Contribution of glutamatergic circuits to enhanced food-seeking in preclinical models of obesity

项目摘要/摘要 目前，美国30%的成年人患有肥胖症，肥胖率每年都在上升(CDC BRFSS， 2012年)。2011年，美国国立卫生研究院发布了一项肥胖症研究战略计划，旨在“鼓励研究界 从不同角度审视肥胖症的流行“。拟议的工作通过以下方式直接满足这一需求 用新方法了解增强线索触发寻食行为背后的神经机制 在肥胖倾向大鼠和肥胖大鼠身上。在人类中，接触到与食物有关的线索(食物线索)，如 烘焙糕点或闪烁的烘焙标志会增加对食物的渴望，从而增加食物的数量 消费(Fedoroff等人，1997年，Soussignan等人，2012年)。肥胖的人更容易患上这些 食物暗示的激励作用，这有助于它们的体重增加(例如，Stices等人，2012年)。我们的长期合作 目的是了解控制食物动机的神经生物学和行为机制 食物提示，以预防和治疗肥胖症。暴露在食物线索中会增加大脑中fMRI的大胆信号 肥胖者与非肥胖者相比，伏隔核(NAC)更强(Stoeckel等人，2008年)。重要的是，在 正常体重个体食物提示诱导的NAC激活的大小预测未来体重增加 (Demos等人，2012)，在超重者中，它预测减肥有困难(Murdaugh，2012；Jensen& Kirwan，2015)。这种增强的NAC反应可能是由谷氨酸传递驱动的，作为AMPA型谷氨酸 受体(AMPAR)是NAC的主要兴奋源，而NAC在这一能力中起着关键作用 食物提示刺激非肥胖大鼠的行为(Kelley，2004；Everitt和Robbins，2005；CromBag等人， 2008年；科比特和巴林，2011年)。然而，到目前为止，还没有研究检查NAC谷氨酸在 任何临床前肥胖症模型。我们的初步数据显示，在肥胖倾向的大鼠中，食物暗示更强烈 与肥胖抵抗大鼠相比，改善觅食行为的作用更强。此外，我们还单独演示了 吃含糖高脂肪的“垃圾食品”会增加NAC表面AMPAR的水平。这表明肥胖-- 易感大鼠可能对经验诱导的NAc内谷氨酸能可塑性更敏感。我们将联合起来 肥胖易感性的啮齿动物模型和饮食诱导的肥胖模型 用药理学和DREADD技术确定脑内谷氨酸能传递的贡献 NAC加强了肥胖倾向和肥胖者对食物线索的动力。这项工作将开启新的 通过更丰富地了解神经行为差异来预防和治疗的途径 在肥胖倾向和肥胖个体中，驱动增强的线索触发的食物动机。

Project Summary/Abstract Currently, 30% of adults in the U.S. are obese, with the prevalence of obesity rising each year (CDC BRFSS, 2012). In 2011, the NIH released a strategic plan for obesity research to “encourage the research community to examine the epidemic of obesity from diverse perspectives”. The proposed work directly addresses this need by using novel approaches to understand the neural mechanisms underlying enhanced cue-triggered food-seeking in obesity-prone and obese rats. In people, exposure to cues associated with food (food cues), like the scent of baking pastries or a blinking bakery sign, can increase craving for food and the increase the amount of food consumed (Fedoroff et al., 1997, Soussignan et al., 2012). Obese people are more susceptible to these motivational effects of food cues, which contributes to their weight gain (e.g., Stice et al., 2012). Our long-term goal is to understand the neurobiological and behavioral mechanisms governing motivation for food induced by food cues in order to prevent and treat obesity. Exposure to food-cues increases the fMRI BOLD signal in the nucleus accumbens (NAc) more strongly in obese vs. non-obese people (Stoeckel et al., 2008). Importantly, in normal weight individuals the magnitude of food cue induced activation of the NAc predicts future weight gain (Demos et al., 2012) and in overweight people it predicts difficulty with weight loss (Murdaugh, 2012; Jensen & Kirwan, 2015). This enhanced NAc response may be driven by glutamate transmission, as AMPA type glutamate receptors (AMPAR) provide the main source of excitation to the NAc, and the NAc plays critical roles in the ability of food cues to motivate behavior in non-obese rats (Kelley, 2004; Everitt and Robbins, 2005; Crombag et al., 2008; Corbit and Balleine, 2011). However, to date, no studies have examined NAc glutamate transmission in any preclinical model of obesity. Our preliminary data show that in obesity-prone rats food cues more strongly invigorate food-seeking behaviors than in obesity-resistant rats. Additionally we have separately demonstrated that eating a sugary-fatty “junk-food” diet increases NAc surface levels of AMPARs. This suggests that obesity- prone rats might be more sensitive to experience-induced glutamatergic plasticity in the NAc. We will combine rodent models of obesity susceptibility and models of diet-induced obesity with behavioral, biochemical, pharmacological and DREADD techniques to determine the contribution of glutamatergic transmission in the NAc to enhanced motivation for food-cues in obesity-prone and obese individuals. This work will open new avenues for prevention and treatment by providing a richer understanding of the neurobehavioral differences driving enhanced cue-triggered motivation for food in obesity-prone and obese individuals.