An issue whose time has come.

Abstract

“Be careful, it's the third rail.” I received this strong advice to steer clear of studying sex differences from a senior colleague around the year 2000 when my research into brain mechanisms of emotional memory began drawing me into the issue of sex differences—or better yet, sex influences—on brain function. And in a way, he was right. For the vast majority of his long and distinguished neuroscience career, exploring sex influences was indeed a terrific way for a brain scientist not studying reproductive functions to lose credibility at best, and at worst, become a pariah in the eyes of the neuroscience mainstream. Why was studying sex differences so taboo? I believe there are several key reasons (for more detail, see Cahill, 2006; Cahill, 2014). First, most neuroscientists knew that sex influences on the brain exclusively concerned sex behaviors (e.g., mating), sex hormones, and a few small brain nuclei mostly in the hypothalamus. Second, most neuroscientists knew that, to the extent sex influences seemed to exist elsewhere, they were not fundamental; rather, they were of secondary importance-—something to be understood after determining the fundamental facts. Third, most neuroscientists knew that sex influences were do to undulating sex hormones, a pesky sort of feature essentially of the female, an unnecessary source of additional variability and one wisest to avoid in the search for the fundamental. This view in turn justified in brain science the still overriding reliance on the male as equal proxy for the female. Finally…politics. Due to a deeply ingrained, implicit (but false) assumption that “equal” means “the same,” most neuroscientists knew, and even feared that establishing that males and females are not the same in some aspect of brain function meant establishing that they were not equal. This assumption is false and deeply harmful, in particular to the health of women (see Cahill, 2014), but remains deeply impactful nonetheless. As a result of these powerful but misguided driving forces, today, sex influences of all types-and-sizes run unexamined and uncontrolled in neuroscience. Peruse the table of contents of any neuroscience journal and you will find that for easily over 95 percent of the studies one can (and in truth, should) ask “in males, or females, or both?” The answer is almost universally unknown, and worse, almost universally assumed not to matter. Fortunately, times are changing. The past 15 to 20 years in particular witnessed an explosion of research (despite the prevailing biases against the topic) documenting sex influences at all levels of brain function. So overpowering is the wave of research that the standard ways of dismissing sex influences (e.g., “They are all small and unreliable,” “They are all due to circulating hormones,” “They are all due to human culture,” and “They don't exist on the molecular level”) have all been swept away, at least for those cognizant of the research. This themed issue of the Journal of Neuroscience Research (JNR) heralds a zeitgeist shift. It is the first ever from a mainstream neuroscience journal entirely devoted to the issue of sex influences on brain/nervous system functioning. Papers from about 70 groups of authors, from those who have been investigating the issue for decades to those uncovering them only recently, forcefully document the fact that sex influences on brain function are ubiquitous, regularly reshaping findings—hence conclusions—at all levels of our field, and powerfully demonstrating how much “sex matters.” The fact that these ubiquitous sex influences are often unanticipated, or that we often cannot say conclusively what they “mean,” only heightens their evident importance, at least for those who believe that women should be treated equally with men by the biomedical research establishment. Consequently the papers in this issue force the conclusion that the status quo in neuroscience (whereby potential sex influences may be safely ignored or dismissed) is no longer scientifically defensible. And in fact, with this issue, JNR is indeed changing the neuroscience status quo. Coinciding with this issue (which will be permanently open access), JNR is announcing editorial policy changes whereby all new submissions to the journal must carefully attend to potential sex influences (see Editorial Comment by Prager, 2017). These new policies dovetail nicely with the new NIH requirements regarding the consideration of sex as a biological variable (see Clayton and Collins, 2014). The French novelist Victor Hugo said, ‘‘there is one thing more powerful than all the armies in the world, and that is an idea whose time has come.’’ The notion that sex matters fundamentally, powerfully, and pervasively for all of neuroscience (not just for reproduction) is an idea whose time indeed has come.