Differential Endogenous Estrogen Exposure Influences Prefrontal Cortex Response to Acute Stress

The present study was conducted to determine the effect of differential endogenous estrogen exposure in rats on stress-induced changes in spatial working memory. Subjects comprised male (n=8) and female (n=10) Sprague-Dawley rats, which were trained to complete a T maze, delayed alternation task. Performance was scored as a percentage of trials during which the correct maze arm was selected. Subjects’ scores were recorded after 1 and 2 hours of restraint stress, as well as after 1 hour of unimpeded movement in a cage placed in the testing room. Restraint stress was effected through physical confinement within plastic, cylindrical tubing. Female subjects underwent each of the testing conditions twice, during periods of high and low endogenous estrogen exposure, as ascertained by microscopic examination of vaginal epithelial cells for estrous cycle stage determination. Females in proestrus (elevated endogenous estrogen exposure) subjected to 1 hour of restraint performed significantly worse than their baseline scores (p=0.0017) or females in estrus (low endogenous estrogen exposure) after 1 hour of restraint (p=0.00014). After 1 hour of restraint, females in proestrus also committed an increased rate of perseverative errors compared to females in estrus, although this increase did not achieve statistical significance (p=0.06). No appreciable differences existed among subject groups in baseline performance or subsequent to 2 hours of restraint stress. Resultant data indicate impaired working memory among female rats under conditions of stress in the context of elevated endogenous estrogen exposure. This study, then, suggests a potential synergistic effect of stress and estrogen in compromising prefrontal cortex function and, therefore, may lend insight into the observed sex-related disparity in the incidence of major depressive disorder and other anxiety-related mood disorders. Acknowledgements Most importantly, I would like to thank Dr. Amy Arnsten for so graciously welcoming me into her lab and allowing me to participate not only in her research but also in a wonderful complement of journal meetings and mentoring sessions. Dr. Arnsten has been invariably generous with her time and teaching, during both the research and writing phases of this project. It has been an enormous privilege to learn from her, and I am inordinately grateful for her willingness to act as my advisor. In addition, I owe a substantial debt of gratitude to Dr. Rebecca Shansky. Despite being in the midst of completing her PhD, Becca always made time to discuss her research with me, to teach, and to share good music. Becca enabled my research experience to be both enriching and a sheer joy; she is an outstanding mentor who has also proven a great friend. I would also like to thank my father, whose willingness to serve as my external reviewer afforded me both the opportunity to benefit from one of the pioneers in neuroendocrinology and an excuse to spend additional time with one of my favorite people in the world. The completion of this paper would not have been possible without the support of the Department of Neurobiology and a research grant from the Office of Student Research.