Estradiol and Glutamate in the Developing Hypothalamus

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DESCRIPTION (provided by applicant): Male and female brains exhibit fundamental morphological differences thought to underlie sex differences in physiology and behavior. Development of the male rodent brain includes the completion of two distinct processes: masculinization and defeminization. In the rodent, estradiol initiates both processes during a restricted sensitive period. During development and adulthood, the medial basal hypothalamus (MBH) is a key target for estradiol. The MBH is important for female sex behavior and a possible site of defeminization in the male brain. Dendritic spines are the major sites of excitatory synapses. In the MBH, newborn males have more dendritic spines than females and treatment of females with testosterone, which is aromatized to estradiol, increases dendritic spines in this region to levels seen in males. Recent work has begun to investigate the mechanism of masculinization. However, little is known about the mechanism by which estradiol induces defeminization and establishes sexually dimorphic patterning in the MBH. Based on preliminary data and previous findings, we propose a novel role for glutamate release and the NMDA receptor in the process of defeminization of the brain and behavior. The goal of this proposal is to elucidate the mechanism by which estradiol induces defeminization of the rodent brain, to increase understanding of sex differences in brain development. Many neurological and psychiatric disorders including autism, affective disorder and schizophrenia exhibit a sex-biased prevalence and/or characteristics. These diseases are frequently disorders of neurochemicals or wiring. Understanding how sex effects normal brain development is necessary to understand how it may develop abnormally in psychiatric disorders.