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

描述(由申请者提供)：这份K23计划旨在为申请者提供受保护的时间、资源和受监督的研究经验，以促进行为免疫学和神经成像领域的独立研究生涯的发展。包括抑郁症在内的神经精神疾病是一个重大的公共卫生问题，高达50%的患者会发生这种疾病，并对治疗依从性、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，外周免疫系统的激活/炎症以及与之相关的炎性细胞因子的释放可能在包括抑郁症在内的神经精神疾病的发展中发挥作用，无论是在内科疾病还是在内科健康的个人中。然而，很少有研究研究外围阐述的细胞因子对大脑的影响，特别是相关的中枢神经系统细胞类型的代谢，包括神经元和胶质细胞。拟议的研究和职业发展计划的长期目标是利用磁共振波谱(MRS)等神经成像技术来衡量抑郁症期间外周炎症对大脑新陈代谢的影响。为了实现这一目标，申请者提出了一项培训计划，其中包括：a)行为神经科学、神经成像和免疫学方面的一套全面的教学方法；b)与主要导师和顾问进行一对一指导；以及c)实践指导下的研究经验。该研究项目旨在研究炎性细胞因子与行为之间的关系，并利用炎性细胞因子干扰素-α诱发神经精神症状的模型。导师实验室之前的工作已经证实，给人类注射α-干扰素可靠地导致抑郁症状，同时诱导中枢神经系统炎症反应。因此，干扰素-α提供了一种独特的模型系统，用于测试神经成像策略，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。这项研究的主要目的是验证这一假设，即干扰素-α诱导的行为和认知变化将与神经胶质激活和兴奋性神经传递标记物的增加有关，同时伴随着神经元存活标记物的减少。这些中枢神经系统代谢变化反过来将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产物(包括喹啉酸)的增加有关。为了验证这些假设，将对50名成年丙型肝炎患者进行干扰素-α治疗前后的研究。单体素质子磁共振波谱将测量包括基底节在内的相关脑区神经胶质细胞激活、兴奋性毒性和神经元功能障碍的生物标志物的浓度，并与免疫激活和犬尿氨酸代谢的血液和脑脊液生物标志物相关联。除了对细胞因子影响行为的机制提供重要的见解外，这些数据还将为申请者详细阐述独立的研究计划提供基础。 与公共健康相关：这份K23提案旨在促进申请者的职业发展，同时探索新的脑成像方法，以调查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患有内科疾病和内科健康的人的抑郁症的发展有关。这项拟议的研究将通过使用先进的神经成像技术来测量服用细胞因子前后的大脑代谢，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，从而探索这些效应的机制。

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.