Glucocorticoid regulation of dopamine circuit function

糖皮质激素调节多巴胺回路功能

• 批准号: 10610046
• 负责人: Ashley Holloway
• 金额: $ 4.3万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2023-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10610046
• 关键词: Affect; Anhedonia; Astrocytes; Automobile Driving; Aversive Stimulus; Award; Behavior; Behavioral; Biochemical; Biological Assay; Biological Sciences; Brain; Buffers; Businesses; Cell Nucleus; Cells; Chronic; Communication; Complement; Corpus striatum structure; Corticosterone; Data; Development; Diagnosis; Dopamine; Electrophysiology (science); Environment; Exhibits; Fellowship; Female; Fiber; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Grant; Growth; Homeostasis; Hormonal; Hormones; Human; Hydrocortisone; Impairment; Individual; Knowledge; Learning; Light; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Mentorship; Midbrain structure; Molecular; Motivation; Mus; Nature; Neurons; Patients; Phosphorylation; Photometry; Physiology; Plasma; Play; Post-Translational Modification Alteration; Postdoctoral Fellow; Preparation; Process; Regulation; Research; Research Personnel; Research Project Grants; Rewards; Risk Factors; Rodent; Rodent Model; Role; Schools; Scientist; Sex Differences; Shapes; Signal Pathway; Signal Transduction; Site; Slice; Stress; Symptoms; Technical Expertise; Techniques; Training; Universities; Vacuum; Work; Writing; base; behavioral impairment; course development; dopamine transporter; dopaminergic neuron; experimental study; glucocorticoid receptor alpha; glucocorticoid-induced orphan receptor; hormonal signals; human female; in vivo; in vivo imaging; insight; male; neurochemistry; neurotransmission; new therapeutic target; nigrostriatal dopaminergic pathway; novel; optogenetics; post-doctoral training; receptor; receptor binding; response; reuptake; reward processing; skills; stress symptom; tenure track; transcription factor; transcriptome sequencing; transmission process

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.

项目摘要 压力沉淀并加剧了许多众多精神病，倾斜的抑郁症 （MDD）MDD的症状包括奖励处理中的缺陷 此外，Evronment。 啮齿动物中的皮质酮），相对于健康个体的血浆。 循环等离子体CORT的增加会导致MDD的症状，例如奖励处理中的缺陷。 多巴胺能信号在奖励处理中起着关键作用，从而阐明了该机制 压力会影响多巴胺能信号传导对于理解压力如何损害奖励处理和 有助于MDD的症状。 应激激素，皮质酮（人类的皮质醇）影响多巴胺能回路功能。 AIM 1.1中的初步数据表明，循环等离子体cort升高会损害寻求奖励的行为 通过损害背纹状体中的多巴胺体内平衡，通过改变后层次的变化 多巴胺转运蛋白的修改，dat。 对于Cort）作为转录因子，可能会导致Cort诱导的多巴胺转录变化 神经元可能会推动Cort对DAT功能1.2的影响，我将研究内源性，如何 循环Cort的水平升高会影响多巴胺神经元中GR诱导的基因表达。 研究可能会为寻找新的治疗靶标的搜索以治疗压力和 动机赤字。 该奖项下的培训计划整合了授予技巧的专业发展课程和 商业管理，以及基因编辑和基因表达的科学培训 大学非常适合大学，以促进申请人的出色专业发展 是商业研究生和生命科学的协作性质。 由于技术的范围 赞助商和共同赞助者之间的专业知识。 在生物医学劳动力及其他地区进行独立的杰出准备。