The role of peripheral metabolic signals in neural reward mechanisms

目的*膳食脂肪是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积木和能量，而且还具有重要的信号作用。饮食3FA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动和神经免疫反应。相比之下，n-3饮食不足会导致大脑中3个水平的降低，会促进类似抑郁的行为，并刺激美味的食物寻求和体重增加。3FA受体GPR120在外周抗炎中起重要作用，但对GPR120在脑内的作用知之甚少。拟议的研究计划的目的是确定大脑GPR120在能量平衡、食物奖励、焦虑抑制行为和大脑奖励回路中的促炎反应中的作用。背景和进展饱和的高脂饮食刺激焦虑抑制行为和蔗糖奖励的方式与循环免疫标记物的升高和小胶质细胞的激活、核因子kappaB(NFB)转录活性的增加和伏隔核(NAC)中促炎标记物的增加有关。值得注意的是，行为损害和NAC炎症特征，包括小胶质细胞的反应性，可以通过病毒抑制NAC中的NFB来阻止。富含饱和脂肪酸的饮食可降低脑内3个水平，从而减少3个信号传导。脂肪酸膜受体GPR120是由3激活的G蛋白偶联受体，介导3在外周巨噬细胞中的抗炎作用。我们最近报道，GPR120在控制动机、情绪和认知的边缘部位表达，中枢GPR120激动剂减少食物摄入量、食物奖励和类似焦虑的行为。我们的初步数据显示，GPR120在小胶质细胞中高度丰富，并表明GPR120激动剂应用于原代小胶质细胞可强烈抑制细胞因子基因的表达。过度和/或长期的小胶质细胞激活与抑郁状态有关，而抑制小胶质细胞的增殖一直是为了抑制体重增加和防止对高脂饮食的炎症反应。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GPR120参与3的分解代谢和神经保护作用的假设。**

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. **