Diversity Supplement for Nkatha Mwenda

项目概要/摘要 不良童年经历（ACE），例如虐待和忽视，一直以来都受到强烈和持续的关注。 与多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。这些疾病给社会带来了巨大的情感和经济损失， 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 ACE 后的精神疾病可能持续数十年，直至成年，并与成人压力源相结合 引发症状。尽管精神疾病给我们国家带来了巨大的负担， ACE 在产生这种负担方面有明显的影响，但我们对潜在的神经机制仍然知之甚少。 不良童年经历后介导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？为什么是 有些人仍然有弹性吗？我假设生命早期阶段的压力持续存在 中脑多巴胺系统的发育可能会改变其结构，从而改变其功能 成人大脑的神经调节，调节成人的应激反应。此外，我建议 早期生活压力造成的多巴胺回路改变的个体差异可以解释 疾病症状后期发展的个体差异。 该项目将利用小鼠作为研究对象，阐明精神疾病易感性的神经回路基础。 模型系统。两种性别的小鼠都会暴露在不同的积极和消极的早期生活条件下，并且 然后使用一组行为测试来测试成年后对压力的敏感性或恢复力 情感功能和动机。使用尖端的神经回路成像技术，包括 CLARITY、 光遗传学和光纤光度测定法，我会问每个特定大脑连接的强度是否 个体受试者可以预测该受试者对压力的敏感性或恢复力。我的清晰方法将 让我广泛而系统地搜索多巴胺电路内与以下内容相关的连接： 压力敏感性，而我的光遗传学和光纤光度测量方法将使我能够跟踪特定的 清醒行为动物在行为改变发生之前、期间和之后的连接强度。 这个项目代表了我利用个体行为差异来深入了解 核心回路功能障碍是多基因和异质性精神疾病的基础。 总之，这些研究的结果将有助于了解多巴胺系统如何调节 复杂的行为，并将指导转化工作，为一些人创造复杂的新回路疗法 精神医学中最困难的问题。

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.