Most research on laboratory animals has been done on males. Any differences between male and female mouse brains have been largely ignored. That could be distorting our search for drugs for conditions such as major depressive disorder, since some existing versions target a brain structure where, at least in rodents, these differences are very large.
Dr Joseph Dougherty of Washington University, St Louis, investigated the locus coeruleus of mice. This brain region is primarily responsible for producing the neurotransmitter norepinephrine, and is activated by depression-inducing inflammatory agents and is targeted by drugs used to treat depression and ADHD.
In Cell Reports, Dougherty and colleagues describe finding an array of genes that were expressed differently depending on the sex of the mice. Most dramatically, the female mice had three times as many prostaglandin receptor EP3s (PTGER3) as their male counterparts. Perhaps even more importantly, there was also a considerably higher expression of two genes, Slc6a15 and Lin28b, known to be associated with major depressive disorder.
Female mice responded to PTGER3-targeting drugs with reduced anxiety-like behavior, while the male mice showed no response. "We thought it really striking that there was this structure in the brain that is the target of these drugs that also has this very profound molecular-level difference between males and females," Dougherty said in a statement.
Naturally, this raises the question as to whether something similar occurs in humans. Pop psychology is filled with references to male and female brains, most of which have no foundation in science. However, the fact that some proclaimed differences have turned out to be wrong does not mean that there are not real differences elsewhere, something which could have many important implications.
As the authors note, depression and anxiety are much more commonly diagnosed in women, while ADHD is more frequently reported in boys. Social factors certainly explain part of this variation, but that doesn't rule out the possibility some of it is biological.
Even if human brains prove to be more similar between the sexes, the work could still add to the growing body of literature showing why limiting research to one sex of lab animal leads to less reliable results. After decades of focus on male mice, Canadian funding agencies recently started requiring scientists to include both sexes evenly unless there was an overriding reason not to, and quickly produced some very unexpected results. The US National Institutes of Health followed suit in 2016, and work like Dougherty's is part of the result.
If Dougherty's findings extend to humans, PTGER3 drugs may offer an alternative treatment to millions of women for whom existing anti-anxiety drugs don't work, something we would never have discovered if we'd continued only testing on male mice.
