Diversity Supplement for Nkatha Mwenda

Nkatha Mwenda 的多样性补充

• 批准号: 10577311
• 负责人: Talia Newcombe Lerner
• 金额: $ 16.27万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10577311
• 关键词: Adult; Adverse event; Affective; Animals; Anxiety Disorders; Behavior; Behavioral; Biological Models; Brain; Complex; Development; Disease; Dopamine; Economics; Emotional; Event; Exposure to; Fiber; Functional disorder; Imaging Techniques; Individual; Life; Link; Measures; Mediating; Medicine; Mental disorders; Midbrain structure; Mood Disorders; Motivation; Mus; Overdose; Persons; Photometry; Predisposition; Preventive measure; Problem behavior; Psychiatric therapeutic procedure; Risk; Societies; Stress; Structure; Substance abuse problem; Suicide; Symptoms; Testing; Therapeutic; Vision; Work; abuse neglect; adverse childhood events; awake; behavior test; biological adaptation to stress; childhood adversity; design; disorder risk; dopamine system; early life stress; high risk; high risk population; individual variation; insight; neglect; neural circuit; neuroregulation; optogenetics; resilience; response; sex; stressor

PROJECT SUMMARY/ABSTRACT Adverse childhood experiences (ACEs), such as abuse and neglect, have been strongly and consistently linked to increased risk for a variety of psychiatric diseases, including anxiety disorders, mood disorders, and substance abuse disorders. These diseases extract a massive emotional and economic toll on society, and their combination can be devastating and even deadly in cases of suicide and overdose. The increased risk for psychiatric disease following ACEs can persist for decades, well into adulthood, and combine with adult stressors to provoke the onset of symptoms. Despite the huge burden of psychiatric disease on our nation, and the clear impact of ACEs in producing that burden, we still have little understanding of the underlying neural circuits mediating increased psychiatric risk following adverse childhood experience. Why does stress during a window of early life confer elevated psychiatric disease risk? And why are some individuals nevertheless resilient? I hypothesize that stress during an early-life period of ongoing development in the midbrain dopamine system may alter the structure, and therefore function, of neuromodulation in the adult brain, dysregulating adult stress responses. Furthermore, I propose that individual variation in the dopamine circuit alterations produced by early life stress may explain individual variation in the later development of disease symptoms. This project will elucidate the neural circuit basis of susceptibility to psychiatric disease using mice as a model system. Mice of both sexes will be exposed to varying positive and negative early life conditions, and then tested for susceptibility or resilience to stress in adulthood using a panel of behavioral tests measuring affective function and motivation. Using cutting edge neural circuit imaging techniques, including CLARITY, optogenetics, and fiber photometry, I will ask whether the strength of specific brain connections in each individual subject is predictive of that subject’s susceptibility or resilience to stress. My CLARITY approach will allow me to search broadly and systematically for connections within the dopamine circuitry that are relevant to stress susceptibility, while my optogenetics and fiber photometry approach will allow me to track specific connection strengths in awake behaving animals before, during, and after the onset of behavioral changes. This project represents my vision of harnessing individual variation in behavior to gain insight into core circuit dysfunctions underlying polygenic and heterogeneously presenting psychiatric disorders. Together, the results from these studies will lead to understanding how the dopamine system regulates complex behaviors and will guide translational work to create sophisticated new circuit therapeutics for some of the most difficult problems in psychiatric medicine.

项目摘要/摘要 不良的童年经历(ACE)，如虐待和忽视，一直是强烈的和持续的 与各种精神疾病的风险增加有关，包括焦虑症、情绪障碍和 药物滥用障碍。这些疾病给社会造成了巨大的情感和经济损失，他们的 在自杀和服药过量的情况下，两者的结合可能是毁灭性的，甚至是致命的。增加的风险 ACEs后的精神疾病可持续数十年，一直持续到成年，并与成人应激源相结合。 以引起症状的出现。尽管精神疾病给我们的国家带来了巨大的负担， ACEs在产生这种负担方面的明显影响，我们仍然对潜在的神经了解很少 调节儿童不良经历后精神风险增加的回路。 为什么生命早期的压力会增加精神疾病的风险？为什么 一些人仍然很有弹性？我假设在生命早期持续的压力 中脑多巴胺系统的发育可能会改变神经元的结构，从而改变其功能 成人大脑中的神经调节，失调成人应激反应。此外，我建议 早期生活压力产生的多巴胺回路改变的个体差异可以解释 个体差异在疾病症状的后期发展。 这个项目将用小鼠作为一个研究对象来阐明精神疾病易感性的神经回路基础。 模型系统。不同性别的小鼠都将暴露在不同的积极和消极的早期生活条件中，并且 然后通过一组行为测试来测试成年后对压力的敏感性或弹性 情感功能和动机。使用尖端的神经电路成像技术，包括清晰度， 光遗传学和纤维光度学，我会问是否在每个特定的大脑连接强度 个体受试者能够预测受试者对压力的敏感度或韧性。我的明确方法将 请允许我广泛和系统地搜索多巴胺回路中与 压力易感性，而我的光遗传学和纤维光度学方法将使我能够跟踪特定的 清醒行为动物在行为变化发生之前、期间和之后的连接强度。 这个项目代表了我的愿景，即利用个人行为差异来洞察 核心回路功能障碍是多基因和异质性精神障碍的基础。 总而言之，这些研究的结果将有助于理解多巴胺系统如何调节 并将指导翻译工作，为一些人创造复杂的新电路疗法 精神医学中最难解决的问题。