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

描述（由申请人提供）：该项目的重点是了解心理病理学中性别差异的机制。我们将研究性别差异的产前雄激素暴露对大脑和行为系统的积极和消极的效价。我们的长期目标是了解性相关的精神疾病风险是如何从身体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电路的发展，并负责对心理健康重要的功能域。产前雄激素被假设为有助于奖励（正价）和情绪记忆（负价）的神经基质。这一假设将在先天性肾上腺增生（CAH）的神经影像学研究中进行验证，CAH是一种遗传性疾病，在产前发育期间导致高雄激素水平。我们将比较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的磁共振成像（MRI），行为和自我报告的奖励和情绪记忆措施。两种性别都受到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别非典型性;因此，女性为雄激素效应的假设检验提供了极好的机会，而男性为CAH相关的非雄激素影响提供了控制，并能够探索雄激素效应的时间和剂量。我们预计，大脑结构和功能的方面，性别之间的差异将在妇女与没有CAH不同，我们研究这一点使用性别差异的措施奖励和情绪记忆系统和功能连接到前额叶皮层（PFC），和大脑结构。与未受影响的姐妹篇相比，患有CAH的女性应该具有（a）对高金钱奖励信号的线索的反应更快，并且在奖励呈现期间纹状体活动增加和纹状体-PFC连接减少，（B）对威胁/恐惧刺激的记忆减少，并且在准确回忆刺激的编码期间改变了侧杏仁核活动和减少了杏仁核-PFC连接，以及（c）男性较大区域的体积增加（杏仁核、下丘脑），女性较大区域体积减小（海马、灰质比例）。其结果将是确定产前生活的重要性，作为一个敏感时期的性别差异的精神疾病，通过显示产前雄激素如何影响电路负责两个性相关领域与性相关的疾病。CAH提供了一个有价值的罕见模型，以确定早期敏感期的重要性，不能很容易地在典型的样本中完成，因此，一个独特的机会，检查机制的基础性相关的精神病理学。未来的工作将集中在确定受青春期激素和性别社会环境影响的神经系统是如何被修改的。

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.