The Neuroimmunology of Anhedonia

描述(由申请人提供)：青少年严重抑郁障碍(MDD)是一个与严重的发病率和死亡率相关的重大公共卫生问题。青春期MDD的异质性阻碍了神经生物学相关因素的识别。为了应对这一挑战，拟议的项目采用了一种维度调查方法，重点关注快感缺失--快感丧失--MDD的核心症状。快感缺乏症可以很容易地量化，并与特定的神经奖励回路联系在一起。在患有MDD的青少年中，快感缺乏症是高度可变的，其严重程度全方位地表现在这一组中。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实验室的聚合数据表明，免疫系统/炎症的外周激活和相关的中枢神经系统变化介导了快感缺失。我们研究了犬尿氨酸途径(KP)，这是一种中枢神经免疫途径，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”)。我们报告了高度缺乏快感的MDD青少年与非快感和健康对照(HC)青少年相比，外周KP的激活和神经毒性负荷的增加。此外，为了评估KP相关的中枢神经系统改变，我们使用了质子磁共振波谱(1HMRS)，这是一种非侵入性成像技术，测量反映神经功能不同方面的大脑代谢物。我们记录了无快感MDD青少年血液KP神经毒素与纹状体胆碱(膜翻转标志物)水平以及前扣带回(ACC)3-氨基丁酸(GABA)水平降低的关系，这与整个MDD组的快感缺乏评分相关。基于这些初步数据，我们建议检验免疫系统的外周激活和伴随的神经代谢变化与快感缺失严重程度特别相关的总体假设。为了验证我们的假设，将对60名抑郁青少年(非精神药物)和40名HC进行研究，他们年龄在12-18岁之间，年龄在4岁之间。快感缺乏症将被定量测量。细胞因子、KP代谢物(包括喹啉酸和3-羟基尿氨酸)、犬尿氨酸3-单加氧酶活性(启动KP神经毒性分支)和唾液皮质醇测定的血样将在隔夜禁食后在AM采集。在一小时内，将通过1HMRS测量反映神经元活性、GABA和膜翻转的神经代谢物的浓度在ACC和纹状体，这是神经回报回路中的区域。

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.