Androgens and Estrogens in the Human Nervous System

生殖激素在中枢神经系统(CNS)中发挥着重要作用。在出生前或出生后的早期发育过程中，睾酮(或其代谢产物)导致表达激素受体的大脑系统的男性化和去女性化，永久性地改变这些部位脑组织的结构细节。雌激素的一种形式，如雌激素，在成人中枢神经系统中也发挥着重要作用，在那里它们在几个神经化学系统中扮演着强大的神经调节剂的角色。管理类固醇激素这些作用的基本原理主要来源于对非人类物种的研究。人们对这些激素在人类和其他灵长类动物大脑中的作用知之甚少。然而，越来越多的证据支持生殖类固醇在一系列认知、行为、食欲和情感功能中的调节作用，以及在几种精神疾病和脑老化中的激素失调。我的实验室的研究使用了广泛的不同方法来调查生殖类固醇对人类中枢神经系统的影响，包括对健康人和内分泌障碍患者的神经心理学研究，结构和功能神经成像，基因分型，以及对中枢神经系统与类固醇浓度自然发生变化的相关性的研究。我们的工作得到了现场实验室的协助，该实验室专门使用尖端的酶免疫分析和放射性同位素方法定量测定人类唾液中的类固醇激素。在接下来的5年里，我们计划研究睾酮和雌二醇对几种认知功能的影响，特别是工作记忆和心理旋转(当我们分析来自外部环境的空间位置信息时，引发的一种认知处理)。具体地说，我们将测试额叶假说，该假说假设雌二醇作用于人类前额叶皮质(PFC)及其所服务的认知功能。其次，我们将使用雄激素活性的生物标记物和成人激素浓度的直接量化来阐明睾酮影响心理旋转和其他空间功能的时机和机制。总而言之，这两条研究路线将有助于揭示生殖类固醇在人类神经系统中的活动时间和部位。

Reproductive hormones play many important roles in the central nervous system (CNS). During prenatal or early postnatal development, testosterone (or its metabolites) brings about the masculinization and defeminization of brain systems that express receptors for the hormones, permanently altering structural details of brain organization at those sites. Hormones such as estradiol, a form of estrogen, also play important roles in the adult CNS where they serve as potent neuromodulators in several neurochemical systems. The fundamental principles that govern these actions of steroid hormones have been derived mostly from studies of nonhuman species. Much less is known about the roles of these hormones in the brains of humans and other primates. However, evidence increasingly supports a regulatory role for reproductive steroids in a range of cognitive, behavioural, appetitive, and affective functions, as well as hormonal dysregulation in several psychiatric conditions and with brain aging. Research in my lab utilizes a wide range of different methods to investigate the effects of reproductive steroids in the human CNS, including neuropsychological studies of healthy people and people who have endocrine disorders, structural and functional neuroimaging, genotyping, and studies of the CNS correlates of naturally-occurring variations in steroid concentrations. We are assisted in our work by an on-site laboratory that specializes in the quantification of steroid hormones in human saliva using cutting-edge enzyme immunoassays and radioisotopic methods. Over the next 5 years, we plan to study the effects of testosterone and estradiol on several cognitive functions, especially working memory and mental rotation (a type of cognitive processing evoked when we analyze spatial positional information from the external environment). Specifically, we will test the frontal lobe hypothesis, which posits that estradiol acts on the human prefrontal cortex (PFC) and the cognitive functions it serves. Secondly, we will use biological markers of androgen activity and direct quantification of adult hormone concentrations to clarify the timing and mechanisms by which testosterone influences mental rotation and other spatial functions. Collectively, these two lines of research will help to shed new light on the timing and sites of activity of reproductive steroids in the human nervous system.