During early brain development, steroid hormone exposure differentiates male from female brain. Although there are numerous physiological and behavioral differences between men and women, perhaps the most profound sex differences are in neurological and psychiatric disorders. For example, women are more likely to exhibit signs of depression, multiple sclerosis, and Alzheimer's disease. Men are more likely to exhibit signs of attention-deficit hyperactivity, autism, and dyslexia. As most sex differences in the brain are a result of early steroid hormone exposure, it is possible that sex differences in some disorders are partly influenced by abnormal steroid receptor action in developing brain. Therefore it is important to understand how steroid receptor activity is regulated in developing brain. Previously, it was assumed that steroid receptors were only activated by steroid hormones;however, recent data indicate that steroid receptors are also activated in the absence of steroid, referred to as ligand-independent activation. Although numerous investigators are currently studying ligand-independent activation of steroid receptors in cell culture assays and in adult female brain, few studies investigate the role of ligand-independent activation of steroid receptors in brain development. We plan to investigate the functional role ligand-independent activation of estrogen receptors (ER) in developing brain. Our recent data indicate that acute changes in dopamine transmission during the first few days of life can dramatically alter the developmental organization of social play behavior by activating ER in a ligand-independent manner. We believe that these data are not only exciting in that they suggest a potential steroid hormone independent mechanism for sexual differentiation of the brain, but they also investigate the developmental organization of social play behavior. As social play behavior is dramatically disrupted in children with Autism and Asperger's syndrome, and social play behavior in rodents has been used as a rodent model for the study of autism, it is possible that these data will further our understanding of how sexually dimorphic social disorders occur during brain development.
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