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

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，资源和监督的研究经验，这将有助于在行为免疫学和神经影像学的界面上发展独立的研究生涯。神经精神疾病（包括抑郁症）是一个重大的公共卫生问题，发生在高达50%的患者中，对治疗依从性、生活质量、发病率和死亡率有重大影响。越来越多的数据表明，外周免疫系统激活/炎症和相关的炎性细胞因子的释放可能在医学疾病以及医学健康个体中的神经精神疾病（包括抑郁症）的发展中起作用。然而，很少有研究已经检查了外周阐述的细胞因子对大脑的影响，特别是相关CNS细胞类型（包括神经元和神经胶质细胞）的代谢。拟议的研究和职业发展计划的长期目标是利用神经成像技术，如磁共振光谱（MRS），测量抑郁症期间外周炎症对大脑代谢的后果。为了实现这一目标，申请人提出了一个培训计划，其中包括：a）一套全面的行为神经科学、神经影像学和免疫学教学法，B）与主要导师和顾问进行一对一监督，以及c）实践监督研究经验。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引起的神经精神症状模型。导师实验室先前的工作已经确定，向人类施用IFN-α可靠地导致抑郁症状，同时诱导CNS炎症反应。因此，IFN-α提供了一个独特的模型系统，用于测试神经成像策略，如MRS，以确定可能参与炎症背景下发生的行为变化的代谢过程。拟议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将与胶质细胞活化和兴奋性神经传递的标记物增加相关，同时伴有神经元活力的标记物减少。这些CNS代谢变化反过来将与CNS炎症反应的激活和马尿酸诱导的兴奋毒性犬尿氨酸代谢物（包括喹啉酸）的增加相关。为了验证这些假设，将对50例成人丙型肝炎患者在IFN-α治疗前后进行研究。将通过单体素质子MRS测量相关脑区域（包括基底神经节）中神经胶质活化、兴奋性毒性和神经元功能障碍的生物标志物的浓度，并将其与免疫活化和犬尿氨酸代谢的血液和脑脊液生物标志物相关联。除了为细胞因子影响行为的机制提供重要见解外，这些数据还将为申请人制定独立研究计划提供基础。 公共卫生相关性：这个K23提案旨在促进申请人的职业发展，同时也探索新颖的大脑成像方法来研究免疫系统对大脑的影响。由激活的免疫系统释放的细胞因子与医学疾病和医学健康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脑代谢，并将脑代谢的变化与麻黄碱诱导的行为变化联系起来，从而探索这些作用的机制。

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.