Immune System & Genetic Modulation of Brain Development & Behavior in Adolescence

摘要 免疫系统异常在几种精神疾病中被反复观察到，包括严重的抑郁症、双相情感障碍和精神分裂症。然而，目前尚不清楚这些改变是潜在的原因还是这些疾病的结果。本研究将探讨炎性标志物在功能和结构调节中的作用，这些炎症标志物受基因构成的调节 在精神障碍出现之前，整个青少年发育期的大脑系统和行为。我们将对160名高危青少年进行纵向研究，这些青少年的基线年龄在12岁到15岁之间，他们的父母被诊断为抑郁症，但他们自己还没有精神疾病诊断。这些儿童将与没有精神障碍家族史的同龄儿童(n=160)进行比较。我们将在五年内检测青少年血液中炎症标志物的水平，并通过使用高密度基因分型技术，将这些水平与免疫系统涉及的基因内的遗传变异相关联，以评估遗传构成在免疫信号中可能发挥的作用。同时，每个受试者将经历一系列的行为和 评估精神障碍的几个潜在风险标记物的生理学评估。这些评估包括：a)应激性生活事件；b)精神症状和障碍的临床评估；c)行为/个性特征的维度测量，包括情绪、焦虑、冲动和敌意；以及d)功能和结构神经成像。在提交拨款时，基线神经成像， 在320名青少年队列中收集并建立了DNA、血浆、淋巴细胞和永生化细胞系。在拟议的项目期间，将每年重新评估青少年，每两年重复两次神经成像方案。通过进行这些纵向研究，我们将能够确定免疫信号的变化是如何由基因构成和细胞周期调节的。 再加上在关键发育时期暴露于不利的环境经历，可能会导致大脑发育和行为的变化，进而可能导致疾病的发生。这些研究将有助于更好地理解精神障碍的发育起源，炎症可能在其中发挥重要作用。

ABSTRACT Immune system abnormalities have been repeatedly observed in several psychiatric disorders, including severe depression, bipolar disorder and schizophrenia. However, it is not clear whether these alterations are an underlying cause or occur as a result of these disorders. The present study will investigate the role that inflammatory markers, as modulated by genetic make-up, play on regulation of functional and structural brain systems and behavior across the adolescent developmental period, prior to onset of psychiatric disorders. We will perform a longitudinal study of 160 high-risk adolescents, between the ages of 12 and 15 years at baseline, who have a parent diagnosed with depression, but who do not yet themselves have a psychiatric diagnosis. These children, will be compared to a cohort of age matched children (n=160) who have no family history of psychiatric disorders. We will examine blood levels of inflammatory markers in the adolescents throughout five years, and will correlate these levels with genetic variations within genes involved in the immune system, by using high-density genotyping techniques, to assess the role that genetic make-up may play in immune signaling. In parallel, each subject will undergo a series of behavioral and physiologic evaluations to assess several potential risk markers for psychiatric disorders. These evaluations include: a) stressful life events; b) clinical assessment of psychiatric symptoms and disorders; c) dimensional measures of behavior/personality traits including mood, anxiety, impulsivity and hostility; and d) functional and structural neuroimaging. At the time of the grant submission, baseline neuroimaging, DNA, plasma, lymphocytes, and immortalized cell lines have been collected and established in the cohort of 320 adolescents. During the proposed project period, adolescents will be reassessed yearly with the neuroimaging protocol being repeated twice at two year intervals. By performing these longitudinal studies, we will be able to identify how changes in immune signaling, as modulated by genetic make-up and in combination with exposure to adverse environmental experiences during a critical developmental period, may lead to changes in brain development and behavior which may in turn lead to disease onset. These studies will lead to a better understanding of the developmental origins of psychiatric disorders in which inflammation may play an important role.