The Neuroimmunology of Anhedonia

快感缺失的神经免疫学

基本信息

批准号：
9173878
负责人：
Vilma Gabbay
金额：
$ 7.09万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-28 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9173878
关键词：
3-aminobutyric acid Address Adolescent Adult Age Aminobutyric Acids Anhedonia Anterior Behavior Biological Markers Biology Blood Blood specimen Brain Characteristics Childhood Choline Classification Corpus striatum structure Data Depressed mood Diagnosis Dimensions Disease Enzymes Etiology Excitatory Neurotoxins Fostering Functional disorder Glutamates Heterogeneity Hour Hydrocortisone Image Imaging Techniques Immune system Inflammation Knowledge Kynurenic Acid Kynurenine Kynurenine 3-monooxygenase Laboratories Link Magnetic Resonance Spectroscopy Major Depressive Disorder Measurement Measures Mediating Membrane Mental Depression Mental disorders Mitochondria Morbidity - disease rate Myelin N-acetylaspartate National Institute of Mental Health Neurobiology Neuroglia Neuronal Dysfunction Neurons Neurophysiology - biologic function Neurotoxins Normal Range Oxidative Stress Pathway interactions Peripheral Pharmaceutical Preparations Phenotype Population Prevention Measures Protons Public Health Quinolinic Acid Recruitment Activity Reporting Rest Rewards Role Saliva Sampling Severities Severity of illness Symptoms System Testing Tryptophan Tryptophan 2,3 Dioxygenase Work Youth base child depression cingulate cortex cytokine density enzyme activity experience hypothalamic-pituitary-adrenal axis innovation insight interdisciplinary approach mitochondrial dysfunction mortality neurochemistry neuroimmunology neurotoxic neurotoxicity neurotransmission non-invasive imaging novel personalized intervention pleasure public health relevance relating to nervous system response reward circuitry symptom cluster treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Adolescent major depressive disorder (MDD) is a major public health concern associated with significant morbidity and mortality. The identification of neurobiological correlates of adolescent MDD has been hampered by the disorder's heterogeneity. To address this challenge, the proposed project adapts a dimensional investigative approach focusing on anhedonia - the loss of pleasure - a core symptom of MDD. Anhedonia can be easily quantified and is tied to specific neural reward circuitry. Among adolescents with MDD, anhedonia is highly variable, with its full range of severity manifesting in this group. These characteristics make anhedonia an ideal candidate for such an approach. Converging data from our laboratory and others' suggest that peripheral activation of the immune system/inflammation and associated CNS alterations mediate anhedonia. We have studied the kynurenine pathway (KP), a central neuroimmunological pathway, which is activated by cytokines and degrades tryptophan into several neurotoxins ("kynurenines"). We reported increased peripheral activation of the KP and neurotoxic load in highly anhedonic MDD adolescents compared to non-anhedonic and healthy control (HC) adolescents. Further, to assess KP-associated CNS alterations, we used proton MR spectroscopy (1H MRS), a non-invasive imaging technique that measures brain metabolites reflecting different aspects of neural function. We documented associations between blood KP neurotoxins and striatal choline (membrane turnover marker) levels along with decreased anterior cingulate cortex (ACC) 3- aminobutyric acid (GABA) levels in anhedonic MDD adolescents, which were correlated with anhedonia scores in the whole MDD group. Based on these preliminary data, we propose to test the overall hypothesis that peripheral activation of the immune system and accompanying neurometabolic alterations are specifically linked to anhedonia severity. To test our hypothesis, 60 depressed adolescents (psychotropic-free) and 40 HC, ages 12-18, Tanner e 4, will be studied. Anhedonia will be measured quantitatively. Blood samples for cytokines, KP metabolites (including quinolinic acid and 3-hydroxykynurenine), kynurenine 3-monooxygenase enzyme activity (initiates the KP neurotoxic branch), and saliva samples for cortisol measures will be collected at AM after an overnight fast. Within an hour, concentrations of neurometabolites reflecting neuronal viability, GABA, and membrane turnover will be measured in the ACC and striatum, regions within the neural reward circuitry, via 1H MRS.

描述（由申请人提供）：青少年重度抑郁症（MDD）是一个与显着发病率和死亡率相关的主要公共卫生问题。青少年 MDD 的神经生物学相关性的识别因该疾病的异质性而受到阻碍。为了应对这一挑战，拟议的项目采用了一种维度调查方法，重点关注快感缺乏——快乐的丧失——MDD的核心症状。快感缺失可以很容易地量化，并且与特定的神经奖励回路相关。在患有重度抑郁症的青少年中，快感缺乏差异很大，其严重程度在该群体中表现得很全面。这些特征使快感缺失成为这种方法的理想候选者。我们实验室和其他实验室的综合数据表明，免疫系统/炎症的外周激活以及相关的中枢神经系统改变介导了快感缺乏。我们研究了犬尿氨酸途径（KP），这是一种中枢神经免疫途径，它被细胞因子激活并将色氨酸降解为几种神经毒素（“犬尿氨酸”）。我们报告称，与非快感缺乏和健康对照（HC）青少年相比，高度缺乏快感的 MDD 青少年的 KP 外周激活和神经毒性负荷增加。此外，为了评估 KP 相关的 CNS 改变，我们使用质子 MR 光谱 (1H MRS)，这是一种非侵入性成像技术，可测量反映神经功能不同方面的大脑代谢物。我们记录了MDD青少年血液KP神经毒素和纹状体胆碱（膜转换标志物）水平以及前扣带皮层（ACC）3-氨基丁酸（GABA）水平降低之间的关联，这与整个MDD组的快感缺乏评分相关。基于这些初步数据，我们建议检验以下总体假设：免疫系统的外周激活和伴随的神经代谢改变与快感缺失的严重程度具体相关。为了检验我们的假设，将对 60 名抑郁症青少年（无精神药物）和 40 名 12-18 岁的 HC（Tanner e 4）进行研究。快感缺失将被定量测量。禁食过夜后，将在上午采集细胞因子、KP 代谢物（包括喹啉酸和 3-羟基犬尿氨酸）、犬尿氨酸 3-单加氧酶活性（启动 KP 神经毒性分支）的血液样本以及用于皮质醇测量的唾液样本。一小时内，将通过 1H MRS 测量 ACC 和纹状体（神经奖励回路内的区域）反映神经元活力、GABA 和膜更新的神经代谢物浓度。