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反复观察到，包括严重抑郁症、双相情感障碍和精神分裂症。然而，目前尚不清楚这些变化是潜在原因还是这些疾病的结果。本研究将探讨炎症标志物在遗传组成的调控下，在调节细胞功能和结构方面的作用。 大脑系统和行为在整个青少年发展时期，在精神疾病发作之前。我们将对160名高危青少年进行纵向研究，基线年龄在12岁至15岁之间，他们的父母被诊断患有抑郁症，但他们自己还没有精神病诊断。将这些儿童与年龄匹配的无精神疾病家族史的儿童（n=160）队列进行比较。我们将在五年内检查青少年的血液炎症标志物水平，并将这些水平与免疫系统相关基因内的遗传变异相关联，通过使用高密度基因分型技术，评估遗传组成在免疫信号传导中可能发挥的作用。同时，每个受试者将接受一系列行为和 生理学评估，以评估精神疾病的几个潜在风险标志物。这些评价包括：a）压力性生活事件; B）精神症状和障碍的临床评估; c）行为/人格特征的维度测量，包括情绪、焦虑、冲动和敌意;和d）功能和结构神经成像。在提交资助的时候，基线神经成像， DNA，血浆，淋巴细胞和永生化细胞系已收集和建立在队列的320名青少年。在拟议的项目期间，将每年对青少年进行重新评估，每两年重复两次神经影像学方案。通过进行这些纵向研究，我们将能够确定免疫信号的变化，如遗传组成和免疫调节， 与在关键发育期暴露于不良环境经历相结合，可能导致大脑发育和行为的变化，这反过来可能导致疾病发作。这些研究将导致更好地了解炎症可能发挥重要作用的精神疾病的发育起源。

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.