Glucocorticoid regulation of dopamine circuit function

项目摘要 压力促使和加剧了许多精神疾病，包括重度抑郁症 （MDD）。MDD的症状包括奖励处理的缺陷，这会影响个体如何参与他们的活动。 环境此外，患有抑郁症的人表现出更高水平的“压力”，皮质醇（CORT; 啮齿类动物中的皮质酮），在其血浆中相对于健康个体。然而，目前尚不清楚， 循环血浆CORT的增加有助于MDD的症状，例如奖赏处理的缺陷。 多巴胺能信号在奖赏过程中起着关键作用，从而阐明了 压力影响多巴胺能信号传导对于理解压力如何损害奖励处理至关重要， 有助于MDD的诊断学。本项目的长期目标是通过以下方法阐明该机制： 这种应激激素皮质酮（人类的皮质醇）会影响多巴胺能回路的功能。 目标1.1中的初步数据表明，循环血浆CORT升高会损害奖励寻求行为 通过改变多巴胺的翻译后表达， 由于糖皮质激素受体（GR;一种受体）的作用， 对于CORT）作为一种转录因子，可能是CORT诱导的多巴胺转录变化 神经元可能驱动CORT对DAT功能的影响。在目标1.2中，我将研究内源性， 和升高水平的循环CORT影响多巴胺神经元中GR诱导的基因表达。结果 这些研究可能为寻找新的治疗靶点治疗应激诱导的 动机缺陷 该奖项下的培训计划整合了格兰披治的专业发展课程， 业务管理，在基因编辑和基因表达分析的科学培训。西北 大学非常适合促进申请人的优秀专业发展，因为 它的商业和生命科学研究生院的合作性质。申请人将在 研究金期间，由于技术范围广泛， 赞助商和共同赞助商之间的专业知识。总的来说，本奖项下的培训将为申请人提供 为在生物医学劳动力和其他领域的独立做好了出色的准备。

PROJECT ABSTRACT Stress precipitates and exacerbates numerous psychiatric disorders, including major depressive disorder (MDD). Symptoms of MDD include deficits in reward processing, which affect how individuals engage with their environment. Moreover, individuals with MDD exhibit higher levels of the ‘stress hormone’, cortisol (CORT; corticosterone in rodents), in their plasma relative to healthy individuals. However, it remains unclear if increased circulating plasma CORT contributes to symptoms of MDD, such as deficits in reward processing. Dopaminergic signaling plays a key role in reward processing, thus elucidating the mechanisms by which stress affects dopaminergic signaling is critical for understanding how stress impairs reward processing and contributes to the symptomology of MDD. The long-term goal of this project is to elucidate the mechanism by which the stress hormone, corticosterone (cortisol in humans), affects dopaminergic circuit function. Preliminary data in Aim 1.1 suggest that elevated circulating plasma CORT impairs reward-seeking behaviors by impairing dopamine homeostasis in the dorsomedial striatum via alteration of post-translational modifications on the dopamine transporter, DAT. Given the role of the glucocorticoid receptor (GR; a receptor for CORT) as a transcription factor, it’s possible that CORT-induced transcriptional changes in dopamine neurons may be driving the effect of CORT on DAT function. In Aim 1.2, I will investigate how endogenous, and elevated levels, of circulating CORT affect GR-induced gene expression in dopamine neurons. The results of these studies may inform the search for novel therapeutic targets for the treatment of stress-induced motivational deficits. The training plan under this award integrates professional development courses in grantsmanship and business management, with scientific training in gene editing and gene expression analysis. Northwestern University is well-suited to facilitate excellent professional development for the applicant due to the collaborative nature of its graduate schools in business and the life sciences. The applicant will conclude the fellowship period with expert training in multiple levels of scientific analysis due to the range of technical expertise between the sponsor and co-sponsor. Overall, training under this award will provide the applicant with exceptional preparation for independence in the biomedical workforce and beyond.