Glucocorticoid regulation of dopamine circuit function

项目摘要 压力会加速和加剧许多精神障碍，包括严重的抑郁障碍 (MDD)。MDD的症状包括奖励处理方面的缺陷，这会影响个人如何参与到他们的 环境。此外，患有MDD的个体表现出更高水平的“应激激素”，皮质醇(Cort； (啮齿动物体内的皮质酮)，相对健康个体的血浆中。然而，目前还不清楚是否 循环中血浆皮质醇的增加导致了MDD的症状，例如奖赏加工的缺陷。 多巴胺能信号在奖赏过程中起关键作用，从而阐明了 应激影响多巴胺能信号转导对于理解应激如何损害奖赏加工和 与MDD的症状有关。这个项目的长期目标是通过以下方式阐明这种机制 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。 Aim 1.1的初步数据表明，循环血浆皮质醇升高会损害寻求奖励的行为 通过翻译后改变损害背内侧纹状体的多巴胺稳态 对多巴胺转运体DAT的修饰。鉴于糖皮质激素受体(GR；A受体)的作用 对于皮质醇)作为一种转录因子，皮质醇可能会诱导多巴胺的转录变化 神经元可能驱动皮质醇对DAT功能的影响。在Aim 1.2中，我将研究内生性、 循环皮质醇水平升高会影响GR诱导的多巴胺神经元基因表达。结果是 这些研究可能有助于寻找治疗应激诱导的新的治疗靶点 动力不足。 这一奖项下的培训计划将专业发展课程整合在一起 企业管理，具有基因编辑和基因表达分析方面的科学培训。西北大学 大学非常适合为申请者提供优秀的专业发展，因为 其商业和生命科学研究生院的合作性质。申请人将得出以下结论： 研究金期间，由于技术分析的范围，专家将接受多层次的科学分析培训 赞助商和联合赞助商之间的专业知识。总的来说，该奖项下的培训将为申请者提供 在生物医学劳动力和其他领域为独立做好了特殊的准备。

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.