Hippocampal and Genetic Mechanisms Underlying Development of Depression in Children at High Family Risk

项目总结 为什么一些患抑郁症的高危儿童会患上精神障碍，而另一些孩子则会保持精神病态-- 免费的？我的最终目标是阐明神经生物学、遗传和环境因素决定 情绪障碍高危儿童的脆弱性或恢复力，以便识别高危儿童 而且可以开发针对抑郁症的新干预措施。这一目标将通过培训和 通过K99/R00奖获得导师资格。初步结果表明，啮齿动物模型的研究结果 代际痛苦会在人类身上复制。具体地说，患有抑郁症和痛苦的父母的后代 有降低海马体结构、认知困难和抑郁症状的较高风险。这个 这项提案中的研究将检验这些啮齿动物模型的最新发现，即海马区的活动 确定对不良事件的敏感度和恢复力，转化为人类的精神病理风险 在一项针对患抑郁症高风险和低风险个体的多代家庭研究中。接下来，我将调查 累积遗传风险的测量是否可以预测海马区结构的个体差异 功能和抑郁症状。我将调查基于多基因风险的全基因组关联研究 分数，并且还推导出特定于改变的齿状齿的基于翻译表达的遗传风险分数 在易感小鼠和有弹性的小鼠中表达脑回基因，并将其应用于人类。最后，确定 海马体测量是否可以预测抑郁症的发生，调查与儿童的相互作用 环境，以及将研究结果扩展到大量不同的人口样本，我将在 青春期儿童大脑和认知发展研究。为了进行这项研究，我将收到 在哥伦比亚大学/纽约州精神病研究所进行的K99阶段培训 由导师和顾问组成的跨学科团队。我的培训将包括：静息状态功能磁共振分析；使用 用于分析大样本MRI数据的管道；计算多基因风险分数并将其纳入 神经影像和临床数据集；以及专业技能。在这个项目中获得的数据将为未来 R01在R00阶段的应用将决定儿童何时出现海马区异常 机制的出现，检查改变的海马体处理对连接的大脑区域和 利用遗传学的发现来发展一种关于异常海马体的分子变化的理论 功能。该项目将阐明高危儿童易患抑郁症的生物学机制。 并给我专业知识，让我成为整合遗传、神经和环境数据的领导者 研究精神病理学代际传播的物种。

PROJECT SUMMARY Why do some children at high risk for depression develop a disorder, while others remain psychopathology- free? My ultimate goal is to elucidate the neurobiological, genetic and environmental factors that determine vulnerability or resilience in children at risk for mood disorders, so that children at highest risk can be identified and new interventions against depression can be developed. This goal will be enabled by the training and mentorship obtained through this K99/R00 Award. Preliminary results show that findings from rodent models of intergenerational distress replicate in humans. Specifically, offspring of parents with depression and distress have decreased hippocampal structure, cognitive difficulties and a higher risk for depressive symptoms. The research in this proposal will examine if recent findings from these rodent models, that hippocampal activity determines susceptibility versus resilience to adverse events, translate to humans at risk for psychopathology in a multigenerational family study of individuals at high and low risk for depression. Next, I will investigate whether measures of cumulative genetic risk predict individual differences in hippocampal structure and function and depressive symptoms. I will investigate genome wide association studies-based polygenic risk scores and also derive a translational expression-based genetic risk score that is specific to altered dentate gyrus gene expression in susceptible versus resilient mice and apply it to humans. Lastly, to determine whether hippocampal measures predict onset of depression, investigate interactions with the childhood environment, as well as extend findings to a large diverse population sample, I will examine these questions in children from the Adolescent Brain and Cognitive Development Study. To carry out this research I will receive training during the K99 phase at Columbia University/New York State Psychiatric Institute from an interdisciplinary team of mentors and advisors. My training will include: resting-state fMRI analysis; using pipelines to analyze large samples of MRI data; calculating and incorporating polygenic risk scores into neuroimaging and clinical datasets; and professional skills. The data obtained in this project will lead to future R01 applications during the R00 phase that will determine when in childhood aberrant hippocampal mechanisms emerge, examine the effects of altered hippocampal processing on connected brain regions and use the genetic findings to develop a theory of the molecular changes underlying aberrant hippocampal function. This project will elucidate biological mechanisms of susceptibility to depression in high-risk children and give me the expertise to become a leader in integrating genetic, neural and environmental data across species to study intergenerational transmission of psychopathology.