Prenatal androgen effects on sex-related neural processing of reward and threat

描述(由申请者提供)：这个项目的重点是了解精神病理学中潜在的性别差异的机制。我们将研究不同性别的产前雄激素暴露对正价和负价的大脑和行为系统的影响。我们的长期目标是了解精神疾病的性相关风险是如何从生理性别分化和社会化过程的相互作用中发展起来的。在这 第一步，我们的目标是确定产前雄激素如何促进显示性别差异的回路的发育，并负责对心理健康至关重要的功能区。出生前的雄激素被认为对奖赏(正价)和情绪记忆(负价)的神经底物有贡献。这一假设将在先天性肾上腺增生症(CAH)的神经成像研究中得到验证。先天性肾上腺增生症是一种遗传性疾病，会在产前发育期间导致高雄激素水平。我们将对20名女性和20名男性CAH患者与他们的同性未受影响的兄弟姐妹在磁共振成像(MRI)、行为和自我报告奖励和情感记忆方面进行比较。男性和女性都会受到CAH的影响，但女性比男性表现出更多的行为影响，因为她们的雄激素水平更具性行为非典型性；因此，女性为雄激素效应的假设检验提供了一个极好的机会，而男性则提供了与CAH相关的非雄激素影响的控制，并使探索雄激素效应的时间和剂量成为可能。我们预计患有和不患有CAH的女性在大脑结构和功能方面的性别差异将有所不同，我们使用性别区分的奖励和情绪记忆系统以及与前额叶皮质(PFC)的功能连接和大脑结构来研究这一点。与未受影响的姐妹相比，患有CAH的女性应该有：(A)在奖励呈现时，对发出高金钱奖励信号的暗示做出更快的反应，纹状体活动增加，纹状体-PFC连接减少；(B)对威胁/恐惧刺激的记忆减少，在准确回忆刺激的编码过程中，杏仁核活动改变，杏仁核-PFC连接减少；以及(C)男性较大区域(杏仁核、下丘脑)的体积增加，女性较大区域(海马体，灰质比例)的体积减少。其结果将是通过展示产前雄激素如何影响负责与性相关障碍相关的两个性相关领域的回路，来确定产前生活作为精神障碍性别差异敏感期的重要性。CAH提供了一个宝贵的罕见模型来确定早期敏感期的重要性，这在典型样本中是不容易完成的，因此也是一个独特的机会来检验性相关精神病理学的潜在机制。未来的工作将集中在确定青春期荷尔蒙和性别化的社会环境如何影响荷尔蒙影响的神经系统。

DESCRIPTION (provided by applicant): This project is focused on understanding mechanisms underlying sex differences in psychopathology. We will study effects of sex-differential prenatal androgen exposure on brain and behavioral systems of positive and negative valence. Our long-term goal is to understand how sex-related risk for mental illness develops from the interplay of physical sexual differentiation and socialization processes. In this initial step, our objective is to determine how prenatal androgens contribute to the development of circuits that show sex differences and that are responsible for functional domains important for mental health. Prenatal androgens are hypothesized to contribute to neural substrates of reward (positive valence) and emotional memory (negative valence). This hypothesis will be tested in a neuroimaging study in congenital adrenal hyperplasia (CAH), a genetic disorder causing high androgen levels during prenatal development. We will compare 20 women and 20 men with CAH to their same-sex unaffected siblings on magnetic resonance imaging (MRI), behavioral, and self-report measures of reward and emotional memory. Both sexes are affected by CAH, but females show more behavioral effects than males because their androgen levels are more sex-atypical; females thus provide an excellent opportunity for hypothesis-testing of androgen effects, whereas males provide control for non- androgen influences related to CAH, and enable exploration about timing and dose of androgen effects. We expect that aspects of brain structure and function that differ between sexes will differ in women with vs. without CAH, and we study this using sex-differentiated measures of reward and emotional memory systems and functional connections to prefrontal cortex (PFC), and brain structure. Compared to unaffected sisters, women with CAH should have (a) faster response to cues signaling high monetary rewards, and increased striatal activity and decreased striatum-PFC connectivity during reward presentation, (b) reduced memory for threat/fear stimuli, and altered lateralized amygdala activity and reduced amygdala-PFC connectivity during encoding of accurately-recalled stimuli, and (c) increased volume in regions larger in men (amygdala, hypothalamus), and reduced volume in regions larger in women (hippocampus, proportion of gray matter). The outcome will be to identify the importance of prenatal life as a sensitive period for sex differences in psychiatric disorders, by showing how prenatal androgens influence circuits responsible for two sex-related domains linked to sex-related disorders. CAH provides a valuable rare model to determine the importance of early sensitive periods that cannot easily be accomplished in typical samples, and thus a unique opportunity to examine mechanisms underlying sex-related psychopathology. Future work will focus on identifying how hormonally-influenced neural systems are modified by pubertal hormones and gendered social environments.