Scientists have identified a gene that that may be involved in premenstrual dysphoric disorder (PMDD) , a condition marked by extreme irritability and mood swings, and other maladies related to hormonal fluctuations of the menstrual cycle.
The experiments studied the gene for a protein that works with estrogen to enhance the adaptability of neurons in the hippocampus, a brain region that plays a key role in mood, cognition and memory.
Experiments on mice by Rockefeller University researchers found that a common human variant of the gene increases anxiety, dampens curiosity and tweaks the effects of estrogen on the brain, impairing memory.
The paper published in the Proceedings of the National Academy of Sciences.
This may help diagnose and treat cognitive and mood disorders related to the menstrual cycle and inform treatments during menopause, such as hormone replacement therapy..
A change in one amino acid in this gene, called brain-derived neurotrophic factor (BDNF), creates the variant BDNF Met, which is carried by 20 to 30 percent of Caucasian women.
Past research showed that it is a risk factor for psychiatric problems such as depression and bipolar disorder and is generally associated with higher anxiety and impaired memory.
Previous research at Weill Cornell Medical College showed that the performance of memory tasks by mice with both the variant and the regular gene depends on where they are in their estrous cycles.
It is the first time that a genotype has been shown to interact with a hormone cycle to influence a cognitive behavior, one reviewer of the paper wrote.
The researchers also show that mice with the variant gene are more skittish – spent much less time in the vulnerable center of a well-lit cage before scurrying to a corner. As a result, they spent less time exploring objects placed in their cage.
“Even though the BDNF Met mice spent less time exploring these objects, they still showed the basic curiosity that all mice show for novel things in their environment,” says author Joanna Spencer.
The research compared the performance of mice with the regular BDNF gene and those with BDNF Met on two main tasks.
One task challenged them to remember where an object was placed in the cage and another that challenged them to recognize the difference between similar objects placed in the cage five minutes and 30 minutes apart.
For example, a real sake cup followed by one built of Legos, for instance, or a small pill bottle and a similar sized bottle of nail polish. The BDNF Met mice were significantly worse at both tasks, and aptitude for the object-placement test depended on the stage of each mouse’s estrous cycle.
When the researchers examined the hippocampus in the mice for clues about the anatomy underlying these differences, they found that the variant gene overall produced more BDNF and the cell receptor for BDNF, called TrkB,
Mice in the high-estrogen period of their cycle produced still more BDNF. The researchers believe that this might reflect an effort in the hippocampus, a brain region important for memory of ongoing events, to compensate for a reduction of BDNF secretion that other research has found in the neurons with the BDNF Met gene.
It is unclear why these brain changes alter behavior. But the differences associated with the estrous cycle suggest strongly that BDNF Met could play an important part in disorders associated with the menstrual cycle, such as PMDD that .afflicts 5 to 10 percent of women.
This adds “to our understanding of basic cellular and molecular mechanisms that underlie the ability of sex hormones such as estradiol to affect behavioral functions outside of reproduction, such as anxiety and memory,” said Bruce S. McEwen, head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at Rockefeller.
