Alterations in dopamine (DA) signaling and reductions in functional connectivity (FC; a measure of temporal correlations of activity between different brain regions) within dopaminergic reward pathways are implicated in the etiology of psychopathology and have been associated with increased concentrations of inflammatory markers, including C-reactive protein. Peripheral and central inflammatory cytokines that have been shown to disrupt DA signaling and corticostriatal FC are associated with C-reactive protein, an acute phase reactant that is used translationally as a marker of systemic inflammation. One factor that can significantly increase systemic inflammation to produce neuroadaptations in reward pathways is a diet that results in fat mass accumulation (e.g. obesogenic diet). The current study in female rhesus monkeys maintained in a standard laboratory chow (n=18) or on obesogenic diet (n=16) for 12-months tested the hypothesis that an obesogenic diet would alter central DA and homovanillic acid (HVA) concentrations, and be associated with increased CRP concentrations and decreased FC between corticostriatal regions at 12-months following dietary intervention. We specifically assessed FC between the nucleus accumbens (NAcc) and two sub-regions of the prefrontal cortex (PFC) previously associated with CRP concentrations, the ventromedial PFC (vmPFC) and the orbitofrontal cortex (OFC), which are also involved in emotional and motivational salience assessment, and in goal-directed behavior, impulse control and the salience/value of food, respectively. Results showed that CSF DA concentrations were decreased (p=0.002), HVA:DA ratios were increased (p=0.016), and body mass index was increased (p=0.047) over the 12-months of consuming an obesogenic diet. At 12-months, females maintained in the obesogenic diet exhibited higher CRP concentrations than females consuming chow-only (p=0.008). Linear regression analyses revealed significant CRP by dietary condition interactions on DA concentrations (β=-5.10; p=0.017) and HVA:DA ratios (β=5.14; p=0.029). Higher CRP concentrations were associated with lower CSF DA concentrations (r=-0.69; p=0.004) and greater HVA:DA ratios only in females maintained in the obesogenic dietary condition (r=0.58; p=0.024). Resting-state magnetic resonance neuroimaging (rs-fMRI) in a subset of females from each diet condition (n=8) at 12-months showed that higher CRP concentrations were associated decreased FC between the NAcc and subregions of the prefrontal cortex (PFC; p's<0.05). Decreased FC between the NAcc and PFC subregions were also associated with lower concentrations of DA and greater HVA:DA ratios (p's<0.05). Overall, these data suggest that increased inflammatory signaling driving heightened CRP levels may mediate the adverse consequences of obesogenic diets on DA neurochemistry and corticostriatal connectivity.

中文翻译：

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肥胖饮食相关 C 反应蛋白预测雌性恒河猴中枢多巴胺和皮质纹状体功能连接性降低

多巴胺能奖赏通路中多巴胺 (DA) 信号传导的改变和功能连接性的降低 (FC；不同大脑区域之间活动的时间相关性的度量) 与精神病理学的病因学有关，并且与炎症标志物的浓度增加有关，包括C-反应蛋白。已显示破坏 DA 信号传导和皮质纹状体 FC 的外周和中枢炎性细胞因子与 C 反应蛋白有关，C 反应蛋白是一种急性期反应物，在翻译上用作全身炎症的标志物。可以显着增加全身炎症以在奖励途径中产生神经适应的一个因素是导致脂肪量积累的饮食（例如致胖饮食）。目前在标准实验室饲料 (n=18) 或致肥饮食 (n=16) 中维持 12 个月的雌性恒河猴研究验证了致肥饮食会改变中枢 DA 和高香草酸 (HVA) 浓度的假设，并且与饮食干预后 12 个月皮质纹状体区域之间 CRP 浓度升高和 FC 降低有关。我们专门评估了伏隔核 (NAcc) 和先前与 CRP 浓度相关的前额叶皮层 (PFC) 的两个子区域之间的 FC，腹内侧 PFC (vmPFC) 和眶额皮层 (OFC)，它们也参与情绪和动机显着性评估，以及目标导向行为、冲动控制和食物的显着性/价值。结果显示CSF DA浓度降低（p=0.002），在食用致肥胖饮食的 12 个月内，HVA:DA 比率增加（p=0.016），体重指数增加（p=0.047）。在 12 个月大时，维持致肥饮食的雌性比只吃食物的雌性表现出更高的 CRP 浓度（p=0.008）。线性回归分析揭示了饮食条件相互作用对 DA 浓度（β=-5.10；p=0.017）和 HVA：DA 比率（β=5.14；p=0.029）的显着 CRP。较高的 CRP 浓度与较低的 CSF DA 浓度（r=-0.69；p=0.004）和较高的 HVA:DA 比率相关，仅在维持致肥胖饮食条件的女性中（r=0.58；p=0.024）。在 12 个月时，来自每种饮食条件（n = 8）的女性子集的静息态磁共振神经成像（rs-fMRI）表明，较高的 CRP 浓度与 NAcc 和前额叶皮层 (PFC) 亚区之间的 FC 降低有关； p<0.05)。NAcc 和 PFC 子区域之间 FC 的降低也与 DA 浓度较低和 HVA:DA 比率较高有关 (p's <0.05)。总体而言，这些数据表明，增加的炎症信号驱动 CRP 水平升高可能介导肥胖饮食对 DA 神经化学和皮质纹状体连接的不利影响。