From The Quarterly, Summer 2010

That women are twice as vulnerable as men to depression, post-traumatic stress disorder (PTSD) and other stress-related disorders is well known. But why is that the case? Is there a biological basis for the disparity? If so, what is it?  



A research team at Children’s Hospital of Philadelphia, led by 2002 NARSAD Distinguished Investigator Rita J. Valentino, Ph.D., has been exploring how males and

females process stress — at the level of molecules within and between cells in the brain. Their studies show a reaction to stress in female brains that potentially exposes them to receiving additional stress signals within the brain.



Our physiological and behavioral responses to stress are orchestrated by a brain chemical called corticotropin-releasing factor, or CRF. Because of CRF’s primary role in stress response and in stress-related disorders, Dr. Valentino and colleagues thought it likely that CRF was also involved in the sex difference in stress vulnerability. (Interestingly, most experiments on stress-related psychopathology have been done only with male

laboratory animals).



CRF communicates with the body’s cells via receptor molecules on the cell surface that “catch” the CRF signal. Once the CRF is received, signaling in the cell is turned on through specific signaling molecules associated with the receptor. Using rats as their experimental models, the researchers conducted a series of studies exposing the animals to different levels of CRF. Among the findings, it was discovered that when injected with low CRF doses, the brain cells of female rats became activated, but the male cells remained unaffected. The reason, it turns out, is that CRF receptors in females are

better linked to the signaling molecules, and thus their cells are more sensitive to CRF effects.  



In another experiment, it was observed that when exposed to high stress levels, male rat-brain cells can essentially retract their CRF receptors — draw them back inside the cell body from the surface, thus reducing the number of receptors for CRF to bind to. Female rats lack the molecule necessary to perform this process and consequently are bombarded with more CRF.



These two results, published in June in the journal Molecular Psychiatry (“Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psycho- pathology”) have attracted considerable scientific attention. This is in part because they help to explain why, when exposed to stress, the brain in female rats — and presumably in human females — works differently from the male brain, exhibiting a heightened response and less nimble molecular adaptation to stress.



In their conclusion, Dr. Valentino, fellow author Debra Bangasser, Ph.D., and colleagues, note that the design and effectiveness of drugs for the treatment of psychiatric disorders could well be influenced by taking sex differences into account.