Family Health Patterns: A Study Across Generations

项目摘要 有酒精中毒家族史的人（FH+）发展酒精使用的可能性是其他人的4到8倍。 与没有此类家族史的个体相比，AUD。我们开发了家庭健康 用于表征FH+年轻成人风险相关表型特征的模式。在我们最近的 在资助期间，我们已经确定了FH+中早期生活逆境（ELA）增加与其（a） 迟钝的应激反应，（B）增加的反社会倾向，（c）不良的情绪调节，和（d）受损 认知绩效在我们的神经影像学研究中，我们确定了额叶白色物质的扩散性变化， 在FH+的年轻人和儿童中，神经束的髓鞘形成和轴突损伤减少， 潜在的神经回路我们解释这些集体研究结果表明，FH+中ELA增加 个体诱导持久的神经生物学变化和随之而来的行为影响，增加AUD风险。 为了指导本提案，我们开发了一个启发式模型，说明ELA如何有助于风险相关的 FH+患者的表型特征。我们认为，趋同的表观遗传和转录组 免疫基因的失调增加炎症和免疫反应性，从而损害髓鞘形成 和/或损害发育中的额叶白色物质束中的轴突。由此造成的沟通障碍， 前额叶皮层的活动有助于增加反社会倾向的表型特征， 情绪调节和认知表现较差，增加AUD风险。在这里，我们建议测试这个模型， 检查炎症基因表达、免疫反应性和大脑白色物质的功能变化 FH+和FH-年轻成人中的髓鞘水平和轴突损伤标志物。然后，我们将研究 这些变量与ELA暴露和风险相关的表型特征。该提案严格建立了 通过测试一种新的总体模型，我们对FH+行为和生物表型的广泛发现 澳元风险。虽然存在大量的临床前证据表明ELA诱导了长期的 免疫系统和由此产生的神经和行为后遗症，我们的建议开辟了新的领域， 利用先进的免疫学和多模式免疫学， 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.