Vol 8, No 4 - Stress
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P o s t e r Estrogen enhances stress-induced prefrontal cortex dysfunction:relevance to Major Depressive Disorder in women The medial prefrontal cortex (PFC) is widely recognized as a site of dysfunction in patients with stress-related dis- orders,8 particularly MDD.Post-mortem studies of sui- cide victims’ brains reveal marked morphological changes—most notably,reduced glia and neuron number in the ventromedial PFC.9 Similarly,magnetic resonance imaging (MRI) studies demonstrate reduced volume of this area in depressed patients,10 as well as abnormal activity.11 The PFC integrates information from multiple brain areas to regulate behavior,thought,and affect12 — functions that are often compromised in MDD patients.13 In animal models,the integrity of the PFC is most com- monly tested using working memory tasks,which require animals to keep information “online”in the absence of external cues,continually update information,and inhibit inappropriate responses.Exposure to stress has consis- tently been shown to impair performance on such tasks in nonhuman primates and male rodents,14 but until recently,neither sex differences nor estrogen effects on this phenomenon had been explored. The first studies to examine sex differences in the effects of stress on PFC function elicited the stress response in young adult male and female rats with injections of vary- ing doses of the benzodiazepine inverse agonist FG7142. FG7142 is a well-documented anxiogenic drug that is fre- quently used as a model for stress,given its reliability in producing the biochemical and physiological effects of stress:increased corticosterone release,increased cate- cholamine turnover,elevated heart rate,and increased blood pressure.15 Moreover,animals that have been administered FG7142 exhibit classic stress-related behav- iors,including defecating,urinating,freezing,and ultra- sonic vocalizations.16 Following FG7142 administration,animals were tested on a classic measure of working memory—delayed alter- nation in the T-maze.At high doses of FG7142,all ani- mals displayed impairment on the T-maze.At lower doses,however,only females showed impairment,sug- gesting that they were more sensitive to the detrimental effects of stress on mPFC function (Figure 1a).To test Copyright © 2006 LLS SAS. All rights reserved It is well documented that exposure to stress can precipitate or exacerbate many mental illness- es,1,2 including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Women are twice as likely as men to develop these disorders,3,4 as well as most anxiety disorders and phobias,5 but the biological causes of this discrepancy are poorly understood.Interestingly, there is evidence that the increased prevalence of MDD in women occurs primarily during the childbearing years,when circulating estrogen is present.6,7 These observations raise questions as to whether men and women have distinct neurobiological responses to stress,and if so,how might estrogen mediate these differences? Attempts to answer these questions in animal models have generated a growing body of literature demonstrating that estrogen can,indeed,modulate the effects of stress in the brain.Moreover,these effects are demonstrable in brain regions rele- vant to MDD,and are consistent with the idea that estrogen might enhance the stress response, promoting a greater vulnerability to mental illness.