MR SPECTROSCOPY TO REVEAL CNS MECHANISMS OF CYTOKINE-INDUCED BEHAVIORAL CHANGE

MR 光谱揭示细胞因子诱导行为变化的中枢神经系统机制

• 批准号: 8081727
• 负责人: Ebrahim Haroon
• 金额: $ 17.66万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081727
• 关键词: Adult; Aspartate; Basal Ganglia; Behavior; Behavioral; Biological Markers; Biological Models; Blood; Blood specimen; Brain; Brain imaging; Brain region; Cerebrospinal Fluid; Choline; Chronic; Communicable Diseases; Data; Development; Development Plans; Disease; Excitatory Amino Acids; Fatigue; Foundations; Generations; Glutamate Metabolism Pathway; Glutamates; Glutamine; Goals; Hepatitis C; Human; Immune; Immune system; Immunology; Individual; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Inositol; Interferon-alpha; Interferons; Interleukin-6; Kynurenine; Laboratories; Laboratory Animals; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Malignant Neoplasms; Measures; Mental Depression; Mentors; Metabolic; Metabolism; Modeling; Monocyte Chemoattractant Protein-1; Morbidity - disease rate; Necrosis; Neuroglia; Neuronal Dysfunction; Neurons; Neuropsychological Tests; Neurosciences; Pathway interactions; Patients; Peripheral; Plasma; Play; Positron-Emission Tomography; Protons; Public Health; Quality of life; Quinolinic Acid; Research; Research Project Grants; Resources; Role; Sampling; Scanning; Signal Pathway; Spinal Puncture; Supervision; Symptoms; Technology; Testing; Time; Training; Virus Diseases; Work; behavior influence; brain metabolism; career; career development; cell type; cognitive change; cytokine; depressive symptoms; design; excitotoxicity; experience; glucose metabolism; imaging modality; immune activation; improved; inflammatory marker; insight; interferon alpha-1; interferon alpha4; mortality; neuroimaging; neuropsychiatry; neurotransmission; novel; peripheral blood; programs; public health relevance; receptor; research and development; treatment adherence; tumor

DESCRIPTION (provided by applicant): This K23 proposal is designed to provide the applicant with protected time, resources and a supervised research experience that will facilitate the development of an independent research career at the interface of behavioral immunology and neuroimaging. Neuropsychiatric disorders including depression in the medically ill are of significant public health concern, occurring in up to 50% of patients and having a major impact on treatment adherence, quality of life, morbidity and mortality. Mounting data indicate that peripheral immune system activation/inflammation and the associated release of inflammatory cytokines may play a role in the development of neuropsychiatric disorders including depression in the medically ill as well as in medically healthy individuals. Nevertheless, few studies have examined the impact of peripherally elaborated cytokines on the brain, especially the metabolism of relevant CNS cell types including both neurons and glia. The long- term objective of the proposed research and career development plan is to utilize neuroimaging technologies such as magnetic resonance spectroscopy (MRS) to measure the consequences of peripheral inflammation on brain metabolism during depression. To accomplish this goal, the applicant proposes a training plan which encompasses: a) a comprehensive set of didactics in behavioral neuroscience, neuroimaging and immunology, b) one-on-one supervision with a primary mentor and consultants, and c) a hands-on supervised research experience. The research project aims to study the association between inflammatory cytokines and behavior and makes use of the model of neuropsychiatric symptoms precipitated by the inflammatory cytokine, interferon (IFN)-alpha. Previous work in the mentor's laboratory has established that administration of IFN-alpha to humans reliably causes symptoms of depression while inducing a CNS inflammatory response. Thus, IFN-alpha provides a unique model system for testing neuroimaging strategies such as MRS to identify metabolic processes that may participate in behavioral changes that occur in the context of inflammation. The primary aim of the proposed research is to test the hypothesis that IFN-alpha-induced behavioral and cognitive changes will be associated with increased markers of glial activation and excitatory neurotransmission, accompanied by decreased markers of neuronal viability. These CNS metabolic changes in turn will be associated with activation of CNS inflammatory responses and cytokine-induced increases in excitotoxic kynurenine metabolites, including quinolinic acid. To test these hypotheses, 50 adult patients with hepatitis C will be studied pre- and post-IFN-alpha. Concentrations of biomarkers of glial activation, excitotoxicity and neuronal dysfunction in relevant brain regions including the basal ganglia will be measured by single voxel proton MRS and correlated with blood and cerebrospinal fluid biomarkers of immune activation and kynurenine metabolism. Aside from providing important insight into the mechanism by which cytokines influence behavior, these data will provide a foundation for the applicant's elaboration of an independent research program. PUBLIC HEALTH RELEVANCE: This K23 proposal is designed to promote the career development of the applicant, while also exploring novel brain imaging methods to investigate the impact of the immune system on the brain. Cytokines released by an activated immune system have been associated with the development of depression in both medically ill and medically healthy individuals. The proposed research will explore the mechanism of these effects by using advanced neuroimaging strategies to measure brain metabolism before and after cytokine administration and relate changes in brain metabolism to cytokine-induced changes in behavior.

