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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=714345
• 关键词: role; peripheral; metabolic; signals; neural

Objectives Dietary lipids are a critical source of 3 polyunsaturated fatty acids (FA) and not only provide essential building blocks and energy for the brain but also have important signalling actions. Dietary 3 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 3 brain levels can promote depressive-like behaviour and stimulate palatable food seeking and weight gain. The 3 FA receptor GPR120 is important for mediating the anti-inflammatory actions 3 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 3 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 (NFB) 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 NFB in the NAc. Diets enriched in saturated FA lower brain 3 levels, and thus reduced 3 signalling may be involved. The fatty acid membrane receptor GPR120 is a G-protein coupled receptor activated by 3 that mediates the anti-inflammatory effects of 3 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 3 using targeted gene intervention, pharmacological and in vitro approaches.

目标 膳食脂质是3种多不饱和脂肪酸（FA）的重要来源，不仅为大脑提供必要的构建模块和能量，而且还具有重要的信号传导作用。膳食3 FA可以改善情绪、认知和行为功能，部分是通过抑制小胶质细胞活性和神经免疫反应。相比之下，n-3饮食缺乏导致大脑水平降低，可以促进抑郁样行为，刺激可口的食物寻求和体重增加。3FA受体GPR 120对于介导外周中的抗炎作用3是重要的，然而关于GPR 120在脑中的作用知之甚少。 拟议研究计划的目的是确定大脑GPR 120在3对大脑奖励回路中的能量平衡、食物奖励、焦虑抑郁行为和促炎反应的作用中的贡献。 背景和进展 饱和高脂饮食刺激焦虑抑郁行为和蔗糖奖励，其方式与循环免疫标记物升高和小胶质细胞活化、核因子κ B（NFB）转录活性增加和髓核（NAc）中促炎标记物增加有关。 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，可以通过病毒抑制NAc中的NFB来阻断。富含饱和脂肪酸的饮食会降低大脑中的β 3水平，因此可能涉及β 3信号的减少。 脂肪酸膜受体GPR 120是由3激活的G蛋白偶联受体，其介导3在外周巨噬细胞中的抗炎作用。我们最近报道GPR 120在控制动机，情绪和认知的边缘系统部位表达，并且中央GPR 120激动减少食物摄入，食物奖励和焦虑样行为。我们的初步数据显示，GPR 120是高度富集在小胶质细胞，并显示GPR 120激动剂应用于初级小胶质细胞强烈抑制细胞因子基因的表达。过度和/或延长的小胶质细胞活化与抑郁状态相关，而抑制小胶质细胞增殖已经抑制了体重增加并防止了响应于高脂饮食的炎症。因此，我们将使用靶向基因干预、药理学和体外方法来检验小胶质细胞GPR 120参与3的分解代谢和神经保护作用的假设。