The Neuroimmunology of Anhedonia

描述（由申请人提供）：青少年重度抑郁症（MDD）是一种与显著发病率和死亡率相关的主要公共卫生问题。青少年重度抑郁症的神经生物学相关性的鉴定一直受到该疾病异质性的阻碍。为了应对这一挑战，拟议的项目采用了一种维度调查方法，专注于快感缺乏——快乐的丧失——重度抑郁症的核心症状。快感缺乏很容易被量化，并且与特定的神经奖赏回路有关。在患有重度抑郁症的青少年中，快感缺乏是高度可变的，其严重程度在该组中表现出来。这些特点使快感缺乏症成为这种方法的理想候选者。来自我们实验室和其他人的数据表明，免疫系统的外周激活/炎症和相关的中枢神经系统改变介导了快感缺乏症。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”）。我们报道了与非快感缺乏症和健康对照（HC）青少年相比，高度快感缺乏症MDD青少年的KP外周激活和神经毒性负荷增加。此外，为了评估与kp相关的中枢神经系统改变，我们使用了质子磁共振光谱（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脑代谢物。我们记录了血液KP神经毒素与纹状体胆碱（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组的缺乏症评分相关。基于这些初步数据，我们建议测试免疫系统的外周激活和伴随的神经代谢改变与快感缺乏严重程度特异性相关的总体假设。为了验证我们的假设，我们将研究60名抑郁青少年（无精神药物）和40名年龄在12-18岁的HC， Tanner e 4。快感缺乏症将被定量测量。血液样本中的细胞因子、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）和唾液样本中的皮质醇测量将在禁食一夜后的上午收集。在1小时内，通过1H MRS测量ACC和纹状体（神经奖赏回路内的区域）中反映神经元活力、GABA和膜更新的神经代谢物浓度。

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.