Department of Pharmacology, University of Michigan, United States.
Department of Pharmacology, University of Michigan, United States; Neuroscience Graduate Program, University of Michigan, United States.
Neuropharmacology. 2018 Mar 15;131:326-336. doi: 10.1016/j.neuropharm.2017.12.039. Epub 2017 Dec 29.
Studies in humans suggest that stronger incentive motivational responses to Pavlovian food cues may drive over-consumption leading to and maintaining obesity, particularly in susceptible individuals. However, whether this enhanced incentive motivation emerges as a consequence of obesity or rather precedes obesity is unknown. Moreover, while human imaging studies have provided important information about differences in striatal responsiveness between susceptible and non-susceptible individuals, the neural mechanisms mediating these behavioral differences are unknown. The Nucleus Accumbens (NAc) mediates cue-triggered reward seeking and activity in the NAc is enhanced in obesity-susceptible populations. Therefore here, we used selectively-bred obesity-prone and obesity-resistant rats to examine intrinsic differences in incentive motivation, and the role of NAc AMPARs in the expression of these behaviors prior to obesity. We found that obesity-prone rats exhibit robust cue-triggered food-seeking (Pavlovian-to-instrumental transfer, PIT). Using intra-NAc infusion of AMPAR antagonists, we show that this behavior is selectively mediated by CP-AMPARs in the NAc core. Additionally, biochemical data suggest that this is due in part to experience-induced increases in CP-AMPAR surface expression in the NAc of obesity-prone rats. In contrast, in obesity-resistant rats PIT was weak and unreliable and training did not increase NAc AMPAR surface expression. Collectively, these data show that food cues acquire greater incentive motivational control in obesity-susceptible populations prior to the development of obesity. This provides support to the idea that enhanced intrinsic incentive motivation may be a contributing factor, rather than a consequence of obesity. In addition, these data demonstrate a novel role for experience-induced up-regulation of NAc CP-AMPARs in PIT, pointing to potential mechanistic parallels between the processes leading to addiction and to obesity.
研究表明，对条件性食物线索更强的激励动机反应可能会导致过度消费，从而导致肥胖，尤其是在易感个体中。然而，这种增强的激励动机是肥胖的结果，还是先于肥胖出现尚不清楚。此外，尽管人类影像学研究提供了关于易感性个体和非易感性个体纹状体反应差异的重要信息，但介导这些行为差异的神经机制尚不清楚。伏隔核（NAc）介导线索触发的奖励寻求，并且在肥胖易感人群中，NAc 的活动增强。因此，在这里，我们使用选择性繁殖的肥胖易感和肥胖抵抗大鼠来检查激励动机的内在差异，以及 NAc AMPAR 在肥胖之前表达这些行为的作用。我们发现，肥胖易感大鼠表现出强烈的线索触发的食物寻求（条件性到工具性转移，PIT）。使用 NAc 内输注 AMPAR 拮抗剂，我们表明这种行为是由 NAc 核心中的 CP-AMPAR 选择性介导的。此外，生化数据表明，这部分是由于肥胖易感大鼠 NAc 中 CP-AMPAR 表面表达的经验诱导增加所致。相比之下，在肥胖抵抗大鼠中，PIT 较弱且不可靠，并且训练不会增加 NAc AMPAR 表面表达。总的来说，这些数据表明，在肥胖发生之前，肥胖易感人群的食物线索获得了更大的激励动机控制。这为增强的内在激励动机可能是肥胖的一个促成因素，而不是肥胖的结果这一观点提供了支持。此外，这些数据表明，NAc CP-AMPAR 的经验诱导上调在 PIT 中具有新的作用，这表明导致成瘾和肥胖的过程之间可能存在潜在的机制相似性。
Zotero 插件