The Neuroimmunology of Anhedonia

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。 公共卫生相关性：目前的项目提出了一个综合的调查策略，利用免疫学和神经化学成像方法来检查神经生物学的快感缺失-快乐的损失-在抑郁的青年。我们专注于快感缺失作为一个连续的和定量的症状，解决了目前的抑郁症分类模式的挑战，这是完全基于一组症状，往往与其他疾病重叠，并代表不同的病因。这种跨学科的方法有望为青少年抑郁症和快感缺乏相关的推定途径提供新的见解，并可能为治疗策略和预防措施提供新的靶点。

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. PUBLIC HEALTH RELEVANCE: The current project proposes an integrated investigative strategy utilizing immunological and neurochemical imaging approaches to examine the neurobiology of anhedonia - the loss of pleasure - in depressed youth. Our focus on anhedonia as a continuous and quantitative symptom addresses the challenges of the current categorical classification schema of depression, which is based exclusively on a cluster of symptoms that often overlap with other disorders and represent distinct etiologies. This interdisciplinary approach is expected to provide novel insights into putative pathways associated with depression and anhedonia in adolescents and may provide novel targets for treatment strategies and prevention measures.