The role of peripheral metabolic signals in neural reward mechanisms

外周代谢信号在神经奖励机制中的作用

• 批准号: RGPIN-2018-06565
• 负责人: Fulton, Stephanie
• 金额: $ 2.91万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=651270
• 关键词: role; peripheral; metabolic; signals; neural

Objectives***Dietary lipids are a critical source of ω3 polyunsaturated fatty acids (FA) and not only provide essential building blocks and energy for the brain but also have important signalling actions. Dietary ω3 FA can improve emotional, cognitive and behavioural functions, in part via supressing microglia activity and neuroimmune responses. In contrast, n-3 dietary deficiency leading to reduced ω3 brain levels can promote depressive-like behaviour and stimulate palatable food seeking and weight gain. The ω3 FA receptor GPR120 is important for mediating the anti-inflammatory actions ω3 in the periphery, yet very little of known about the role of GPR120 in the brain. The objective of the proposed research program is to determine the contribution of brain GPR120 in the actions of ω3 on energy balance, food reward, anxio-depressive behaviour and pro-inflammatory responses in brain reward circuitry.******Background and progress***A saturated high-fat diet stimulates anxio-depressive behaviours and sucrose reward in a manner tied to elevations in circulating immune markers and activation of microglia, increased nuclear factor kappa B (NFκB) transcriptional activity and increased pro-inflammatory markers in the nucleus accumbens (NAc). Notably, behavioural impairments and NAc inflammatory signature, including microglia reactivity, by can be blocked by viral inhibition of NFκB in the NAc. Diets enriched in saturated FA lower brain ω3 levels, and thus reduced ω3 signalling may be involved. ******The fatty acid membrane receptor GPR120 is a G-protein coupled receptor activated by ω3 that mediates the anti-inflammatory effects of ω3 in peripheral macrophages. We recently reported that GPR120 is expressed in limbic sites controlling motivation, emotion and cognition, and that central GPR120 agonism decreases food intake, food reward and anxiety-like behaviour. Our preliminary data reveal that GPR120 is highly enriched in microglia and show that GPR120 agonist application to primary microglia robustly suppresses cytokine gene expression. Excessive and/or prolonged microglial activation is associated with depressive states whereas inhibiting microglia proliferation has been to suppress body weight gain and prevents inflammation in responses to a high lipid diet. Accordingly, we will test the hypothesis that microglial GPR120 is involved in the catabolic and neuroprotective effects of ω3 using targeted gene intervention, pharmacological and in vitro approaches. **

膳食脂质是ω - 3多不饱和脂肪酸（FA）的重要来源，不仅为大脑提供必需的组成部分和能量，而且具有重要的信号传导作用。膳食中ω - 3脂肪酸可以改善情绪、认知和行为功能，部分原因是通过抑制小胶质细胞活动和神经免疫反应。相反，n-3饮食缺乏导致ω -3大脑水平降低，可以促进类似抑郁的行为，刺激美味食物的寻找和体重增加。ω3脂肪酸受体GPR120在外周介导ω3的抗炎作用中起重要作用，但对其在脑中的作用知之甚少。本研究计划的目的是确定脑GPR120在ω3对能量平衡、食物奖励、焦虑抑郁行为和脑奖励回路中促炎症反应的作用中的贡献。******背景与进展***饱和高脂肪饮食刺激焦虑抑郁行为和糖奖励的方式与循环免疫标志物和小胶质细胞激活的升高、核因子κB （NFκB）转录活性的增加和伏隔核（NAc）促炎标志物的增加有关。值得注意的是，行为障碍和NAc炎症特征，包括小胶质细胞反应性，可以通过NAc中NFκB的病毒抑制来阻断。富含饱和脂肪酸的饮食降低了大脑ω3水平，因此可能涉及ω3信号的减少。******脂肪酸膜受体GPR120是ω3激活的g蛋白偶联受体，可介导ω3在外周巨噬细胞的抗炎作用。我们最近报道了GPR120在控制动机、情绪和认知的边缘部位表达，并且中枢GPR120激动作用减少食物摄入、食物奖励和焦虑样行为。我们的初步数据显示GPR120在小胶质细胞中高度富集，表明GPR120激动剂应用于原代小胶质细胞可以显著抑制细胞因子基因的表达。过度和/或长时间的小胶质细胞激活与抑郁状态有关，而抑制小胶质细胞增殖可以抑制体重增加并防止高脂饮食引起的炎症。因此，我们将通过靶向基因干预、药理学和体外方法来验证小胶质GPR120参与ω3的分解代谢和神经保护作用的假设。**