The Influence of Fetal Testosterone on Emotional Processing, Amydala Neurocircuitry, and Risk for Affective Disorders in Childhood

摘要 了解精神障碍的神经发育和早发性起源对于改善精神障碍的治疗至关重要。 提高儿童和青少年及其家庭的生活质量，并通过早期教育减轻社会负担 识别和干预。我的长期职业目标是成为一名资金充足的独立调查员 研究生物性别和激素在情感神经发育和儿童风险中的作用， 青少年情感障碍发作。胎儿激素可能具有永久性的组织效应， 性激素的基础，甚至可能限制，随后的组织和激活作用， 青春期的大脑回路因此，胎儿和青春期激素暴露的相互作用可能有助于 情感障碍风险的个体和性别差异。尽管我做了大量的研究 使用磁共振成像（MRI）方法研究典型神经发育的经验，目前 申请将为我提供评估情绪处理的多学科培训和指导 儿童和青少年的心理健康，以及招募和收集儿童和青少年的成像数据。 临床样本。该提案的具体研究目标允许通过以下方式发展这些技能 研究胎儿睾丸激素水平的增加如何影响情绪处理及其神经基质， 包括儿童的杏仁核及其与前额叶皮层的连接。为了实现这一目标，我将 通过研究具有导致高胎儿宫内窘迫的临床状况的患者来解决这些紧迫的问题 睾丸激素暴露，称为经典先天性肾上腺增生（CAH）。利用情感 扫描仪内外的行为任务，记录紧张性和阶段性心率和皮肤 电导活动，并实施多模态磁共振成像（MRI），我将调查 对40例CAH儿童（年龄10 - 15岁）的情绪加工、杏仁核和前额叶结构及连接进行了研究 8至12岁，50%的女孩）和40个对照组的年龄，性别和青春期早期成熟匹配。通过确定 胎儿睾丸激素如何影响儿童后期的情感神经发育， 研究将集中在纵向跟踪这些年轻人，以调查他们在中年时期的荷尔蒙变化。 青春期后期可能与胎儿激素程序相互作用，从而增加情感障碍的风险。长期 该提案的目标是加强和完善我在儿童和青少年精神病学，情感 神经科学、儿科临床神经影像学和内分泌学。最终，一个有指导的 职业发展奖将是建立一个富有成效的发展神经影像学的关键下一步 实验室致力于提高我们的理解，并创造更好的预防方案，个人， 以及在儿童和青春期开始出现的情感障碍风险方面的性别差异。

Abstract Understanding neurodevelopmental and early onset origins of mental disorders is essential to improve the quality of life for children and adolescents and their families, and to reduce societal burden through early identification and intervention. My long-term career goal is to become a fully funded, independent investigator to study the role of biological sex and hormones in emotional neurodevelopment and risk for childhood and adolescent onset of affective disorders. Fetal hormones may have permanent organizational effects that lay the foundation for, and may even limit, subsequent organizational and activational effects of sex hormones on brain circuits during puberty. Thus, the interaction of both fetal and pubertal hormone exposure may contribute to individual and sex-based differences in risk for affective disorders. Although I have extensive research experience studying typical neurodevelopment using magnetic resonance imaging (MRI) methods, the present application will provide me with multidisciplinary training and mentorship in assessing emotional processing and mental health in children and adolescents, as well as recruiting and collecting imaging data in pediatric clinical samples. The specific research aims of this proposal allow for development of these skillsets by investigating how increased fetal testosterone levels impact emotional processing and its neural substrates, including the amygdala and its connectivity with the prefrontal cortex, in children. To accomplish this goal, I will address these pressing questions by studying patients with a clinical condition that leads to high fetal testosterone exposure, known as classical Congenital Adrenal Hyperplasia (CAH). Utilizing emotional behavioral tasks both inside and outside the scanner, recording tonic and phasic heart rate and skin conductance activity, and implementing multi-modal magnetic resonance imaging (MRI), I will investigate emotional processing, as well as amygdala and prefrontal structure and connectivity in 40 CAH children (ages 8 to 12 years, 50% girls) and 40 controls matched for age, sex, and early pubertal maturity. By determining how fetal testosterone influences emotional neurodevelopment in late childhood in the current study, future research will focus on longitudinally following these youth to investigate how hormonal changes during mid-to- late puberty may interact with fetal hormonal programming to confer risk for affective disorders. Long-term goals of the proposal are to enhance and refine my training in child and adolescent psychiatry, affective neuroscience, pediatric clinical neuroimaging, and endocrinology. Ultimately, the opportunity of a mentored career development award will be a critical next step to building a productive developmental neuroimaging laboratory dedicated to improving our understanding of, and creating better prevention programs for, individual and sex differences in the risk for affective disorders that begin to emerge during childhood and adolescence.