Estradiol and Glutamate in the Developing Hypothalamus

描述（由申请人提供）：男性和女性的大脑表现出基本的形态差异，被认为是生理和行为上的性别差异的基础。雄性啮齿动物大脑的发育包括完成两个不同的过程：男性化和非女性化。在啮齿动物中，雌二醇在一个有限的敏感期启动这两个过程。在发育和成年期间，内侧基底下丘脑（MBH）是雌二醇的关键靶点。MBH对女性的性行为很重要，也可能是男性大脑中女性化的一个部位。树突棘是兴奋性突触的主要部位。在MBH中，新生的雄性比雌性有更多的树突棘，用睾酮治疗雌性，它被芳香化成雌二醇，增加了这个区域的树突棘到雄性的水平。最近的工作已经开始研究男性化的机制。然而，关于雌二醇在MBH中诱导去雌性化和建立两性二态模式的机制知之甚少。基于初步数据和先前的发现，我们提出谷氨酸释放和NMDA受体在大脑和行为的去女性化过程中的新作用。本研究的目的是阐明雌二醇诱导啮齿动物大脑去雌性化的机制，以增加对大脑发育中性别差异的理解。包括自闭症、情感障碍和精神分裂症在内的许多神经和精神疾病都表现出性别偏见的患病率和/或特征。这些疾病通常是神经化学物质或神经线路的紊乱。理解性如何影响正常的大脑发育对于理解它如何在精神疾病中异常发展是必要的。

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.