Androgens and Estrogens in the Human Nervous System

在过去的30年里，动物研究表明，生殖激素对中枢神经系统(CNS)有广泛的影响。例如，雌激素(雌性生殖时期产生的主要雌激素)在几个神经化学系统中是一种强有力的神经调节剂，其中枢神经系统效应表现为行为、感知和认知的变化。虽然动物数据很丰富，但关于人类中枢神经系统中荷尔蒙影响的知识却出人意料地稀少。这是一个重要和值得注意的理论差距，特别是考虑到这种效应与理解中枢神经系统与激素水平正常变化的相关性，这些激素水平在一生中(例如随着年龄的增长)或在临床条件下(例如前列腺癌的雄激素剥夺疗法)。我的实验室研究雄激素和雌激素在正常人脑中的作用，这在加拿大研究人员中很少见。我们过去的工作表明，生殖类固醇通常调节各种认知、行为、食欲和情感功能，并且可能随着年龄的增长或在某些精神健康状况下调节失调。综合一些证据，我们最近假设(Hampson，2019)前额叶皮质(PFC)是健康成年人大脑的关键作用部位--性类固醇可能通过影响两个部分不同但相互连接的调节控制系统来调节某些认知或评估过程，这两个系统分别位于背侧和腹侧PFC，分别参照外部上下文线索或内部身体相关或动机线索实施行为控制，并且对雌激素和雄激素具有不同的敏感性。在接下来的5年里，我们计划通过使用专门的测试来测试我们的理论，这些测试招募PFC的目标区域，结合免疫分析来量化激素浓度、基因分型，以及潜在的大脑功能成像。我们将开始确定受影响的神经化学机制和特定的认知过程。我们期望在PFC中发现睾酮和雌二醇的作用之间的质的差异，我们预测，高水平的循环雌二醇将促进工作记忆和其他严重依赖背外侧皮质的功能，可能是通过多巴胺能机制。我们还打算继续我们早期的工作，使用虚拟环境来研究内侧颞叶部位雄激素驱动的影响。所有研究都涉及在自然生理条件下进行测试的人。这项工作将促进我们对人类中枢神经系统中受雄激素和雌激素影响的部位和功能过程的理解。如果预测的效果被发现，它将识别受类固醇影响的新的认知过程，并暗示PFC是一个作用场所。它将扩展目前处于神经内分泌科学前沿的理论，并允许我们对基于性别的男性和女性生物学有更全面的理解。

In the past 30 years, animal studies have shown that reproductive hormones have a wide range of effects in the central nervous system (CNS). For example, the hormone estradiol (major estrogen produced during a female's reproductive years) is a potent neuromodulator in several neurochemical systems, and its CNS effects manifest themselves as changes in behaviour, perception, and cognition. While animal data are plentiful, knowledge of hormonal effects in the human CNS is surprisingly sparse. This is an important and noteworthy theoretical gap, especially given the obvious relevance of such effects to understanding the CNS correlates of normal variations in hormone levels that occur over the lifespan (e.g. with aging) or in clinical conditions (e.g. androgen deprivation therapy for the treatment of prostate cancer). A rarity among Canadian researchers, my lab studies effects of androgens and estrogens in the normal human brain. Our past work suggests that reproductive steroids normally regulate a variety of cognitive, behavioural, appetitive, and affective functions, and may be dysregulated with aging or in certain mental health conditions. Bringing some of the evidence together, we recently hypothesized (Hampson, 2019) that the prefrontal cortex (PFC) is a key site of action in healthy adult brains--sex steroids may modulate certain cognitive or evaluative processes via effects on 2 partially distinct but interfacing regulatory control systems vested in the dorsal and ventral PFC that exert behavioural control by reference to external contextual cues or internal body-related or motivational cues respectively, and that are differentially sensitive to estrogens vs androgens. Over the next 5 years, we plan to test our theory by using specialized tests that recruit target regions of the PFC, combined with immunoassays to quantify hormone concentrations, genotyping, and potentially, functional brain imaging. We will begin to identify the neurochemical mechanisms and specific cognitive processes that are affected. We expect to find qualitative differences between the effects of testosterone vs estradiol in the PFC, and we predict that high circulating estradiol levels will facilitate working memory and other functions heavily dependent on the dorsolateral cortex, perhaps via a dopaminergic mechanism. We also aim to continue our earlier work using virtual environments to study androgen-driven effects at medial temporal lobe sites. All studies involve people tested under natural physiological conditions. This work will advance our understanding of the sites and functional processes that are influenced by androgens and estrogens in the human CNS. If the predicted effects are found, it will identify novel cognitive processes influenced by steroids and implicate the PFC as a site of action. It will expand theories currently at the forefront of neuroendocrine science, and allow us to develop a fuller understanding of male and female sex-based biology.