描述（由申请人提供）：本 K23 提案旨在为申请人提供受保护的时间、资源和受监督的研究经验，这将有助于在行为免疫学和神经影像学领域独立研究事业的发展。包括医学疾病患者抑郁症在内的神经精神疾病是重大公共卫生问题，其发生率高达 50%，对治疗依从性、生活质量、发病率和死亡率产生重大影响。越来越多的数据表明，外周免疫系统激活/炎症以及相关的炎症细胞因子的释放可能在神经精神疾病（包括医学疾病患者和健康个体的抑郁症）的发展中发挥作用。然而，很少有研究探讨外周细胞因子对大脑的影响，特别是相关中枢神经系统细胞类型（包括神经元和神经胶质细胞）的代谢。拟议研究和职业发展计划的长期目标是利用磁共振波谱（MRS）等神经影像技术来测量抑郁症期间周围炎症对大脑代谢的影响。为了实现这一目标，申请人提出了一项培训计划，其中包括：a）行为神经科学、神经影像学和免疫学方面的一套全面的教学法，b）由主要导师和顾问进行的一对一监督，以及c）动手实践关于监督研究经验。该研究项目旨在研究炎症细胞因子与行为之间的关联，并利用炎症细胞因子干扰素 (IFN)-α 引发的神经精神症状模型。导师实验室之前的工作已经证实，对人类施用 IFN-α 确实会引起抑郁症状，同时诱发中枢神经系统炎症反应。因此，IFN-α 提供了一个独特的模型系统，用于测试神经影像学策略（例如 MRS），以识别可能参与炎症背景下发生的行为变化的代谢过程。本研究的主要目的是检验以下假设：IFN-α 诱导的行为和认知变化与神经胶质活化和兴奋性神经传递标志物增加有关，同时伴随着神经元活力标志物减少。这些中枢神经系统代谢变化反过来与中枢神经系统炎症反应的激活和细胞因子诱导的兴奋性犬尿氨酸代谢物（包括喹啉酸）的增加有关。为了检验这些假设，将对 50 名成年丙型肝炎患者在 IFN-α 治疗前和治疗后进行研究。将通过单体素质子 MRS 测量相关大脑区域（包括基底神经节）中神经胶质激活、兴奋性毒性和神经元功能障碍的生物标志物浓度，并将其与血液和脑脊液中免疫激活和犬尿氨酸代谢的生物标志物相关联。除了提供对细胞因子影响行为的机制的重要见解之外，这些数据还将为申请人制定独立研究计划提供基础。 公共健康相关性：这项 K23 提案旨在促进申请人的职业发展，同时还探索新颖的大脑成像方法来研究免疫系统对大脑的影响。激活的免疫系统释放的细胞因子与患有疾病和健康的个体的抑郁症的发展有关。拟议的研究将通过使用先进的神经影像学策略来测量细胞因子给药前后的大脑代谢，并将大脑代谢的变化与细胞因子诱导的行为变化联系起来，探索这些效应的机制。