Ho Tiffany C, Teresi Giana I, Segarra Jillian R, Ojha Amar, Walker Johanna C, Gu Meng, Spielman Daniel M, Sacchet Matthew D, Jiang Fei, Rosenberg-Hasson Yael, Maecker Holden, Gotlib Ian H
Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States.
Department of Psychology, Stanford University, Stanford, CA, United States.
Front Psychiatry. 2021 Apr 15;12:642976. doi: 10.3389/fpsyt.2021.642976. eCollection 2021.
Animal models of stress and related conditions, including depression, have shown that elevated peripheral levels of inflammatory cytokines have downstream consequences on glutamate (Glu) in the brain. Although studies in human adults with depression have reported evidence of higher inflammation but lower Glu in the anterior cingulate cortex (ACC), the extent to which peripheral inflammation contributes to glutamatergic abnormalities in adolescents with depression is not well-understood. It is also unclear whether antioxidants, such as ascorbate (Asc), may buffer against the effects of inflammation on Glu metabolism. Fifty-five depressed adolescents were recruited in the present cross-sectional study and provided blood samples, from which we assayed pro-inflammatory cytokines, and underwent a short-TE proton magnetic spectroscopy scan at 3T, from which we estimated Glu and Asc in the dorsal ACC. In the 31 adolescents with usable cytokine and Glu data, we found that IL-6 was significantly positively associated with dorsal ACC Glu (β = 0.466 ± 0.199, = 0.029). Of the 16 participants who had usable Asc data, we found that at higher levels of dorsal ACC Asc, there was a negative association between IL-6 and Glu (interaction effect: β = -0.906 ± 0.433, = 0.034). Importantly, these results remained significant when controlling for age, gender, percentage of gray matter in the dorsal ACC voxel, BMI, and medication (antidepressant and anti-inflammatory) usage. While preliminary, our results underscore the importance of examining both immune and neural contributors to depression and highlight the potential role of anti-inflammatory compounds in mitigating the adverse effects of inflammation (e.g., glutamatergic neuroexcitotoxicity). Future studies that experimentally manipulate levels of inflammation, and of ascorbate, and that characterize these effects on cortical glutamate concentrations and subsequent behavior in animals and in humans are needed.
应激及相关病症（包括抑郁症）的动物模型表明，外周炎症细胞因子水平升高会对大脑中的谷氨酸（Glu）产生下游影响。尽管针对成年抑郁症患者的研究报告显示，前扣带回皮质（ACC）存在炎症加剧但Glu水平降低的证据，但外周炎症在青少年抑郁症患者谷氨酸能异常中所起的作用程度尚不清楚。同样不清楚的是，抗氧化剂（如抗坏血酸（Asc））是否可以缓冲炎症对Glu代谢的影响。在本横断面研究中招募了55名抑郁症青少年，他们提供了血液样本，我们从中检测促炎细胞因子，并在3T条件下进行了短TE质子磁共振波谱扫描，从中我们估计了背侧ACC中的Glu和Asc。在31名有可用细胞因子和Glu数据的青少年中，我们发现白细胞介素-6（IL-6）与背侧ACC中的Glu显著正相关（β = 0.466 ± 0.199，P = 0.029）。在16名有可用Asc数据的参与者中，我们发现背侧ACC中Asc水平较高时，IL-6与Glu之间存在负相关（交互作用效应：β = -0.906 ± 0.433，P = 0.034）。重要的是，在控制年龄、性别、背侧ACC体素中的灰质百分比、体重指数和药物（抗抑郁药和抗炎药）使用情况后，这些结果仍然显著。虽然是初步结果，但我们的研究结果强调了研究免疫和神经因素对抑郁症影响的重要性，并突出了抗炎化合物在减轻炎症不良反应（如谷氨酸能神经兴奋毒性）方面的潜在作用。未来需要进行实验性调节炎症水平和抗坏血酸水平，并描述这些对动物和人类皮质谷氨酸浓度及后续行为影响的研究。
