Diversity Supplement for Nkatha Mwenda

项目总结/摘要 不良童年经历（ACE），如虐待和忽视，一直是强烈和一贯的 与各种精神疾病的风险增加有关，包括焦虑症，情绪障碍， 物质滥用障碍这些疾病对社会造成了巨大的情感和经济损失， 在自杀和过量服用的情况下，这种组合可能是毁灭性的，甚至是致命的。的风险增加 ACE后的精神疾病可持续数十年，直至成年，并与成人应激源结合联合收割机 引发症状尽管精神疾病给我们的国家带来了巨大的负担， ACE在产生这种负担方面的明显影响，我们仍然对潜在的神经系统功能知之甚少。 回路介导不良童年经历后增加的精神病风险。 为什么早期生活中的压力会增加精神疾病的风险？为什么要 有些人仍然有韧性？我假设，在生命早期的压力， 中脑多巴胺系统的发育可能会改变大脑的结构，从而改变大脑的功能。 成年人大脑中的神经调节，成年人压力反应失调。此外，我建议， 早期生活压力引起的多巴胺回路改变的个体差异可以解释 在后期疾病症状发展中的个体差异。 这个项目将阐明神经回路基础的易感性精神疾病使用小鼠作为一个 模型系统两种性别的小鼠将暴露于不同的阳性和阴性早期生活条件， 然后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。使用最先进的神经回路成像技术，包括可重复性， 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的强度 个体受试者可预测受试者对压力敏感性或恢复力。我的能力方法将 允许我广泛而系统地搜索多巴胺回路中的连接， 压力敏感性，而我的光遗传学和光纤测光方法将允许我跟踪特定的 连接强度在清醒的行为动物之前，期间和之后的行为变化的发病。 这个项目代表了我的愿景，即利用行为中的个体差异来洞察 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，并将指导翻译工作，为一些 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.