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

高家庭风险儿童抑郁症发展的海马和遗传机制

• 批准号: 10574571
• 负责人: Milenna Tamara van Dijk
• 金额: $ 12.77万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574571
• 关键词: Adolescent; Adverse event; Affect; Age; Award; Biological; Brain; Brain region; Child; Childhood; Classification; Clinical; Clinical Data; Clinical Research; Cognitive; Collection; DNA; Data; Data Set; Development; Diagnosis; Dimensions; Disease; Distress; Ensure; Environment; Environmental Risk Factor; Event; Exercise; Family; Family Study; Frequencies; Functional Magnetic Resonance Imaging; Future; Gene Expression; Gene Expression Profile; Generations; Genetic; Genetic Polymorphism; Genetic Risk; Goals; Hippocampus; Human; Hyperactivity; Impairment; Individual; Individual Differences; Intervention; Knowledge; Link; Longitudinal Studies; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Mediating; Mental Depression; Mentors; Mentorship; Methods; Modeling; Molecular; Mood Disorders; Mus; Neurobiology; Neurons; Neurophysiology - biologic function; New York; Outcome; Parents; Phase; Population; Population Heterogeneity; Predictive Factor; Predisposition; Preparation; Psychopathology; Recording of previous events; Research; Rest; Risk; Risk Estimate; Risk Factors; Rodent; Rodent Model; Sampling; Stimulus; Structure; Symptoms; Testing; Training; Translating; Universities; Variant; Work; Youth; adverse childhood events; blood oxygenation level dependent response; clinical phenotype; cognitive development; cohort; demographics; dentate gyrus; depressive behavior; depressive symptoms; disability; examination questions; experience; genome wide association study; high risk; high risk population; intergenerational; large datasets; mortality; mouse model; neural; neurogenesis; neuroimaging; novel; offspring; polygenic risk score; population based; resilience; response; risk prediction; sex; skills; theories; translational approach; transmission process

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.

项目摘要 为什么一些抑郁症高危儿童会发展成一种障碍，而另一些儿童则仍然是精神病理学- 免费？我的最终目标是阐明神经生物学，遗传和环境因素， 易患情绪障碍的儿童的脆弱性或复原力，以便确定最高风险儿童 可以开发新的抗抑郁干预措施。这一目标将通过培训和 通过K99/R 00奖获得的指导。初步结果显示，啮齿动物模型的研究结果 在人类身上复制。具体来说，患有抑郁症和痛苦的父母的后代 海马结构减少，认知困难和抑郁症状的风险更高。的 这项提议的研究将检验这些啮齿动物模型的最新发现， 决定了对不良事件的敏感性与弹性，转化为精神病理学风险的人类 在一项多代家庭研究中，研究对象是抑郁症高危和低危人群。接下来，我将调查 累积遗传风险的测量是否可以预测海马结构的个体差异， 功能和抑郁症状。我将调查基于全基因组关联研究的多基因风险 评分，并且还推导出对改变的齿状突起特异的基于翻译表达的遗传风险评分。 脑回基因在易感小鼠和恢复小鼠中的表达，并将其应用于人类。最后，确定 海马测量是否预测抑郁症的发作，调查与儿童的相互作用， 环境，以及扩大调查结果，以大量不同的人口样本，我将研究这些问题， 青少年大脑和认知发展研究的儿童。为了进行这项研究，我将收到 在哥伦比亚大学/纽约州立精神病研究所的K99阶段， 跨学科的导师和顾问团队。我的培训将包括：静息状态功能磁共振成像分析;使用 分析MRI数据的大样本的管道;计算并将多基因风险评分纳入 神经成像和临床数据集;和专业技能。该项目获得的数据将导致未来 R 00阶段期间的R 01应用将决定儿童时期异常海马的时间 机制出现，检查海马处理改变对连接的大脑区域的影响， 利用遗传学的发现来发展一个关于异常海马神经元的分子变化的理论 功能这个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，使我成为整合遗传，神经和环境数据的领导者。 研究精神病理学的代际传递。