Family Health Patterns: A Study Across Generations

项目总结 有酗酒家族史(FH+)的人酗酒的可能性是家族成员的4到8倍 与没有这种家族史的人相比，有精神障碍(AUD)的人。我们发展了家庭健康 模式项目，以表征FH+年轻成年人的风险相关表型特征。在我们最近的 在资助期间，我们已经确定了FH+早期生活逆境(ELA)增加与他们(A)之间的密切联系 迟钝的应激反应，(B)反社会倾向增加，(C)不良情绪调节，和(D)受损 认知表现。在我们的神经成像研究中，我们确定了额叶白质弥散率的变化。 FH+的年轻人和儿童的神经束，表明髓鞘形成和轴突损伤减少 潜在的神经回路。我们对这些集体发现的解读是，FH+的ELA增加 个体会导致持久的神经生物学变化和随之而来的行为效应，从而增加AUD的风险。 为了指导目前的提案，我们开发了一个启发式模型，说明ELA如何有助于风险相关 FH+人群的表型特征。我们认为，收敛的表观遗传和转录本 免疫基因的失调会增加炎症和免疫反应，从而损害髓鞘形成。 和/或损伤额叶白质束发育中的轴突。由此导致的与和的沟通受损 来自前额叶皮质有助于增加反社会倾向的表型特征 较差的影响调节和认知表现，增加AUD风险。在这里，我们建议通过以下方式测试此模型 检测炎性基因表达、免疫反应功能改变和脑白质 FH+和FH-青壮年的髓鞘水平和轴突损伤标志物。然后，我们将研究 这些变量具有ELA暴露和风险相关的表型特征。这项提议严谨地建立了 关于我们通过测试一个新的总体模型对FH+行为和生物学表型的广泛发现 澳元风险。虽然大量的临床前证据表明ELA导致了长期的失调 免疫系统和由此产生的神经和行为后遗症，我们的建议通过以下方式开辟了新的天地 使用先进的免疫学和多模式综合检查人类的这些关系 神经成像以及深入的行为和临床评估。

PROJECT SUMMARY Individuals with a family history of alcoholism (FH+) are 4 to 8 times more likely to develop an alcohol use disorder (AUD) compared to individuals with no such family histories. We developed the Family Health Patterns project to characterize risk-related phenotypic characteristics of FH+ young adults. During our recent funding period, we have identified robust links between increased early life adversity (ELA) in FH+ and their (a) blunted stress reactivity, (b) increased antisocial tendencies, (c) poor affect regulation, and (d) impaired cognitive performance. In our neuroimaging studies, we identified diffusivity changes in frontal white matter tracts in both FH+ young adults and children, suggesting decreased myelination and axon damage in underlying neural circuitry. We interpret these collective findings to suggest that increased ELA in FH+ individuals induces lasting neurobiological changes and consequent behavioral effects that increase AUD risk. To guide the present proposal, we developed a heuristic model of how ELA contributes to risk-related phenotypic characteristics in FH+ persons. We propose that convergent epigenetic and transcriptomic dysregulation of immune genes increase inflammation and immunoreactivity, thereby impairing myelination and/or damaging axons in developing frontal white matter tracts. The resulting impaired communication to and from the prefrontal cortex contributes to phenotypic characteristics of increased antisocial tendencies and poorer affect regulation and cognitive performance, increasing AUD risk. Here we propose to test this model by examining inflammatory gene expression, functional changes in immunoreactivity, and cerebral white matter myelin levels and axon damage markers in FH+ and FH– young adults. We will then examine relationships of these variables with ELA exposure and risk-related phenotypic characteristics. This proposal rigorously builds on our extensive findings on FH+ behavioral and biological phenotypes by testing a novel, overarching model of AUD risk. While extensive preclinical evidence exists illustrating ELA induces long-lasting dysregulation of the immune system and resulting neural and behavioral sequela, our proposal breaks new ground by comprehensively examining these relationships in humans using advanced immunology and multimodal neuroimaging together with in-depth behavioral and clinical assessments.