review is written for neuroscientists who may not have considered sex as a biological variable previously but who now are navigating the best way to adapt their research programs to consider this important biology. We first provide a brief overview of the evidence that male versus female differences in the brain are biologically and clinically meaningful. We then present some fundamental principles that have been forged by a dedicated but small group of ground-breaking researchers along with a description of tools and model systems for incorporating a sex differences component into a research project. Finally, we will highlight some key technologies that, in the coming years, are likely to provide critical information about sex differences in the human brain.