Androgens and Estrogens in the Human Nervous System

人类神经系统中的雄激素和雌激素

• 批准号: RGPIN-2020-04989
• 负责人: Hampson, Elizabeth
• 金额: $ 4.01万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=764034
• 关键词: Androgens; Estrogens; Human; Nervous; System

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.

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，雌性激素雌二醇（雌性在生育期产生的主要雌激素）是几种神经化学系统的有效神经调节剂，其对中枢神经系统的影响表现为行为、感知和认知的改变。虽然动物数据丰富，但关于激素对人类中枢神经系统影响的知识却少得惊人。这是一个重要的和值得注意的理论差距，特别是考虑到这些效应与理解在生命周期（例如随着衰老）或临床条件（例如用于治疗前列腺癌的雄激素剥夺疗法）中发生的激素水平正常变化的中枢神经系统相关性的明显相关性。我的实验室研究雄激素和雌激素对正常人大脑的影响，这在加拿大研究人员中是罕见的。我们过去的工作表明，生殖类固醇通常调节多种认知、行为、食欲和情感功能，并可能随着年龄增长或某些精神健康状况而失调。综合一些证据，我们最近假设（Hampson, 2019），前额叶皮层（PFC）是健康成人大脑中的一个关键作用部位——性类固醇可能通过影响位于PFC背侧和腹侧的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，这两个系统分别通过参考外部上下文线索或内部身体相关或动机线索来施加行为控制。它们对雌激素和雄激素的敏感性是不同的。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，这些测试可以招募PFC的目标区域，结合免疫测定来量化激素浓度，基因分型，以及潜在的功能脑成像。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。我们期望发现睾酮和雌二醇对PFC的影响之间的质的差异，我们预测高循环雌二醇水平将促进工作记忆和其他严重依赖背外侧皮层的功能，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的雄激素驱动效应。所有的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，它将确定受类固醇影响的新的认知过程，并暗示PFC是一个作用部位。它将扩展目前处于神经内分泌科学前沿的理论，并使我们能够更全面地了解男性和女性的性别生物学。