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、资源和受监督的研究经验，以促进行为免疫学和神经影像学领域独立研究事业的发展。包括抑郁症在内的神经精神疾病是严重的公共卫生问题，高达50%的患者出现这种疾病，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/炎症和相关的炎症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，无论是在医学上患病的个体还是在医学上健康的个体。然而，很少有研究检查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（包括神经元和胶质细胞）的代谢。提出的研究和职业发展计划的长期目标是利用神经成像技术，如磁共振波谱（MRS）来测量抑郁症期间外周炎症对脑代谢的影响。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)行为神经科学，神经影像学和免疫学方面的综合教学，b)与主要导师和顾问的一对一监督，以及c)实际监督研究经验。本研究项目旨在研究炎症细胞因子与行为之间的关系，并利用炎症细胞因子干扰素(IFN)- α诱发的神经精神症状模型。导师实验室之前的工作已经确定，给人注射ifn - α确实会引起抑郁症状，同时诱导中枢神经系统炎症反应。因此，IFN-alpha为测试神经成像策略（如MRS）提供了一个独特的模型系统，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验证ifn - α诱导的行为和认知变化与神经胶质激活和兴奋性神经传递标志物的增加有关，并伴有神经元活力标志物的降低。这些中枢神经系统代谢变化反过来又与中枢神经系统炎症反应的激活和细胞因子诱导的兴奋毒性犬尿氨酸代谢物（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ifn - α治疗前和治疗后的研究。在包括基底节在内的相关脑区，神经胶质激活、兴奋毒性和神经元功能障碍的生物标志物浓度将通过单体素质子MRS测量，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。除了对细胞因子影响行为的机制提供重要的见解外，这些数据将为申请人制定独立的研究计划提供基础。

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.