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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）是一个主要的公共卫生问题，与显著的发病率和死亡率相关。青少年抑郁症的神经生物学相关性的识别受到障碍的异质性的阻碍。为了应对这一挑战，拟议的项目采用了一个维度的调查方法，重点是快感缺失-快乐的丧失-MDD的核心症状。快感缺失可以很容易地量化，并与特定的神经奖励回路有关。在患有MDD的青少年中，快感缺乏是高度可变的，其严重程度在该组中表现得淋漓尽致。这些特征使快感缺乏成为这种方法的理想候选者。来自我们实验室和其他实验室的汇总数据表明，免疫系统/炎症的外周激活和相关的CNS改变介导快感缺乏。我们已经研究了犬尿氨酸途径（KP），一种中枢神经免疫途径，其被细胞因子激活并将色氨酸降解成几种神经毒素（“犬尿氨酸”）。我们报道了与非快感缺乏和健康对照（HC）青少年相比，高度快感缺乏的MDD青少年的KP和神经毒性负荷的外周激活增加。此外，为了评估KP相关的CNS改变，我们使用了质子磁共振波谱（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脑代谢物。我们记录了血液KP神经毒素和纹状体胆碱（膜转换标志物）水平沿着的相关性，以及快感缺失型MDD青少年前扣带皮层（ACC）3-氨基丁酸（GABA）水平的降低，这与整个MDD组的快感缺失评分相关。基于这些初步的数据，我们建议测试的整体假设，外周激活的免疫系统和伴随的神经代谢的改变是专门联系到快感缺乏的严重程度。为了验证我们的假设，60名抑郁症青少年（无精神药物）和40名HC，年龄12-18岁，坦纳e 4，将进行研究。将对快感缺乏进行定量测量。过夜禁食后，将在上午采集用于细胞因子、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）的血液样本和用于皮质醇测量的唾液样本。在一小时内，将通过1H MRS在ACC和纹状体（神经奖励回路内的区域）中测量反映神经元活力、GABA和膜周转的神经代谢物浓度。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increased ventricular cerebrospinal fluid lactate in depressed adolescents.

DOI：
10.1016/j.eurpsy.2015.08.009
发表时间：
2016-02
期刊：
European psychiatry : the journal of the Association of European Psychiatrists
影响因子：
0
作者：
Bradley KA;Mao X;Case JA;Kang G;Shungu DC;Gabbay V
通讯作者：
Gabbay V

The role of the kynurenine pathway in suicidality in adolescent major depressive disorder.

Kynurenine途径在青春期重度抑郁症中的自杀性中的作用。

DOI：
10.1016/j.psychres.2015.03.031
发表时间：
2015-06-30
期刊：
PSYCHIATRY RESEARCH
影响因子：
11.3
作者：
Bradley, Kailyn A. L.;Case, Julia Ac.;Khan, Omar;Ricart, Thomas;Hanna, Amira;Alonso, Carmen M.;Gabbay, Vilma
通讯作者：
Gabbay, Vilma

Functional domains as correlates of suicidality among psychiatric inpatients.